Clinical Project Management: 10 Best Practices at a Glance

by Susan Wiskow, Senior Clinical Project Manager




Excellence in clinical project management requires vision, understanding, adaptability, disciplined effort, and unrelenting focus on achieving your goals. Consistent implementation of best practices throughout the lifecycle of the project, as suggested below, is a key component to the success of your clinical project.

1. Understand the goal of the project and how it fits in to goals of company. Who will pay for the device? What data are you seeking?
2. Conduct a risk analysis to assess risk and plan mitigation strategies.
3. Who are your stakeholders? Address how to meet their needs in the Project/Communication Plan.

4. Recruitment planning starts with the first conversation you have with potential sites. If you wait until you notice trends in slow enrollment, you have wasted too much time. Build time into your site qualification process to discuss and document plans for subject recruitment.
5. Develop a process to move several activities forward concurrently during the start-up phase.
6. Partnering a Risk Based Monitoring approach with a strong Data Management Plan is a proven strategy to improve the quality of the data. It also reduces costs and hastens timelines to study completion.

Best Tools
7. Use available tools such as 21CFR11 compliant electronic trial master file (eTMF) and electronic Case Report Form (eCRF) database to manage essential documents and reporting trial data. This allows you to see the progress of document collection at any time, sites can upload documents, monitoring activities can be conducted remotely, and it helps ensure your trial is always inspection-ready.
8. Discern what metrics you will need to track from the beginning of the study and design reports accordingly. For example, create reports on: Enrollment, CRF completion, Monitoring SDV status, Adverse Events, and/or Deviations by Sites.

Execute to Achieve Goals
9. Execute, measure, and adjust throughout the entire study.
10. Learn to prioritize. Ask: does this potentially jeopardize subject safety? Is integrity of the endpoint data intact?

Lessons Learned
At the end of the trial, assess and communicate with your team on how can you do it better, smarter, and faster the next time.

RCRI experts can help you at any point during your clinical trial, contact please contact Samantha Thrun at or 952-224-2260 for more information.

CDRH’s Use of Early Feasibility Studies

by Russ Olson, Regulatory Senior Principal Advisor

CDRH’s guidance document for Early Feasibility Studies (“Investigational Device Exemptions (IDE’s) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies”) was issued October 1, 2013. On August 23rd of this year, CDRH announced changes for how it will handle Early Feasibility Studies (EFS) for medical devices and manufacturers should take note.

These EFS studies are typically small in size (up to 15 patients) and generally short term. They’re conducted to develop data that is used to further develop new medical devices or therapies and are not intended to develop adequate data for device approval by itself. Additional IDE supplements are needed for additional clinical studies with different devices until a pivotal study is conducted that is used for device approval.

The long-term goal of FDA was to allow early feasibility studies for innovation of new medical devices while protecting the safety of the patients enrolled in the study. FDA recognized that often the devices used in early feasibility studies are not fully developed medical devices and may not have all the test data expected for final device designs. So, CDRH sought to work with study sponsors to balance pre-study test data and system design to minimize development costs while still protecting patient safety. Primarily using the pre-submission process accomplished this.

Clarification on the Guidance
The announcement leaves the existing guidance documents in place, but adds a specific contact point for each CDRH review group to assist study sponsors. Now it should be easier for sponsors to reach the right CDRH experts to discuss proposed studies and patient safety. A new web page has links to many IDE resource documents and outlines the process the recommend to study sponsors. It also has links to information on the Expedited Access Pathway, another pathway to help certain medical device development efforts reach the market in as short a time as possible. Access the guidance here:

RCRI has expert design and clinical teams to navigate guidelines, identify the best regulatory pathway, and negotiate the ideal development and clinical study approach for your medical device. Please contact Samantha Thrun at or 952-224-2260 to get the discussion started.



Understanding IVDR Technical Documentation

by Carol Ryerson, Senior Regulatory Principal Advisor

The European Medical Device Regulations 2017/745 and In Vitro Diagnostic Regulations 2017/746 were entered into force on May 26, 2017. Medical device manufacturers need to be in full compliance with the new regulation by May 26, 2020.

What’s in the Regulation?
The IVDR definitions section does not include the term “technical documentation.” Instead, the authors refer to technical documentation throughout the text of the regulation. In fact, two full Annexes (II and III) are devoted to describing what constitutes “technical documentation.” Some notified bodies refer to the technical documentation as “living” documentation and use the terms “technical file” and “technical documentation” interchangeably. The IVDR calls for maintaining current and up-to-date documentation and mandates annual updates for Class C and D devices. One of the new items in this new regulation is the Performance Evaluation Report (PER).

What Guidance is Available?
It’s too early yet to find specific guidance that covers the new IVDR requirements. In the meantime, manufacturers should carefully read through Annex II and III’s substantial detail on technical documentation. A 2011 guidance also offers an outline which can be a good starting point to build a technical documentation file for an IVD product, GHTF – STED (SG1/ N063:2011): “Summary Technical Documentation (STED) for Demonstrating Conformity to Essential Principles of Safety and Performance of In Vitro Diagnostic Medical Devices.” Although written for medical devices, not IVDs, the MEDDEV 2.7/1 rev 4, June 2016, Clinical Evaluation: A Guide for Manufacturers and Notified Bodies Under Directives 93/42/EEC and 90/385/EEC provides helpful guidance on preparing the report on clinical evidence referred to as the Performance Evaluation Report in the IVDR.

Technical Documentation
As regulatory affairs professionals, we are used to thinking of compiling submissions in order to meet country-specific marketing requirements. Yet the IVDR calls for living documentation, requiring updates as the product journeys through its life cycle. How will this work when the business likely already has processes established to maintain other “living” quality record files such as: Design History File, Device Master Record, labeling, and complaints? The EU technical documentation will be a subset of all of these files and more. Careful consideration will need to be given to establishing the required technical documentation for your products and maintaining the file. Annex II states: “the technical documentation shall be presented in a clear, organized, readily searchable and unambiguous manner.”

See Table 1 below for a suggested outline of the content of the Technical Documentation based on Annex II (published 22 February 2017). The Performance Evaluation Report (PER), described in Article 56 of the IVDR, includes three elements: scientific validity, analytical performance, and clinical performance. The final section of the PER presents a conclusion that the clinical evidence presented supports the device is safe and consistent with state of the art. The IVDR is specific on this point:

“The data and conclusions drawn from the assessment of those elements shall constitute the clinical evidence for the device. The clinical evidence shall be such as to scientifically demonstrate, by reference to the state of the art in medicine, that the intended clinical benefit(s) will be achieved and that the device is safe. The clinical evidence derived from the performance evaluation shall provide scientifically valid assurance, that the relevant general safety and performance requirements set out in Annex I, are fulfilled, under normal conditions of use.”

The PER for IVD products is analogous to the Clinical Evidence Report (CER) for medical devices described in MEDDEV 2.7.1, rev 4.

Table 1. Technical Documentation Outline

  1. Regulatory information
    • Trade name
    • Classification
    • UDI – DI
  2. Device Description, Variants and Accessories
    • Device description and specification
    • Intended use and indications for use
    • Summary and Explanation
    • Principles of Procedure
    • Components, reactive ingredients
    • Specimen collection (if applicable)
    • Instruments (if applicable)
    • Software (if applicable)
    • Variants/ Configurations
    • Accessories
  3. Market History
    • Overview of Previous Generations
    • Overview of Similar Devices
  4. Design and Manufacturing Information
    • Design Information
    • Manufacturing Information
  5. General Safety and Performance Requirements
    • General Safety and Performance Principles Checklist¹
    • List of Technical Standards
  6. Benefit-Risk Analysis and Risk Management
  7. Product Verification and Validation
    • Analytical Performance
    • Clinical Performance
    • Performance Evaluation Report²
    • Stability
    • Software Verification and Validation (if applicable)
    • Sterilization (if applicable)
    • Origin of tissues, cells and substances of animal, human or microbial origin (if applicable)
    • Measuring Function Accuracy (if applicable)
    • System Performance (if applicable)
  8. Post-Market Surveillance
  9. Labeling

Design Dossier
For products that require submission of technical documentation to a notified body as a pre-market review step prior to placing the product on the market, a design dossier needs to be created. Think of the design dossier as a snapshot of the technical documentation at a single point in time. The design dossier may be a subset of the technical documentation. Regulatory affairs professionals should establish procedures to store copies of design dossiers submitted for notified body review that are distinct from the “living” files designated as the full technical documentation of the product. It’s important to document the content of the design dossier used to obtain the original market approval and report changes to the product as appropriate in subsequent design dossier submissions to the notified body. Table 2 provides a sample Design Dossier outline.

 Table 2. Design Dossier Outline

  1. TOC
  2. Introduction
  3. Summary Information
  4. Device Description, Variants and Accessories
    • 4.1 Device Description
    • 4.1 Market History
  5. General Safety and Performance Principles Checklist¹
  6. Benefit-Risk Analysis and Risk Management
  7. Design and Manufacturing Information
    • 7.1 Device Design
    • 7.2 Manufacturing Processes
    • 7.3 Manufacturing Sites
  8. Product Verification and Validation
    • 8.1 Analytical Performance
    • 8.2 Clinical Performance
    • 8.3 Performance Evaluation Report²
    • 8.4 Stability
      • 8.4.1 Claimed shelf life
      • 8.4.2 In use stability
      • 8.4.3 Shipping stability
    • 8.5 Software Verification and Validation
  9. Labels and IFU
  10. Post-Market Surveillance
  11. Conclusion
  12. Draft Declaration of Conformity

To make sure you have all your IVDR documentation in place, contact Samantha Thrun at or 952-224-2260 to be put in touch with an RCRI expert.

1Previously referred to as the Essential Requirements Checklist.
2The Performance Evaluation Report is similar to a CER for medical devices.


5 Steps Toward Faster Clinical Study Start-Up

Susan Wiskow, Senior Clinical Project Manager

One of the first questions I am asked as a Clinical Project Manager is “how fast can you get a trial up and running and get the first subject enrolled?” The answer, of course, is “that depends.” It depends on trial complexity, if the protocol is final, the type and number of sites being targeted, availability of the subject population, and many other factors. However, here are five steps you can take to help reach this critical milestone faster without sacrificing quality.






  1. Fine-tune your site qualification process to proactively identify high-performing sites and apply risk management principles in identifying sites with potential barriers to enrollment. In other words, establish metrics to define high quality sites, such as evidence of high enrollment for similar studies and site responsiveness including contract and IRB turnaround times. Likewise, identify barriers to avoid such as sites with history of inspection findings and limited research staff. Ask for evidence to support claims made by sites.
  2. Establish contract and budget parameters for negotiations in advance and track negotiations using a means visible to key stakeholders, such as an electronic Trial Master File (eTMF). Using this approach saves time in negotiations and having to seek approvals at each stage. Also, making the progress visible keeps all parties accountable and can help to identify and resolve issues earlier on in the process. The metrics you track will also be helpful when deciding whether to use a site for future studies.
  3. Track and maintain site and sponsor essential documentation in eTMF. Documents are collected and uploaded in real time to an eTMF. Here the sponsor, CRO, and sites have visibility and access to what is on file, based on selected permissions, without having to provide copies separately to each involved party. Being able to see at a glance what documents are left to be collected prior to activation allows all parties to focus on critical tasks.
  4. Use reliable central IRBs where possible. Working with high-quality central IRBs can significantly speed the process of protocol and consent approval compared to institutional IRBs.
  5. Create tools tailored to your study, to easily measure progress and to ensure no critical steps are missed. Use tools such as a comprehensive checklist to ensure protocol requirements, such as study specific training and other regulatory requirements, are met. Even better, ready-made eTMF trackers or reports can be used to manage all documentation required prior to site activations and track completion progress. Use of such tools can also help avoid errors and reduce regulatory risk.

These five steps can reduce your study start-up timelines, which should in turn lead to quicker enrollment. To learn more about RCRI’s ready to use solution, please contact Samantha Thrun at or 952-224-2260.

Clinical Compliance: Questions to Ask During Your Entire Clinical Development Program

by Jill Cernohous, Senior Principal Advisor

Waiting until the end of a clinical study to start preparing for an FDA inspection can be disastrous. Early interventions allow issues to be addressed in real-time instead waiting until the end of a study. Implementing quality control measures to anticipate issues before they occur and identify and address issues in real-time can save money, minimize study delays, allow for better resolution of issues, ensure audit readiness at all times, and improve data integrity. FDA conducted over 1,100 BIMO inspections in 2015 with 301 conducted by CDRH. Are you ready for an inspection? The time to start preparing for an FDA BIMO inspection is now regardless of the current phase of your study.

Consider the following as part of the quality control process to help ensure compliance throughout the life of a study.

Study Kick-Off

  • With what regulations does the study need to comply?
  • Are individuals managing the study qualified to fulfill their roles, and is documentation on file to support their qualifications?
  • Are there sufficient written procedures in place to ensure the study is conducted in compliance with the study protocol and applicable regulations? Do these procedures encompass all critical areas? Has compliance with these procedures been documented?
  • Are all vendors qualified, and is there sufficient documentation to support their qualifications? Are there procedures in place surrounding vendor qualification and management?
  • Does the study require registration on
  • Is site staff qualified to fulfill their roles and is documentation on file to support their qualifications?
  • Are adequate site agreements in place and have financial disclosures been obtained and any potential conflicts of interest addressed?

Study Management

  • Is the study adequately monitored to ensure compliance with the protocol and applicable regulations, and are the monitoring activities, including close-out of action items, documented? Are instances of site non-compliance being sufficiently addressed, and is compliance being secured in a timely manner?
  • Are sponsor and site audits being conducted early during the enrollment period to confirm compliance and adequate monitoring, and identify any potential issues?
  • Are study-related documents being maintained in accordance with good documentation practices?
  • Are test articles being adequately controlled and maintained under proper conditions with limited access, proper labeling, and accurate accountability records?
  • Can the investigators demonstrate adequate oversight of the study at their sites? Can the sponsor demonstrate adequate oversight of the entire study?

Study Closure

  • Are study personnel familiar with record retention requirements?
  • Are sponsor and site audits being conducted to ensure sites are ready for potential FDA inspection?
  • Are study personnel trained on what to do in the event of an FDA inspection?
  • Are all sites closed and have all test articles been accounted?
  • Has the trial master been file verified as accurate and complete?

Compliance is critical to any clinical study, and compliance planning should begin before the first subject is enrolled. In order to be successful and ensure a study meets regulatory requirements, compliance measures need to be incorporated at every step in the process.

RCRI expert advisor can assist with your clinical study compliance needs. Contact Samantha Thrun at or 952-224-2260.


Understanding the Medical Device Single Audit Program (MDSAP)

by Leslie Blyakhman, Regulatory Project Director and
Tim Robinson, Regulatory Project Director

The current medical device regulatory environment is highly dynamic with changes to ISO 13485 and European regulations well underway. The latest new wrinkle is the introduction of the Medical Device Single Audit Program (MDSAP).

What is MDSAP?
The Medical Device Single Audit Program (MDSAP) is an international initiative led by the Regulatory Authorities of the International Medical Device Regulatory Forum (IMDRF). The intent of the program is to establish a single audit system to meet the quality system audit requirements of the five Regulatory Authorities:

  • Therapeutic Goods Administration (Australia)
  • ANVISA (Brazil)
  • Health Canada (Canada)
  • MHLW/PMDA(Japan)
  • US Food and Drug Administration (United States).

The principle behind the MDSAP is the use of recognized third-party auditors (Auditing Organizations) to conduct a single audit of a medical device manufacturer to satisfy the various Quality Management System requirements of the participating organizations.

How Does the MDSAP Impact My Organization?
After three years in a pilot phase, MDSAP moved into the operational phase in January 2017, when all five Regulatory Authorities choose to continue to participate in the program. The program is voluntary, with one note of critical importance: Health Canada will continue to participate in the program, but will be making a full transition from the Canadian Medical Devices Conformity Assessment System (CMDCAS) to MDSAP. Manufacturers intending to sell in Canada after January 1st, 2019, will need to be certified to MDSAP. Medical device license applications containing CMDCAS certificates will not be accepted after January 1, 2019.¹

What Do I Need to Consider?
Medical device manufacturers should consider which geographies they sell to and determine whether certification to MDSAP will be necessary or beneficial. If a manufacturer decides to pursue MDSAP certification, they should consider the timing of upcoming certification assessments (e.g., transition to ISO 13485:2016, new MDR/IVDR requirements) and license applications to determine optimal timing before contacting their Auditing Organization to schedule a MDSAP audit. A poorly-timed transition may result in redundant audits and additional costs.

How Can I Ensure A Smooth Transition?
Given the other major regulatory changes impacting the device industry, successfully implementing multiple new regulations while simultaneously transitioning to MDSAP will require a considerable amount of effort. Organizations should take steps to ensure their quality systems are MDSAP-audit ready. Start with a gap assessment and/or mock audit to help you determine your current state of readiness, identify areas of concern, and proactively address any identified issues. Based on the findings, design a remediation program to fill the gaps.

RCRI experts are knowledgeable in all applicable regulations, and are happy to assist you with MDSAP transition planning guidance, gap assessments, and audit services. Please contact Samantha Thrun at or 952-224-2260 for more information.

¹Health Canada MDSAP FAQ

Clinical Strategy – It’s All in the Planning

by Mary Kay Sobcinski, Senior Principal Advisor, Clinical Sciences

No matter how short or long a trip, getting from point A to point B always requires planning. Even a routine trip to the grocery store requires knowing where you’re going, how you’re going to get there, and why you’re going. The more complicated the trip, the more complex and critical the planning process is to ensure you arrive at your destination on time, within budget, and that you have the right list or equipment you need to successfully complete your journey.

Define the Roadmap
You can view your clinical strategy similarly: it’s a roadmap outlining your direction, scope, goals, key stops along the way, and what to do when you arrive to accomplish your objectives. A well-defined, thoughtfully-developed clinical strategy will guide both short- and long-term decisions, prioritize objectives, define and allocate resources, and establish your clinical development program timeline.

Innovative devices require innovative clinical strategies to develop the evidence needed to support your goals. Medical device research, while governed by federal regulations, has an element of flexibility that’s not readily seen in pharmaceutical research. There may be unique clinical trial designs or regulatory pathways to consider; don’t lock yourself into thinking “there’s only one way” to do something, resort to checking off boxes for trial design considerations, or follow a formulaic approach.

Define the Corporate Goals
Before you create your clinical strategy, you need to understand the corporate strategy for the product, including reimbursement, regulatory, and marketing goals. Ask your stakeholders: “What defines success for this project? What are our overall objectives and key milestones?”

Be sure you know what the regulators, payers, and market actually want, not what you think each wants. You need to understand stakeholder expectations and then translate those expectations into results.

Understand the Market
Look at the state of the art alternative and competitive therapies for the disease condition(s) you’re targeting to fully understand your market opportunities and barriers. Many sponsors mistakenly think regulatory approval is the #1 or only goal, but this is rarely the case.

A successful clinical strategy considers all of your product and marketing goals and translates them into a robust clinical program plan, inclusive of individual trial design(s): the right endpoints are crafted, the right investigators are selected, the right patients are enrolled, the right data points are collected, and the appropriate statistical methods are planned to ensure regulatory approval, attainment of maximum reimbursement, successful market launch, and ultimately, market adoption.

It’s All in the Planning
As you design your strategy, define what success looks like – for the trial as well as for your overall product and corporate goals.

  • Define success and the accompanying objectives to lay the foundation of your strategy.
  • Design the strategy itself: identify the unique project criteria and demands, assess the risks to project success, and develop a risk mitigation plan.
  • Identify the tactics (actions) you’ll implement to carry out the plan. Layout and plan your resource needs, ensure your timeline is reasonable and feasible, assess risks that may hinder or even prevent project success and identify mitigations to manage them. Once you’ve formulated your goals into an executable strategy with effective tactics, it’s time:
  • Operationalize your plan. Along the way, adapt new tactics to overcome challenges and be open to adjusting goals if warranted. Develop the evidence needed to meet your myriad of goals, and ultimately, communicate your results to the stakeholders and the market.

As a trip plan helps assure a successful journey, mapping out your clinical strategy will steer you to your destination: meeting your regulatory, reimbursement, marketing, and corporate goals efficiently and effectively.

RCRI has expert advisors in clinical strategies and can help at whatever stage you are in your planning. Contact Samantha Thrun at or 952-224-2260.

Developing an Effective Reimbursement Strategy – If You Build It, Will They Come?

by Tom Hughes, Health Economics and Reimbursement Senior Principal Advisor

You and your team have been working hard to gain approval and successfully launch your device. However you may be forgetting an important consideration for market success – Reimbursement.

The healthcare landscape is changing rapidly and companies that fail to develop a reimbursement roadmap will be at a disadvantage. Left unchecked, healthcare expenditures are projected to be almost 20% of the U.S. gross domestic product in 2023 (Kaiser Family Foundation, 2014)1. The goal of policy makers, payers, and other stakeholders is to bend this cost curve. No longer will new technology be reimbursed simply because it has FDA approval. Regulatory clearance only gives medical device companies the opportunity to market a device – it does nothing to ensure payment for a device or product. Payers and providers are now requiring technology innovators to demonstrate both clinical AND economic value before they will consider the use of a new product. And, if financing is a critical consideration in your business plan, be prepared for investors to ask hard questions about whether there is a path to reimbursement for your technology in addition to asking if you have met minimum regulatory requirements. Failing to have a plan to address these issues may leave you stalled in the market place.

Make Reimbursement a Priority
With reimbursement planning, you can boost the chances of market success and optimization for your technology. If you are developing a new technology, plan your reimbursement strategy early in the product development phase. Early planning can contribute to design considerations that take advantage of reimbursement requirements. Also, you may be able to save time, money, and effort by adding clinical and economic value endpoints to your regulatory approval studies for a new technology.

Case in point: The federal government recently recognized the need for early payer input. In late 2016, the FDA implemented new regulations inviting Medicare and private payers to join study sponsors at presubmission meetings to discuss evidentiary endpoints important to the payer community.

Even if your technology is already in the marketplace, you should continually review your reimbursement needs. Coverage, coding, and payment policies are constantly changing and can have a significant impact – positively or negatively – on payment for your product.

Making reimbursement a priority is a simple two-step process. First, conduct a reimbursement assessment to understand the existing payment landscape for your product. Secondly, use the assessment to develop a plan to take advantage of payment opportunities or to address gaps in reimbursement: the need for evidence development, coding initiatives, or obtaining payment from payers.

Conduct a Reimbursement Landscape Assessment
As the old cliché goes, you can’t know where you are going until you know where you are. A reimbursement assessment is a survey of the current coverage, coding, and payment landscape for your medical technology. It helps you understand where your product fits in the ever-changing healthcare reimbursement ecosystem. Just as importantly, it helps identify reimbursement challenges and opportunities as you move forward. While individual assessments will vary depending on the technology, common elements include the following:

  • Coverage Status – How are payers such CMS, private payers, Medicaid, etc. looking at the device?
  • Current Coding – What codes are physicians, facilities (hospitals, outpatient, ASCs), homecare, etc. using?
  • Payment – How does reimbursement compare to charges?
  • Competing/Proposed Technologies – Are there similar products?
  • Status of Evidentiary Needs – Does the technology improve health outcomes and is it cost effective?
  • Findings and Recommendations for Strategic Plan – What does the assessment tell you about strategic planning needs?

Wherever you are in your product development cycle, conducting a Reimbursement Landscape Assessment is essential to optimizing the market opportunity for your medical technology.

Develop and Implement a Strategic Reimbursement Plan

Once you have conducted a comprehensive Reimbursement Landscape Assessment, use the information to develop a Strategic Reimbursement Plan. A well-designed plan should help you gain clarity on what reimbursement initiatives need to be completed and when. Below are examples of key elements to consider, and when, for your plan:

Activity Product Development Phase Clinical Study Phase Post Launch
Prepare reimbursement budget X
Build reimbursement expertise X X X
Collect meaningful data to demonstrate value X X X
Gain payer acceptance X X X
Implement coding initiatives X X
Obtain payment X
Align capabilities to execute initiatives X X


A well-conceived and well-executed Strategic Reimbursement Plan based on a comprehensive review of the Reimbursement Landscape for your technology can be the difference between success and failure in this era of value-based medicine.

To learn more, please contact Tom Hughes, JD, Principal Advisor, Health Economics and Reimbursement expert at

1 Kaiser Family Foundation calculations using NHE data from Centers for Medicare and Medicaid Services, Office of the Actuary, National Health Statistics Group, 2014

Working with a CRO – Tips from the Sponsor’s Perspective

by Barb Duerr, Principal Clinical Project Manager, Clinical Sciences

Congratulations! You’ve just selected the contract research organization – CRO – that best fits your goals, timeline, budget and philosophy. You’re confident that your team, study, and company will be successful! What’s next? Whether you are expecting a “turn-key” solution from your chosen CRO or are partnering with them for a portion of a larger project, there are important considerations to explore to ensure a collaborative relationship and an outstanding clinical project.

I recently returned to the CRO world after three years on the sponsor side. As a sponsor, I had the opportunity to work with different CROs on various aspects of clinical research projects. As a result, I have a few tips to share regarding how you, as a sponsor, can get off to the best start possible, maintain a strong working relationship with your chosen CRO, and ultimately run a successful study.

Establish Clear Roles and Responsibilities Early
Once the dust has settled and the contract and work orders are signed, the first order of business with your CRO is to confirm and document the roles and responsibilities of each party in detail. A kick-off meeting with your CRO is the perfect time to do this. Questions to resolve include:

  • Who is driving the project, thinking proactively, anticipating next challenges, and proposing next steps?
  • Who will be leading team meetings and issuing meeting minutes and action items?
  • Who is responsible for driving the completion of action items?
  • Who is responsible for ensuring enrollment is on track?

This is the time to set very clear expectations. It’s not just about defining roles and responsibilities; it’s also the time to discuss in detail how responsibilities will be fulfilled.

Allocate Appropriate Sponsor Resources to Manage the CRO
Ensure that your upper management does not underestimate resource needs from the sponsor side. It’s a mistake to think that it’s “all in the CRO’s hands” and that few to no sponsor resources are needed. There is a balance between micromanaging your CRO and taking a totally hands-off approach. The right balance comes from the CRO and the sponsor being comfortable with the established roles and responsibilities and trusting each other to independently perform as agreed. Ensuring that you, as the sponsor, have a dedicated resource to work with the CRO is vital to the success of your project.

Hold the CRO Accountable and Voice Your Concerns Early
Once the sponsor and CRO have established clear roles and responsibilities, it’s important for the sponsor to hold the CRO accountable. Ask yourself:

  • Is the CRO performing as you expected? Meeting timelines? Staying within budget?
  • Is the quality of the CRO deliverables up to your company’s standards?
  • Do your sites enjoy working with the CRO staff? If not, do you understand why?
  • Have there been changes in scope?
  • Have expectations been made clear?

If you, as the sponsor, are not satisfied with any aspect of the CRO’s performance, no matter how small it may seem, don’t hesitate to voice your concerns. The earlier the better! Resist the urge to just fix it yourself. It is your responsibility to ensure that you understand the situation and provide constructive, relevant, timely feedback to your CRO.

Communicate, Communicate, and Communicate Some More!
As with any relationship, clear and frequent communication is the key to a productive, collaborative, and effective sponsor-CRO partnership. Establish your preferred method of communication at the start and be willing to adjust as challenges and opportunities arise. Be clear about what and when to communicate via phone call, versus in a meeting, or in an email.

Implementing these simple tips can help ensure that you have a positive relationship with your CRO, which is the foundation for a successful clinical study.

RCRI’s consultants are experts in strategic partnerships with sponsors and can help ensure your study is a successful one. Email or call Samantha Thrun at or 952-224-2260 to get the discussion started.


Collection of Race and Ethnicity Data in Clinical Trials: A Summary of FDA’s Guidance for Industry and Food and Drug Administration Staff

by Angie Sullivan, Senior Clinical Project Manager

The Food and Drug Administration (FDA) recently updated its 2005 guidance on collection of race and ethnicity data. The new guidance, Collection of Race and Ethnicity Data in Clinical Trials, issued on October 26, 2016, clarifies expectations for how this data is collected.

Drugs, Devices, and Biologics
FDA requires race and ethnicity data to be collected for drug, device, and biologic studies. Sponsors who hold an IND are required to report annually on the number of subjects enrolled by age, race, and gender. Additionally, IND sponsors must summarize safety and effectiveness data for important demographic groups. Similar to drug studies, device, and biologics studies should follow the recommendations outlined in the new guidance document. Device manufacturers should also maintain awareness of FDA’s draft guidance document Evaluation and Reporting of Age, Race, and Ethnicity Data in Medical Device Clinical Studies (June 2016).

The following documents contributed to the creation and implementation of the new guidance:

  • Department of Health and Human Services Report and Guidance (1999) The Improving the Collection and Use of Racial and Ethnic Data in HHS report describes HHS policy (updated in 2011). It clearly states that the minimum standard categories in OMB Policy Directive 15 should be used when collecting and reporting data in HHS data systems or reporting HHS funded statistics.
  • ICH E5 – Guidance on Ethnic Factors in the Acceptability of Foreign Clinical Data (1999) This guidance defined ethnic factors that affect response in terms of both intrinsic and extrinsic issues. It also introduced the multi-regional clinical trial study design as one means to evaluate treatment response heterogeneity and extrapolation.
  • National Institutes of Health Initiatives, Revitalization Act (1996) This act eventually led the NIH to ensure that women and minorities were included as study participants, unless their exclusion was justified due to circumstances specified by NIH guidelines. Additionally, the act states clinical trials were to be conducted in a manner that would elicit information across genders and diverse racial and ethnic subgroups.
  • FDA Regulations, Guidances, and Section 907 of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) FDASIA Section 907 directed FDA to outline “recommendations for improving the completeness and quality of analyses of data on demographic subgroups in summaries of product safety and effectiveness data and in labeling; on the inclusion of such data, or the lack of availability of such data, in labeling; and on improving the public availability of such data to patients, health care providers, and researchers.”

Differences between racial and ethnic groups include intrinsic factors (e.g. genetics, metabolism, elimination) and extrinsic factors (e.g. diet, environmental exposure, sociocultural issues), as well as interactions between these factors. These differences have been shown to influence response to various medical products, therefore important to any clinical trial. For example, FDA cites significantly different response rates across races and ethnicities to topically applied products, dialysis treatment, antihypertensive agents, antidepressants, antipsychotics, and beta blockers.

What to Collect
FDA recommends the following two-question format and categories be used for collection of race and ethnicity data. Note that the questions below are presented in a format that can easily be incorporated into a Case Report Form (CRF) and that race and ethnicity data should be self-reported by the study participant whenever possible.

1. Do you consider yourself to be Hispanic/Latino or not Hispanic/Latino? (Select only one)

Hispanic or Latino: A person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin, regardless of race. The term, “Spanish origin,” can be used in addition to “Hispanic or Latino.”

Not Hispanic or Latino

2. Which of the following five racial designations best describes you? (Select one or more)

American Indian or Alaska Native: A person having origins in any of the original peoples of North and South America (including Central America), and who maintains tribal affiliation or community attachment.

Asian: A person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent, including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam.

Black or African American: A person having origins in any of the black racial groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to “Black or African American.”

Native Hawaiian or Other Pacific Islander: A person having origins in any of the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands.

White: A person having origins in any of the original peoples of Europe, the Middle East, or North Africa.

If more detailed race and ethnicity information is desired (e.g. for clinical trials conducted outside of the US), refer to the guidance document for additional sub-category recommendations for the Hispanic/Latino, Asian, and Native Hawaiian or Other Pacific Islander categories.

How to Present the Data
INDs, NDAs, and BLAs should submit tabulated demographic data based on the Demographic Rule (refer to 21 CFR 312.33(a)(2) and 21 CFR 314.50(d)(5)). Beginning in May 2017, CDER and CBER will require electronic submission of marketing applications. Refer to the ICH M4E eCTD Guidance (section and table for a suggested, tabular display of demographic characteristics by treatment group.

IDEs and PMAs, as well as any other relevant device submissions, should follow 1.) The 2016 Collection of Race and Ethnicity Data in Clinical Trials Guidance; and 2.) The recommendations found within the draft Evaluation and Reporting of Age, Race, and Ethnicity Data in Medical Device Clinical Studies once finalized.

For assistance collecting and/or reporting race and ethnicity data for your clinical trials, please contact Samantha Thrun at or 952-224-2260 to be put in touch with an RCRI expert.



Successful 510(k) Clearance: Use a Regulatory Consultant

by Julie Underdahl, Regulatory Project Director

Considering regulatory requirements throughout the medical device development process is critical to a successful market approval. Regardless of your target market, addressing requirements early in the process will help you build a solid submission to government agencies and a sustainable post-market plan. This blog focuses on the 510(k) process as an example of ways to effectively use a regulatory consultant in device development and launch.

Determining and Meeting Requirements

A legal manufacturer’s responsibility for regulatory compliance in device development varies slightly between geographies, but quality device documentation can support multiple markets if planned appropriately. Following design control requirements, a device manufacturer will determine the documentation required for device design, risk analysis, performance requirements, and verification of these requirements. They will also determine device and process validations, as well as design transfer requirements so that once clearance or approval of the device is obtained, the devices manufactured will continue to meet the requirements reviewed by the regulatory agencies.

How to Navigate It All
Utilizing a regulatory consultant during the device requirements development stage can be extremely helpful. The device design requirements drive the rest of the deliverables used in the 510(k) submission, such as indications for use, device description, labeling, use conditions, biocompatibility, and performance data results. These will be specific to your device development and link to risk analyses to demonstrate safety and effectiveness. Essentially, the 510(k) process verifies that the design outputs meet the design inputs. This requires completed device documentation such as inputs, device specifications, risk analyses, verification protocols with acceptance criteria that align with inputs, and verification test results that demonstrate that the criteria has been met. Because each device is different in use and indications, the exact deliverables will vary.

FDA’s Code of Federal Regulations detail the requirements of Design Control (21 CFR 820.30) and required elements of a 510(k) (21CFR 807.87). Multiple guidance documents have been issued to help manufacturers through the medical device development process, some of which are device specific. FDA also has helpful links on their website that explain the 510(k) process and design control connection. Taken directly from the FDA website regarding 510(k) preparation, the quote below describes this relationship very well.

“Device specific guidance documents describe in detail the information which should be included in the 510(k) to enable FDA to determine SE (Substantial Equivalence) for that particular type of device. These guidance documents should be consulted at the device planning stage. In addition, the design control requirements (21 CFR 820.30) of the Quality System regulation should be reviewed as well since much of the information and data developed to meet design controls is the same information included in the 510(k).”

Using a regulatory consultant at this stage can help your development team navigate the regulations and FDA guidances. Here are some key benefits a regulatory consultant can provide to a development project team:

  • Create a comprehensive regulatory strategy for target markets to ensure regional requirements are included in the development process.
  • Review deliverables such as design requirement documentation and verification testing plans to determine if they will meet the regulatory agencies’ requirements and expectations.
  • Assistance in planning essential evidence for the proposed device’s substantial equivalence to the predicate device critical for 510 (k) submissions. The comparison of the devices’ intended use, design, materials, and performance should support that the proposed device poses no new or different risks than the predicate device and is therefore substantially equivalent.

A Successful Submission
As the evidence of substantial equivalence, device safety, and performance is gathered, the next step is to create a 510(k) submission that demonstrates general and specific device requirements have been met. At this stage, you can lean on the expertise of a regulatory consultant to develop a submission that best reflects your unique device and all your development efforts. From creating meaningful content based on your device documentation to meeting eCopy and Refusal to Accept requirements of the 510(k) process, a regulatory consultant can help you smoothly move through the submission stage.
The regulatory consultant can also represent your company to FDA as the official correspondent for the submission. This can be helpful in coordinating any interactive or formal review inquiries about the submission and its supporting documents.

A Smooth Post-Clearance Phase
In the case of the 510(k), once clearance is obtained, the post-market stage of your device begins. With comprehensive and compliant device documentation and quality systems built during the development stage, post-market requirements and device or process changes can be easily managed. Here too, is an opportunity to utilize a regulatory consultant when needed to determine the best pathway for your company when changes occur throughout the full product lifecycle.
Planning and executing a comprehensive device development project that will translate smoothly into a successful submission can be a challenging feat. Utilizing a regulatory consultant at key points in the process can help identify and bridge gaps. RCRI’s experienced staff can help you navigate this path from concept to marketed device and to even product obsolescence.

Please contact Samantha Thrun or 952-224-2260 to be connected to a regulatory expert.

MDR and IVDR: The Final European Vote

by Carol Ryerson, Senior Principal Advisor

Europe is on the verge of implementing new regulations for medical devices and IVD products. As you may already know, final versions of the European Medical Devices Regulations (MDR) and the In Vitro Diagnostics Medical Devices Regulation (IVDR) were released on 22 February 2017. The final European Parliament vote is scheduled for 20 March 2017. If passed, these new regulations could become effective as early as May 2017. There is a three-year transition to full compliance for medical devices and a five-year transition for IVD products.

The MDR combines two previous directives Medical Device Directive, MDD (93/42/EEC) and Active Implantable Medical Devices Directive, AIMD (90/385/EEC). The most sweeping and wide-reaching changes are in the IVDR, as all products are within the scope of the new regulation, currently marketed products as well as new product introductions.

A new risk-based classification scheme will be applied to IVDs with the requirement for Notified Body review of all Class III and IV devices and some Class II devices. Notified bodies are expecting a four-fold increase in the number of products requiring pre-market review of design dossiers; as many as 80% of currently marketed IVD products will require involvement of a Notified Body.

What Manufacturers Need To Do
IVD manufacturers will need to develop a comprehensive plan to bring their documentation into compliance with the new regulation and work closely with their Notified Body to schedule timely reviews in order to meet the 2022 timeline for full compliance and keep their existing products on the market. In some cases, additional clinical studies will be required to fully meet the new clinical evidence requirements. There is no guidance written yet that describes how Notified Bodies will interpret the requirements of the regulation for IVDs. Much of the currently available guidance on technical documentation format was either written for medical devices or was published prior to the issuance of the IVDR. The new regulation describes technical documentation as living documents that shall be kept up to date throughout the life cycle of the device. This will require a new way of thinking for IVD product developers where design files are typically made final at the end of product development and not touched again.

Watch the RCRI blog for more information on how to meet the Technical Documentation and Clinical Evidence requirements in the new IVDR regulation.

Contact RCRI expert consultants for assistance, email or call Samantha Thrun at or 952-224-2260.


Reimbursement and Today’s Healthcare Environment

by Lisa Olson, President
and Tom Hughes, Senior Principal Advisor Reimbursement and Health Economics

Regulatory clearance or approval of a device was once the primary challenge for bringing a new or improved medical product to the patient. Now, the shifting sands of the healthcare environment have created a new dynamic. Determining how a device is to be paid for has taken on more importance than ever before. Thus, understanding the interactions and concerns of all of the stakeholders is critical to forging a successful pathway.

With the introduction of the Affordable Care Act and value-based medicine, more stakeholders have been introduced into the healthcare delivery system and are involved in the decision-making process. Understanding how each of the groups interacts and their unique pressure points can help determine the most effective path to reimbursement.

Stakeholder Interests
Gone are the days when the physician or healthcare provider made all of the decisions about purchasing devices. In today’s environment, the providers themselves are facing decreased reimbursement for providing care and for the utilization of devices while experiencing higher overhead costs to run practices and more scrutiny regarding quality of care. These pressures flow through to hospitals and other facilities where healthcare is delivered. This change is largely driven by payers, both commercial and government. Commercial payers are concerned about rising healthcare costs and expect providers to demonstrate positive clinical outcomes as efficiently and cost effectively as possible. Similarly, government payers are facing budget constraints and high demand due to an aging population which is causing unsustainable increases in program costs. The American public, the consumers of healthcare, are also experiencing growing concerns about the rising cost of premiums and access to quality care. Employers too are now concerned about rising insurances rates that impact their balance sheets. Given all of this, it is easy to see that each piece of the puzzle is creating overall downward pressure on reimbursement.

In light of the market pressures, understanding how to obtain adequate reimbursement is important so that the proper steps can be taken early in the device development process to address stakeholder needs. There are three primary elements of reimbursement: coverage, coding, and payment. While they are interrelated, each component has unique challenges and requirements.

Coverage refers to a set of rules that explain when a payer will or will not pay for a product or service. Coverage can vary by payer and depends on what each payer considers to be medically necessary. In general, payers want to see regulatory approval, strong clinical evidence demonstrating the treatment is at least as beneficial as the established alternative, and a demonstration of the treatment’s cost-effectiveness. Payers expect well-designed clinical trials with results published in peer-reviewed journals. Support from the physician community and professional societies are also increasingly important to adoption and coverage of new technology.

Coding refers to the sets of alphanumeric codes that are the language of billing. Providers use codes to tell a payer what products or services were provided and why. There are three main sets of codes: CPT, HCPCS, and ICD-10-CM. Choosing the right code to accurately describe a product or service while maximizing payment requires a detailed understanding of the coding structures. If no code exists, it is important to understand the approval process for acquiring a new one – whether it be a CPT code used by physicians to describe what is done to a patient, or an HCPCS code which describe products not described by CPT codes. Finally, it is important to understand that choosing the wrong code creates not only financial implications but also legal culpability.

is driven by the coding systems and is probably the most complicated element of reimbursement. Although coding drives payment, reimbursement is not quite as simple as just submitting an active code. Payment is driven by complex payment methodologies that differ depending on the site of care where delivery is provided. For example, payment for the same procedure in an Ambulatory Surgery Center (ASC) is often less than payment for the same procedure performed in a hospital outpatient facility.

A final consideration to keep in mind is that the FDA and payers have different evidence requirements. The FDA wants to see evidence showing that a new technology is safe and effective prior to market approval. Payers want to see evidence demonstrating that a technology improves health outcomes and is cost effective. Consequently, to differentiate a new technology and save costs in the development lifecycle, companies should consider inclusion of clinical and economic endpoints in their FDA study design.

Given all of these complexities, what do you need to remember? First, a growing number of stakeholders are focusing on the cost and value of new technology as part of their reimbursement decision-making process. Second, evidence is a key factor in adoption and coverage of any new technology. Objective data obtained through well-designed studies that demonstrate overall patient benefit gives assurance of overall value to the broad stakeholder audience. Planning to gather this clinical and economic data early in the FDA study design phase can save time and money by leveraging the costs of running a study to meet multiple goals. Finally, development of a reimbursement strategy that is integrated with a company’s regulatory and clinical evidence development strategy is critical to business success in today’s healthcare reform environment.

To connect with an RCRI expert on your reimbursement strategy, contact Samantha Thrun or 952-224-2260.

Join us for the Webinar “Reimbursement: Understanding the Key Concepts to Maximize Business Success” on March 28. For more information and registration, go here


Clinical Trial Site Selection: Best Practices

by Angie Sullivan, Senior Clinical Project Manager

One of the most important aspects of a clinical trial is selecting optimal study sites. The ability to identify, engage, and effectively work with experienced and competent sites is a key factor of clinical trial success. Site qualities such as team dynamics, administrative requirements (i.e. requisite forms and signatures), procedures, resource availability, and experience ultimately impact both study timelines and data quality and integrity. Site selection has the potential to dramatically impact product approval timelines and corporate finances.

ICH Guideline for Good Clinical Practice (GCP)
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) weighs in on Investigator selection in its Guideline for Good Clinical Practice (November 2016). Basic principles include the selection of qualified and experienced investigators and adequate site resources to properly conduct the trial. Investigators/Institutions must agree to conduct the trial in compliance with GCPs, applicable regulatory requirements, and the IRB/EC-approved protocol requirements. Additionally, investigators/institutions must agree to comply with data recording/reporting procedures, permit monitoring, auditing, and inspection, and to retain essential documents in accordance with sponsor requirements. The sponsor and investigator/institution are expected to sign the protocol (or an alternative document) to confirm this agreement.

FDA Investigator Lists
A fundamental step in the site selection process is to verify that potential investigator(s) are not listed on FDA’s Debarment List or Disqualification Proceedings List. Both of these are publicly available through FDA’s Compliance Actions and Activities page.

Site Identification
Potential study investigators/sites may be identified in a myriad of ways, including:

  • Authorship of relevant journal article(s)
  • Prior participation in other studies supported by the sponsor
  • Participation in similar studies listed on
  • Specialty clinics/sites relative to the study product (e.g. hypoxia labs for pulse oximetry devices)
  • Presentations or attendance at scientific meetings
  • Referrals from other investigators
  • Familiarity with a unique study product (or similar study product)

It is important to note that potential investigators should never be identified, nor selected, based on financial incentives for any party, as this introduces unacceptable bias into the clinical trial.

Site Selection
Ideally, an adequate list of potential sites will be generated upfront from which a certain number of sites will be selected. While it is sometimes necessary to spread out the site selection process over many months, such an approach can impact study enrollment timelines as well as subject distribution among sites.

The Site Qualification Form
A study-specific Site Qualification Form (or “questionnaire”) should be developed in order to assess a site’s compatibility with study requirements and expectations. Typical topics include IRB approval timelines, FDA inspection history, past clinical trial experience, conflicts of interest, access to medical records, overall time to activation, staff available to support the study, and anticipated enrollment numbers. Study-specific topics should include investigator experience with the disease, product and/or procedure, adequate facilities, equipment and/or laboratory, and familiarity with a particular data collection method (e.g. electronic data capture systems). The Site Qualification Form should be thorough enough to allow the sponsor to make an informed decision on whether or not to consider the site for participation.

Review and Comparison of Potential Study Sites
An early indication of a site’s eagerness and ability to perform is how quickly they respond to meeting requests and/or turnaround of a fully-completed Site Qualification Form. As the forms are returned, a spreadsheet can be a good tool to evaluate and compare site information. Each site, along with key criteria from the qualification form, should be listed in the spreadsheet. For clinical trials with a large number of sites and/or complex qualification criteria, the sponsor should consider developing a ranking system for the most important criteria in order to create a more objective selection process. For example, when determining an investigator’s level of expertise, a ‘1’ may be used to represent 0-5 product uses, a ‘2’ may be used to represent 5-10 product uses, and so on. In such a scenario, higher numbers would be used to indicate more favorable responses. Each site is then issued a final, representative number derived from their responses to the Site Qualification Form, allowing for simple and objective comparison. Taking it a step further, certain qualification criterion may be of greater importance to the sponsor, and thus may be weighted as desired.

Having an open mind and taking an objective approach are important when comparing sites. Predictors of high-performing study sites are not necessarily related to extensive previous trial experience, a high volume of publications, or a well-known name. Smaller or lesser-known sites and private practices can be gems when it comes to research.

What About the Study Budget?
Individual study budgets are often largely unknown during initial site evaluation and comparison. Study costs differ between sites for a multitude of reasons and are reviewed and negotiated during the activation phase. However, key budget-related questions might be included in the Site Qualification Form such as the institutional overhead fee, IRB approval fees, etc. For clinical trials in which site budgets are an important factor for site selection, more sites may be chosen to enter the activation phase than are needed. In this case, a message should be sent to site personnel stating that not all sites will ultimately be approved for participation in the study.

The Site Qualification Visit
The sponsor should consider performing site qualification visits to verify and/or further explore the site’s responses on the Site Qualification Form. The visits may be conducted in person, over the phone, or in some cases not at all. Visits are typically conducted when there is no prior working relationship between the sponsor and site, or when a significant amount of time has passed since working together on a previous project.

The site selection process should be conducted in accordance with a sponsor’s formal Standard Operating Process (SOP). Materials related to site selection should be retained for all potential investigators, whether or not they are ultimately selected for study participation. Such materials should include a spreadsheet or list of all considered sites which clearly identifies the reason(s) for selection or non-selection, and all documents should be attributable.

Site Selection Follow-Up
Timely follow-up by the study sponsor after receipt of a completed Site Qualification Form/Visit helps to build credibility, develop site enthusiasm for the project, and foster a positive working relationship. Additionally, the site’s responses on the form are a reflection of its current status, so a delayed response from the sponsor may necessitate re-visiting the information.

The site selection process is an exciting time for both the sponsor and the sites and will set the stage for a successful partnership and ultimately, a successful clinical trial. For assistance in your site selections, please contact Samantha Thrun at or 952-224-2260 to be put in touch with an RCRI expert.



The Six-Minute Hallway Walk – Not As Simple As It Appears

by David France, Principal Advisor

The six-minute hallway walk (6MHW) is a practical and simple test that is often used to measure changes in functional status of heart and lung disease patients. It’s increasingly used for measuring the status of normal elderly adults and those with other conditions such as Fibromyalgia, Scleroderma, or hip or knee arthroplasty.

Other tests used to assess functional status, such as treadmill or bicycle exercise testing, require the availability of equipment and are often not natural or comfortable for the patient and can require familiarization before actual testing. This has led to the 6MHW being the test of choice unless metabolic data are required.

Thorough Protocol is Essential
Although a simple test, the 6MHW requires a strict protocol to control as many variables as possible that may affect the outcome of the test. During clinical studies, this protocol must be followed consistently at all sites. Simple variables such as how the evaluator interacts with the patient during the test can markedly change the motivation of the patient and the results of the test: Are the evaluators provided a script to help standardize interactions/motivation? Where is the evaluator standing in relation to the patient during the walk? The test protocol must address these and other details and site training must reinforce the importance of strict adherence.

The American Thoracic Society (ATS) and others have released guidelines or 6MHW protocols1 that vary in the level of detail but attempt to limit the effect of outside influences on the test outcome. They describe the training and equipment required, the walking course, preparing the patient for the walk, the role of the tester/evaluator and how to coach the patient during the walk, measurements, when to terminate the test, etc.

Determine the Variables
It is also important to consider variables prior to the test itself. Very few protocols address the condition of the patient when arriving at the facility for the test in a direct way. For example, the ATS guidelines simply state: “Patients should not have vigorously exercised within two hours of beginning the test.” For some patient groups, such as those with heart failure, the walk from the car or public transportation to the office may easily qualify as vigorous exercise and may have exhausted the patient. Is the evaluator going to wait for two hours before starting the test? Unlikely. So if the condition of the patient on arrival is often not properly controlled, the test results may vary greatly for an individual patient on subsequent tests or between patients because of pre-test fatigue level and not due to a true change in functional status.

When writing the 6MHW protocol and training the evaluators and subjects, considerations should be in place to minimize the effect of the patient’s exertion just getting to the medical facility. The needs may vary from location to location, but considerations to control pre-6MHW fatigue (such as providing drop off wheelchair service consistently upon arrival to minimize walking prior to the test, or performing the test later in the visit to allow more time for the patient to recover) should be evaluated.

RCRI experts are experienced with the conduct and potential pitfalls of the 6MHW and are happy to consult with you and provide assistance when constructing your 6MHW protocol. Contact Samantha Thrun at or 952-224-2260 for more information.

1 ATS Statement: Guidelines for the Six-Minute Walk Test, Am J Respir Crit Care Med, Vol 166. pp 111–117, 2002


Sponsor Obligations for Registration and Results of Clinical Trials:
A Summary of FDA’s New Final Rule

by Angie Sullivan, Senior Clinical Project Manager

FDA’s new final rule, Clinical Trials Registration and Results Information Submission (42 CFR Part 11), was published on September 21, 2016 and becomes effective January 18, 2017. Responsible parties will have 90 calendar days to become compliant following the effective date.

The database was developed by the National Library of Medicine (NLM) in response to the statutory mandate of section 113 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) to establish, maintain, and operate a data bank of information on certain clinical trials. Additionally, it supports NLM’s statutory mission to improve access to information to facilitate biomedical research and the public health. The database became publicly available in February 2000. Definitions and requirements related to the database can be found in Title VIII Sec. 801 of the Food and Drug Administration Amendments Act of 2007 (FDAAA).

Summary of the New Final Rule
The underlying intent of the rule is to help patients find trials for which they might be eligible, enhance the design of clinical trials, prevent duplication of unsuccessful or unsafe trials, improve the evidence base that informs clinical care, increase the efficiency of drug and device development processes, improve clinical research practice, and build public trust in clinical research. To this end, the Final Rule describes requirements for 1) registering and 2) submitting primary results information for applicable clinical trials to Trials which are funded by NIH must now adhere to the separate, new final NIH policy.

Registration Overview
A responsible party (i.e. the study sponsor, or the delegated principal investigator under certain conditions – see 42 CFR § 11.10) must register an applicable clinical trial at no later than 21 days after enrollment of the first subject. Registration consists of 1) descriptive information, 2) recruitment information, 3) location and contact information, and 4) administrative information. For products which are available under expanded access, a responsible party must submit a separate expanded access record to with details about how patients may obtain access to the investigational product if the data elements outlined in 42 CFR §11.28(c) have not already been submitted.

Results Overview
The results submission requirements apply to any applicable clinical trial with a primary completion date on or after January 18, 2017. A responsible party must submit summary results to no later than one year after the primary completion date. In certain situations, results submission may be delayed (typically for no more than two years) if a responsible party submits a certification to For example, results submission may be delayed for a manufacturer-sponsored clinical trial of an approved drug for which an application has been filed seeking approval of the new use being studied. Refer to 42 CFR § 11.44 for additional information related to delayed submission of results.

Results information must consist of tables summarizing: 1) participant flow information, 2) demographics and baseline characteristics of enrolled subjects, 3) primary and secondary outcomes, and 4) adverse events. Adverse event results are to be presented in separate tables; one which summarizes all serious adverse events, one which summarizes other adverse events that exceed a frequency of 5 percent within any study arm, and a third table which summarizes all-cause mortality, with the number and frequency of deaths by study arm. Additionally, the clinical trial protocol and statistical analysis plan must be submitted in a common electronic document format along with study results. Personally identifiable information and trade secret and/or confidential information may be redacted from the protocol, unless such information is required to be submitted.

Updating the Study Record
All submitted information must be updated at least annually, with some data elements to be updated more frequently; a few such data elements include overall recruitment status, study start date, and individual site status. Refer to 42 CFR § 11.64 for additional database updating requirements, including those related to expanded access use. The responsible party is required to address any apparent errors, deficiencies, and/or inconsistencies within the timeframes set forth within the Final Rule.

Posting Submitted Information
Registration and results information will generally be posted no later than 30 days after it is submitted to For trials of unapproved and uncleared devices, NIH is prohibited from posting registration information unless the responsible party authorizes NIH to do so. Additional posting information can be found in 42 CFR § 11.35 and § 11.52.

Defining an Applicable Clinical Trial
42 CFR Part 11 § 11.22(b) offers guidance for determination of an applicable clinical trial for studies initiated on or after January 18, 2017 and should be used as a primary resource. In general, a trial that meets one or more of the conditions listed below is considered an applicable clinical trial:

  • The trial includes one or more sites in the United States.
  • The trial will study a drug, biological, or device product that is manufactured in the United States or its territories and is exported for use in a clinical trial outside the United States.
  • The trial will be conducted under an IND or IDE.

According to NIH, trials considered to be “applicable clinical trials” generally include:

  • Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase 1 investigations, of a product subject to FDA regulation.
  • Trials of Devices: Controlled trials with health outcomes, other than small feasibility studies and pediatric post-market surveillance.

The final rule considers all interventional clinical trials with one or more arms and with one or more pre-specified outcome measures to be controlled clinical trials. Complete statutory definitions and more detailed information about the meaning of “applicable clinical trials” may be found in the current “Elaboration of Definitions of Responsible Party and Applicable Clinical Trial.” NIH also provides basic guidance in the form of a flowchart.

What About Non-Applicable Clinical Trials? accepts information on trials other than those legally required to be registered in support of the mission of the NLM and other policies such as those from the International Committee of Medical Journal Editors (ICMJE). Sponsors should strongly consider registering all studies in the event that publication becomes desirable.

A Notice of Noncompliance may be issued to a responsible party who has failed to comply with the registration and submission requirements set forth in the Final Rule. Civil monetary penalties may be imposed and a responsible party who commits a prohibited act(s) may be the subject of an injunction action or criminal prosecution. Furthermore, the NIH may terminate funding for NIH sponsored research.

To be put in touch with an RCRI clinical expert that can help you become compliant, please contact Samantha Thrun at or 952-224-2260.



The New FDA: CDRH 2017 Focus Points and Priorities

by Lisa Olson, President

After years of criticism from both the public and government, the FDA took note that they were failing in their mission to protect the safety of patients and promote the innovation of new medical products in the United States. This wasn’t due to a lack of ability or desire, but rather was a result of entrenched systems that didn’t address the current realities of the medical products industry. The FDA took a hard look at their systems, processes, and procedures and has been working on meaningful change. Now, the FDA, and in particular CDRH (Center for Devices & Radiologic Health), publicly sets out strategic priorities, surveys their teams, and measures their results. Based on their findings, adjustments to targets are made. Strategic plans are made in two-year fiscal cycles, but modifications are announced and made annually to refine actions. Taking note of these new FDA priorities can help you prepare and adjust your regulatory strategies for better interactions with the agency.

Ten Priorities Defined
In the most recent update, the FDA has expanded its focus to ten main priorities. But, in their introduction to the FY2017 Regulatory Science Priorities document, the FDA tips their hand to their new pressure points. The importance of driving innovation and progress forward to improve the health of patients in the US is acknowledged by the CDRH over and over. Additionally, the language used demonstrates their intention to garner and use input from all stakeholders including clinicians, industry, and patients.

The recent update doesn’t represent a massive departure from the initial FY16-FY17 plan, but rather a refinement of the priorities. One clear theme across the ten priorities is the need for new tools to evaluate medical products before they get to the patient. However, CDRH is also clearly stating they don’t believe that the tools emerging now have been subjected to enough evaluation to prove their utility. Thus, as manufacturers are asked to bear massive amounts of data gleaned from repositories as diverse as registries, electronic health records, payer (private and public) databases and other data warehouses, analysis techniques must be well-thought out with proof for robustness and explained. The unique challenge CDRH puts forth on setting up these priorities (and thus decision-making processes requiring tools that don’t exist yet) is that any work presented to them must be comprehensive, cohesive, and clearly demonstrate the link to the principals being met.

Several of the priorities are more tactical in nature, such as the focus on biocompatibility and biological evaluation, predictive modeling, and antimicrobial/sterilization/reprocessing effectiveness. It is evident from the text that CDRH is asking for more than just a rote execution of old methodologies. Instead, the requirement is increased to require a thoughtful, scientifically argued approach to provide evidence that is reflective of the risks of the specific medical product.

While the FDA introduced the importance of patient-centric regulation several years ago, there were large gaps in what that meant and how it could be executed. This latest communication provides a bit more insight into expectations and raises the importance of patient-preference studies to the overall clinical evaluation of a medical product. This is taken one step further with the suggestion that information be gathered specifically in clinical trials to seek the level of risk a patient is willing to accept in light of a disease state. This is a new question for trials where before the key data centered on safety and benefit.

Intended Guidance Projects
As an additional signal of their thinking, the FDA recently released their list of intended guidance projects. The list is divided in to three components:

  1. A-list, those guidances they intent to publish
  2. B-list, those guidances they hope to address
  3. The retrospective review list

Once again, the FDA has set out an aggressive plan of attack for guidances. The A-list should be of particular interest to any company that intends to market in the United States. Why? For the last several years, regulatory action has closely mirrored the A-list guidances. Thus, the A-list provides great insight into FDA hot buttons.

For FY2017, the A-list is providing several key insights. First, the FDA is actively trying to work with industry. Three of the guidances focus on how to work with the FDA. Not only can these be used as how-to manuals, but as these guidances are currently open for review, the FDA is clearly asking for industry input through the comment process. Second, the FDA is unmistakably driving even more incorporation of “risk” into the decision-making process as three documents deal with different aspects of risk. Third, the FDA has acknowledged the power and impact of Next Generation Sequencing (NGS) to medical practice. It intends to issue three guidances on how NGS can be used in patient treatment.

In this most recent update to the strategic priority document, CDRH has crafted a cohesive approach to achieve their mission. While not every point is laid out in detail, there is enough information and signals on their thinking to be able to make logical adjustments to regulatory strategies that will lead to better, more successful agency interactions.

RCRI can help you navigate these new focus points and priorities and guide you through the FDA regulatory process. Contact Samantha Thrun at or 952-224-2260 to connect with a regulatory expert.

2016-2017 Strategic Priorities:

2017 Update:

2017 Guidances:


Changing Perspectives: Inside the Clinical Research Coordinator (CRC) and Clinical Research Associate (CRA) Mind

by Kelly Sullivan, CRA (and former CRC)

Often during a clinical trial a CRC or a CRA wants to know what the other is thinking. If there is not a good flow of communication between the two clinical colleagues, it can be difficult to understand the reasoning behind actions. A CRC will often wonder: What will the CRA will be focusing on when they review documents? What will the CRA find and what will I have to do about the findings? A CRA may question: Why doesn’t the site have better documentation? Why is the CRC consistently making the same errors? How can I re-train them (sometimes for the second or third time) so that this is no longer an issue?

This blog is intended to provide some insight and promote good communication between CRCs and CRAs.

Understanding the CRC Role
CRCs are on the front lines for clinical trials and their focus is largely on patients (and a little less on paperwork).

Depending on the research site, CRCs are often involved in multiple clinical trials and have to plan their schedule down to the minute to accommodate trial activities while also providing high-quality subject care. It can become difficult to provide good documentation when you have a blood draw, ECG, and questionnaire to administer every five minutes. Mistakes and protocol deviations are bound to happen and documentation becomes a chore. At the site level, it can feel like the CRA and sponsor are disconnected from how the protocol plays out in real time.

Additionally, now that clinical trials have shifted towards a risk-based monitoring approach, it can cause the site anxiety if there are a lot of data points potentially not being reviewed by the CRA. It should become a priority for the CRC to ask the CRA what is going to be monitored at 100% in order to start an open communication about risk-based monitoring.

Understanding the CRA Role
CRAs are responsible for making sure sites carry out the protocol the way the sponsor intended as outlined in the monitoring plan.

During risk-based monitoring, the CRA is focused on critical data points that vary between studies. It has become extremely important for the CRC to communicate issues or trends happening at the site level. If an issue arises and the CRA isn’t likely to review the data point, they count on the CRC to bring the issue to light.

The Importance of Documentation
When the CRA arrives on site, they look for clear and concise documentation. CRAs do not have a relationship with the study subjects and rely on documentation to understand how the subjects are doing beyond the data points collected. Lack of documentation prevents the sponsor from having an accurate idea of the effects of their investigational product.

CRCs and CRAs should always keep in mind the phrase “If it isn’t documented, it didn’t happen.”

Ongoing Training
Good documentation surrounding small mistakes or protocol deviations helps to avoid loss of data. But looking for repetitions of the same type of mistake can help to point out where re-training needs to occur. Providing re-training to the entire site (not just the lead CRC or Principal Investigator) brings the site’s focus back to critical data and study end points. If the same errors are reoccurring, there could be an issue surrounding the CRA training. Having an in-house CRA or project manager provide re-training could be a positive way to introduce the site to additional outlets or resources when the on-site CRA is unavailable.

Whatever your role might be in a clinical trial, it is easy to lose focus on the big picture. Instead of concentrating on the development of a new medical device or medication, we sometimes narrow our attention to smaller issues and personal deadlines. By bringing the focus back to the big picture and shifting perspectives, we as a clinical trial team are able to work more efficiently and effectively together.

RCRI can assist in all stages of clinical study operations and can help ensure proper communication between study professionals. Contact Samantha Thrun at or 952-224-2260 to be put in touch with an RCRI expert.


When to Submit a 510(k) for a Change to an Existing Device:
Understanding the New Draft FDA Guidance

by Rachel Kennedy, Senior Principal Advisor, Regulatory

On August 8, 2016, the US Food and Drug Administration (FDA) released two separate draft guidance documents clarifying its policy for when manufacturers should submit a 510(k) for changes made to an existing medical device or its software. Previous guidance was issued on January 10, 1997, while an update released in 2011 was met with strong industry opposition and subsequently withdrawn. The new guidance documents include useful case examples and flowcharts to assist with assessing product changes.

What’s New?
Identification of new or significantly modified risks is the only aspect that is really new in this guidance. There are two new points of emphasis relating to device risk profile. First, any change made with the intent to significantly improve the safety or effectiveness of the device (e.g., in response to a known risk or adverse event) must be submitted within a new 510(k). This is the first question of the main flowchart, capturing a broader group of changes than those previously identified as changes associated with recall or corrective action. The second point of emphasis is the need to first conduct a risk-based assessment of the change to determine whether the change could significantly affect the device’s safety or effectiveness, either positively or negatively. Application of risk management is further clarified to state that both safety and effectiveness should be considered in evaluating a device’s risk profile. The guidance also recommends manufacturers consider the potential for unintended consequences of a change.

The guidance provides a detailed discussion of the distinction between Intended Use and Indications for Use. Substantive changes in indications for use could significantly affect safety or effectiveness and will require submission of a new 510(k). Case examples are given to address common changes that may or may not constitute a major change in intended use for determination of whether to submit a new 510(k). Further clarification is provided with regard to changes in Labeling or Instructions for Use that are separate from the indication statement, where those changes might impact the indications. Examples include addition of expanded or new instructions: how to interpret diagnostic data, a new procedural technique not described in original labeling, device use in a different patient population, and device use in a different type of joint, organ, bone, vasculature or tissue. Additionally, a change from single to multiple use should be considered to impact indications for use. The assessment of risks is also captured in the flowchart, signifying FDA’s keen interest in emphasizing risk management.

Technology, Engineering and Performance
The discussion on changes in control mechanism, operating principle, energy type is generally consistent with the previous guidance. The method of sterilization is a determining factor in the evaluation of whether a change is likely to impact performance or biocompatibility. Manufacturers can find clear direction based on established categories of sterilization methods where novel sterilization methods generally require a new 510(k). Changes to packaging or expiration dating are also relatively straightforward, while significant detail has been added to the discussion of other changes in design. Dimensional changes to a device are also discussed such as performance changes, or addition of wireless communication. The guidance recommends evaluation of the criticality of the dimension in relation to the magnitude of the change. With respect to performance changes, those intended to significantly affect device safety and effectiveness will require submission of a new 510(k). For performance changes that do not meet this criteria, the change should be further evaluated for any impact to use of the device, identification of any new or significantly modified risks, a need for clinical data, and whether any unexpected issues were uncovered through verification and validation activities. Addition of wireless communication features is likely to require submission of a new 510(k), while changes to the wireless communication protocol will need to be considered for the same impacts as other technology, engineering and performance changes as per the flowchart.

Changes in materials encompass material type, formulation, chemical composition, and processing methods. New suppliers are viewed as a change (answer is “yes” for the flowchart) in materials. Further assessment then depends on the nature of contact with the material. The key change in guidance involves risk assessment for all devices that have direct or indirect contact with body tissues or fluids, regardless of whether the device is an implant. A new biocompatibility concern is identified as a new type of biocompatibility test that was not required for the original device submission while increased concern is described as no change to the type of testing but the presence of information to indicate a potential for toxicity.

IVD Devices
IVD device changes must consider technology, engineering, and performance, as well as changes in materials. The guidance provides examples of changes that likely alter the operating principle – including changes in detection reagents and critical reaction components. The bottom line for changes that alter operating principle inclusion of modified performance data in labeling will likely require submission of a new 510(k). The previous guidance referred to changes in “performance specifications” whereas the new guidance refers to changes in “operating principle”. Risk assessment is also an important driver for the requirement to submit a new 510(k), based on identification of new or significantly modified risks. The risk assessment should identify any change to cut-offs or clinical decision points when considering if a new 510(k) is required.

Finally, the guidance includes a new section to describe principal factors to consider in conducting a risk assessment for determination of whether a device modification leads to a significant change in the device’s risk profile.

Impact of the Guidance
This draft document is currently released for comment only, but companies will want to review their procedures for documenting evaluation of changes. Once final, it will be important to capture all elements of the flowcharts in documenting (e.g. Letter to File) a decision not to submit a new 510(k) for a modification to a cleared device.

Review the document for any impacts to your business. If something is unclear, submit comments during the comment period (90 days from publication in the Federal Register) as directed on the cover page of the guidance.

RCRI can assist manufacturers in applying the new guidance to their existing devices. Contact Samantha Thrun at or 952-224-2260 to be put in touch with an RCRI Regulatory expert.


MEDDEV 2.7/1 rev 4
Driving Significant Changes to Clinical Evaluation Reports

by Craig Rotzoll, Regulatory Project Director

The revised European guidance regarding Clinical Evaluations (MEDDEV 2.7/1 rev 4) was released in June 2016. It revealed a course change to a more prescriptive and demanding set of expectations. Much of the information contained in the previous version appears to have been repackaged to walk the CER authors (“evaluators”) through the process in a more systematic fashion.
As a result, each stage of the process (termed stages 0: Scoping, 1: Identify, 2: Appraise, 3: Analyze, 4: CER) is now presented within a focused section of the updated document. Detailed instructional criteria and expectations for each of the stages are also provided as appendices and further guide the process and anticipate the output.

    All should note that this guidance update has a significant impact on the methodology and final draft of all new or updated CERs. As such, it is important that each manufacturer carefully reads and understands the effect of this new revision. Though not exhaustive, the following bullets highlight areas with additional emphasis which impact the content and methods employed for updating CERs:

  • State of the art: Though lightly included in the previous version, the updated version now suggests the inclusion of a separate literature search designed to exclusively retrieve detailed information on current knowledge/state of the art. Such information includes: applicable standards; description, natural course and consequences of the medical condition; description of the available options including risks and benefits; treatment hazards due to the technology or materials, etc. The search strategy and retrieved information are suggested to appear as a separate section within the CER.
  • Essential Requirements: There is now a heightened awareness and emphasis of the Essential Requirements in regards to the planning (i.e., scoping), analysis, and conclusion of the clinical evaluation. While a reference to the Essential Requirements was omitted in the Analysis of the Clinical Data section of the previous version, the new version dedicates a multiple page appendix to this topic.
  • Equivalent Devices: Appendix 12 (Activities of Notified Bodies) states the notified body “should challenge the ability of the manufacturer to access information that are relevant to the demonstration of equivalence” and concedes that a determination of equivalence “might be difficult or impossible in case of limited access to the technical documentation of the devices.” Much of the information now needed to prove equivalence may require proprietary access to the proposed equivalent device’s specifications and performance test data, or may require new sponsored testing. Though the base areas of equivalency remain the same (i.e., the clinical, technological, and biological realms) the bar for equivalency has been raised considerably to a point in which previously included “equivalent devices” might now only be eligible for the state of the art discussion.
  • Evaluators: The manufacturer is to define the requirements of the evaluator (individual or team) and justify the choice of the evaluator(s).
  • CER Updates: Updates are to occur “at least annually” for significant risk devices and for those devices that are not yet “well established” OR every two to five years (coordinated with the notified body) for non-significant risk devices that are “well established.” Please note the key term here is “well established,” which unfortunately was not defined in the updated guidance.

The full European Commission guidance can be found at

Contact Samantha Thrun at or 952-224-2260 to be put in touch with an RCRI advisor who can make sure all your CERs are in compliance.


Five Reasons Why You Need to Launch
Risk-Based Monitoring in Your Clinical Trials

by Susan Wiskow, Senior Clinical Project Manager

For years it was thought the only way to assure quality in clinical research trials was to conduct 100% on-site data monitoring. However with more requirements for post-market studies and larger sample sizes and/or increased number of sites needed to complete pre-market studies, the regulatory environment is changing. Companies are competing to execute studies with strict completion timelines, tight budgets, and limited resources. These factors make 100% on-site data monitoring less feasible and risk-based monitoring (RBM) an attractive solution.

As a medical device CRO working with hundreds of clients from small start-ups to Fortune 500 companies, we find the majority of the companies approaching us to run their clinical trials are currently considering RBM. Yet at a recent RBM presentation, the most common reason provided by attendees for NOT using a risk-based approach to monitoring was the fear of the unknown. To help mitigate this fear, medical device manufacturers should consider these top reasons why RBM should be implemented:

1. Risk-Based Monitoring is Supported by Regulatory Agencies
FDA specifically withdrew the 1988 guidance suggesting 100% source data verification and released a new guidance for “Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring” in August 2013:

In this new guidance, FDA now encourages the use of centralized monitoring practices, as appropriate, with correspondingly less emphasis on on-site monitoring, and embraces innovative enhancements to monitoring techniques saying:

“FDA believes it is reasonable to conclude that the flexibility described in ICH E6 and ISO 14155:2011 was intended to permit innovative approaches to improve the effectiveness of monitoring. Notably, the advancement in electronic systems and increasing use of electronic records (i.e., electronic data capture (EDC) systems) facilitate remote access to electronic data and, increasingly, to some source data …. We expect that the pharmaceutical and device industries will, for the foreseeable future, continue to use some amount of on-site monitoring, but we anticipate decreased use of on-site monitoring with evolving monitoring methods and technological capabilities.”

Additionally, in September 2013, European Medicines Agency released a reflection paper on risk-based quality management in clinical trials:

Here the Agency states: ”Sponsors are expectedto move towards a more systematic and risk-based approach.” There is a need to find better ways to make sure that limited resources are best targeted to address the most important issues and priorities, especially those associated with predictable or identifiable risks to the wellbeing of trial subjects and the quality of trial data and results.”

2. Risk-Based Monitoring Improves the Quality of Critical Data.
RBM begins with the identification of critical data and the potential failure points in collecting these data in order to determine the best combination of approaches (centralized data review, source data verification by monitors (remotely or on-site), statistical review, etc.). By identifying and prioritizing critical data upfront, it makes the best use of available resources and improves the quality of the most important data.

3. Risk-Based Monitoring Assists in Retaining High Performing Monitors.
Using a combination of RBM approaches means fewer on-site visits and reduced risk of travel burnout. In addition, monitors can participate in centralized data review and the eagle’s view approach to examine data across sites, expanding their skill set and leading to increased job satisfaction and better staff retention.

4. Risk-Based Monitoring Reduces Risks and Identifies Potential Issues Earlier.
By implementing the use of technological advances, central statistical checks, ongoing data reviews and metric reports, issues can be identified and addressed earlier reducing overall risk of poor or incomplete data. In addition, it is suggested to build quarterly or monthly review meetings in your RBM Plans to assess current risk levels for each study site, review trends, and compare metrics across sites. For example, if you observe multiple sites with the same types of deviations, this may prompt you to identify the need to conduct additional training, or to revise the protocol if needed. While comparing data across sites, you may identify an outlier with higher than typical serious adverse event rates, which should prompt you to investigate. Or, by comparing values you expect to change over time, you may identify suspect data requiring further investigation, i.e. a subject whose weight never changes from visit to visit. These examples may be more difficult to identify in traditional monitoring approaches, where the monitor is focused on comparing a subject’s CRF data to the available source documents to ensure the numbers were transcribed correctly.

5. Risk-Based Monitoring Reduces Costs and Shortens Study Timelines.
Depending on the scope of your project, the number of on-site monitoring visits may be reduced allowing for fewer monitors to be assigned to your trial and significantly decreasing travel costs. Also, many sites charge a fee for each monitoring visit and thus, this fee may be reduced for remote visits, and would not apply for centralized data reviews – resulting in further cost reductions. In addition, by reducing the time needed to travel to conduct monitoring visits and write and review reports, your team has more time to focus on subject enrollment, data cleaning, and endpoint evaluation – thus, completing the study more quickly.

For more information or to get started incorporating risk-based monitoring into your clinical trial, contact an RCRI expert advisor. Email Samantha Thrun at or call 952-224-2260.


Implementing the New US-EU Privacy Shield Policy

by Bergetta Dietel, Clinical Research Associate
Since 2000, US companies that conduct clinical trials in the European Union have relied on the Safe Harbor Agreement to legally transfer data collected in the EU to the US. But in October 2015, the Court of Justice of the European Union (CJEU) found that the Safe Harbor Agreement did not meet EU data protection standards and ruled that it was invalid. This left the US and EU scrambling to develop a new framework to cover transatlantic data transfers for the roughly 4,500 US companies that had been using Safe Harbor. In response, the US-EU Privacy Shield Policy was adopted and put into effect August 1, 2016. How does the new policy impact those in Clinical Research and should further changes be expected?

“Safe Harbor” was the name of an agreement between the United States Department of Commerce and the 28-member European Union that regulated the way that US companies could export and handle the personal data of European citizens. It was put in place to allow US companies and organizations to meet EU data protection requirements under the EU’s 1995 Data Protection Directive because the United States approach to personal data protection was not considered sufficient for EU standards.

Since then, there have been several events that weakened and ultimately toppled the Safe Harbor Agreement, not the least of which was the revelations regarding US surveillance programs and collection of private data that came to light in the Snowden leaks.

The New Privacy Shield
“Privacy Shield” was created in February 2016 as a collaborative effort between the US and EU that released a new set of principles intending to provide the framework for privacy protection the CJEU had not found with Safe Harbor. The same principles are addressed but with added safeguards for data protection, multiple avenues for redress, and strong protection and oversight mechanisms for users of data.

Despite these additions, Privacy Shield may still not be enough to satisfy the EU courts that data transferred to the US will be sufficiently protected. In April 2016, the Article 29 Working Party (WP29) released its opinion of the Privacy Shield draft adequacy decision. The WP29 is an independent European advisory body on data protection and privacy. In the opinion, they acknowledged significant improvements with Privacy Shield’s proposal, but also highlighted several concerns.

Concerns to Pharmaceutical and Medical Research
1. Key-Coded Data

Privacy Shield, like Safe Harbor, does not cover key-coded data. However, EU data protection laws protect key-coded data. The WP29 recommended that the language of the Privacy Shield framework should clarify that, while it does not cover key-coded data, other safeguards such as the Standard Contractual Clauses or Binding Corporate Rules must protect such data.

2. Protection of Data Transferred to Public Entities
WP29 also stated concern about data transfers (especially sensitive medical data) to a public body such as a US regulator that is not self-certified as being Privacy Shield compliant and that Privacy Shield was designed more for data transfers between private entities. The working party recommended that Privacy Shield should include appropriate measures be taken with transfers for regulatory purposes to ensure protection of an EU subject’s fundamental rights.

3. Exemptions
Privacy Shield states in its supplement pertaining to pharmaceutical and medical research that, “A pharmaceutical or medical device company does not have to apply the Privacy Shield Principles in its product safety and efficacy monitoring activities, including the reporting of adverse events and the tracking of patients/subjects using certain medicines or medical devices, to the extent that adherence to the Principles interferes with compliance with regulatory requirements.” The WP29 did not agree that regulatory requirements could justify such broad exemptions.

4. Deleted Personal Data Protection
WP29 was also concerned that Privacy Shield does not contain language that requires personal data be deleted once they are no longer needed for the purpose for which they were collected. They were also concerned about the complex redress mechanisms.

It is not surprising that many of the sticking points that may impact clinical research revolve around the regulatory process because the process potentially includes a US agency receiving the personal data – which is still a major concern in the EU with regards to privacy.

Amendments to Privacy Shield
Given these concerns, it wasn’t surprising that the Article 31 Committee, established by Data Protection Directive 95/46/EC to protect the rights and freedoms of EU citizens with respect to the processing of personal data, required some modifications to the original Privacy Shield before they would formally adopt it. Specifically, the Data Integrity and Purpose Limitations principle now provides further details on requirements regarding data retention. Next, the Accountability for Onward Transfer principle now includes a requirement for a third-party agent to notify an organization if it can no longer meet its obligations under Privacy Shield Principles. In these cases, the third party agent must take appropriate steps to remediate. Additions were also made to clarify the Recourse Mechanism and organizations wishing to join Privacy Shield must designate a contact to handle any complaints, questions or any other issues that may arise related to protected data.

Now That It’s Been Adopted, Will It Fair Better than Safe Harbor?
Not necessarily. The concerns of the WP29 may not have been adequately addressed and those concerns may make Privacy Shield more vulnerable in the EU courts to being invalidated just like its predecessor. What’s more, in April 2016 the EU formally adopted a new General Data Protection Regulation to become effective in spring 2018. It has even higher standards for data protection that the EU Data Protection Directive.

What Should Manufacturers Do Now?
Despite it’s uncertain future, manufacturers need to understand the new Privacy Shield expectations and develop a robust program now. The US Department of Commerce started accepting Privacy Shield self-certifications on August 1st and has posted a self-certification guide. Although there may be further changes, adopting Privacy Shield principles will be required for those whose research includes transatlantic data transfer. Implementing the principles now will mean less work in the future as well as demonstrating a good faith effort to protect private data.

Get assistance with becoming self-certified today. Please contact Samantha Thrun at or 952-224-2260 to connect with an RCRI expert.

Privacy Shield text:

CJEU court decision invalidating Safe Harbor:

Congressional Research Service Report:

Article 29 Data Protection Working Party:

European Data Protection Supervisor Opinion 30May2016:

Final Privacy Shield Annexes 12Jul2016:

Laboratory Developed Tests (LDTs):
Understanding the Impact of FDA’s Forthcoming Regulatory Oversight

by Ambreen Athar M.S., Senior Regulatory Affairs Specialist

Regulatory History of LDTs
FDA asserts that regulatory oversight of Laboratory Developed Tests (LDTs), a subset of in vitro diagnostics (IVD), has been applicable since the 1976 Medical Device Amendment of the FD&C Act. Since then, FDA has exercised enforcement discretion of LDTs due to their lack of complexity and minimal risk. The Clinical Laboratory Improvement Amendments (CLIA) Program was concurrently given authorization to regulate laboratory operations and testing processes. In more recent years, FDA has noted an increase in complexity and risk of LDTs, in addition to the rapid growth of the industry since 1976. FDA believes these changes, along with specific LDT case studies, warrant an increase in regulatory oversight. Although FDA has attempted to balance innovation and public safety by using a phased-in, risk-based approach to LDTs, laboratory groups have challenged FDA’s legal justification for their proposed oversight.

FDA’s prioritized publication list (A-list) of final guidance documents addresses FDA’s position and includes the Policy for Regulatory Oversight of Laboratory Developed Tests (LDTs). Two draft guidances, Framework for Regulatory Oversight of Laboratory Developed Tests (LDT) and FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs) were issued on October 3, 2014. In essence, finalization of the guidances will require developers of LDTs to be compliant with regulations similar to those of medical device manufacturers. Critical to your continuity in the LDT industry will be both understanding and applying FDA requirements as detailed below.

What is an LDT?
LDTs are in vitro diagnostic devices (IVD) that are intended for clinical use and are designed, manufactured, and used within a single laboratory. An example of a simple LDT would be a test measuring a single analyte such as sodium. An example of a complex LDT would be a DNA sequencing test to detect genetic variants.

How Will LDTs be Classified?
FDA will rely upon the existing medical device classification system to evaluate the risk of a category of LDTs – either Class I, II, or III. Classification is based upon the controls necessary to provide a reasonable assurance of the safety and effectiveness of the device. Class I devices represent the lowest-risk category while Class III devices represent the highest-risk devices. FDA intends to issue a guidance to describe what the Agency considers to be Class I, II, or III within 24 months of finalization of the final guidance.

How Will the Final Guidance Impact You?
FDA’s proposed framework will require manufacturers of LDTs to comply with four main requirements:

  1. Notification and/or Registration and Listing – Class I, II, and III LDTs will require either notification and/or registration and listing with FDA within six months of the finalization of the guidance.
  2. Medical Device Reporting – Beginning six months following the release of the final guidance, LDTs will be required to satisfy Medical Device Reporting requirements and requirements for Corrections and Removals.
  3. Pre-market Review – FDA will require pre-market review for higher risk (Class III, PMA) LDTs, followed by moderate risk (Class II, 510(k)) LDTs. Pre-market review will include evaluation of the clinical validity of the LDT.
  4. Quality System Regulation (QSR) – LDT manufacturers will need to meet requirements of 21 CFR Part 820 (Quality Systems Regulation).

When Will New Requirements be Implemented?
Once the finalized LDT guidance documents are released, the phased-in implementation of the requirements will begin as outlined below.










Although the final guidance will outline a phased-in approach, organizations should prepare for the upcoming release of the guidance by:

  1. Identifying a proposed classification for your LDT device(s);
  2. Understanding the requirements of a pre-market submission, with special attention to clinical validity;
  3. Performing a gap assessment between the Quality System Regulation and current processes and procedures; and,
  4. Planning for pre-submission meetings with FDA and planning for applicable pre-market submissions.

RCRI experts can help you prepare for the upcoming release of FDA’s LDT framework. Please contact Samantha Thrun at or 952-224-2260 for further information.


FDA Issues New Guidance on ISO 10993-1
Part 2 of a 2 part series on Biological Evaluations

by Sheila Gretsch Payzant, J.D., Regulatory Specialist

General considerations were covered in the last blog on the new FDA guidance on the biological evaluation of medical devices. In this blog, we’ll go the next step and outline some of the more detailed testing considerations FDA offers to help you set up the right approach.

Safe Biocompatibiltiy Profile Parameters
The new guidance provides instructional information and a “rule of thumb” for sponsors in selecting sufficient testing to establish a safe biocompatibility profile for their device. Specific endpoint considerations are also provided to each type of biocompatibility testing. Sponsors now have recommendations regarding:

• biocompatibility testing of cytotoxicity
• sensitization
• hemocompatibility
• pyrogenicity
• implantation
• genotoxicity
• carcinogenicity
• reproductive and developmental toxicity
• extractable/leachable and degradation assessments

Preparing Extracts
Recommendations for the preparation of extracts are also provided in the new guidance. These include a method for determining the appropriate amount of the test sample, the polarity of solvents used, and the conditions for testing. In most cases, a ratio of surface area to extractant volume should be used. A mass to extractant volume ratio may be used if the surface area cannot be calculated. The choice of extractants is critical to proper evaluation and should incorporate both polar and non-polar solvents. When performing extractions, elevating temperatures to simulate sustained exposure is recommended. And, all testing should be performed, if possible, on the device in its final finished form.

Testing “Special” Components

When a device is comprised of certain “special”componets, the FDA now provides guidance for testing these materials.  It includes:

  • biocompatibility testing of in situ polymerizing
  • testing for biological harm due to mechanical failure
  • specialized testing that may be needed for devices that have submicron or nanotechnology components
  • special considerations for absorbable materials, as standard assay timepoints may not capture critical endpoints

Additional Direction
The new guidance document also has several attachments to support their recommendations. They include:

  • evaluation endpoints that should be considered depending on length and type of contact
  • biocompatibility assessments that should be included in device master files
  • biocompatibility documentation summary
  • flowchart for evaluation of the need for biocompatibility tests
  • test report contents:
    – note: the report should include a discussion of any test-specific issues that might have affected the results in any situation where a potential toxicity is indicated.
  • examples of component and device documentation
  • glossary of key biocompatibility terms

The recently released guidance from the FDA synthesizes and expands upon its former recommendations for use of ISO 10993-1 by medical device developers to support their submission for distribution of their device in the U.S. market. It is a clear attempt to help manufacturers through the process of biological evaluation.

The final guidance may be found at:

While this two part blog series outlined the key points of the new guidance, to adequately determine how the guidance may impact the biocompatibility testing of your medical device, contact Samantha Thrun at 952-952-224-2260 or to set up a call with an RCRI expert.

FDA Issues New Guidance on ISO 10993-1
Part 1 of a 2 part series on Biological Evaluations

by Sheila Gretsch Payzant, J.D., Regulatory Specialist

On June 16, 2016, the Food and Drug Administration (FDA) issued its final guidance on “Use of International Standards Organization 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.” This document replaces the draft guidance issued in April 2013 and provides comprehensive recommendations for biocompatibility testing of medical devices to support clearance for the U.S. market. In part 1 of this blog series, you’ll find an overview of critical aspects of biological evaluations.

Biocompatibility Testing on Medical Devices

Why? Biocompatibility testing on medical devices needs to be done to determine the potential for an unacceptable adverse biological response. Biocompatibility testing is a critical component in establishing the safety and effectiveness of the medical device in submissions to the FDA.

When? Biocompatibility testing of a medical device must be considered if the materials of the device will have direct or indirect contact with human tissue, if changes including material changes to an existing device could affect tissue contact or if significant changes are made to the manufacturing process.

How? One of the key principles in this guideline is that sponsors should engage in a risk-based analysis to determine whether an unacceptable adverse biological response is created by bodily contact before delving into new or additional biocompatibility testing for the device. In order to correctly conduct and assess a biological evaluation of the device, it is essential that developers know and understand the materials of which the device is composed and the chemistry of these materials. Inherent to this understanding is knowledge of the formulation of the components, additives (i.e., colorants and antioxidants), potential contaminants and residues from the manufacturing process, the effect of combining and processing these materials, and whether the ultimate outcome will be a product that is biocompatible with human contact.

Then, once the risks have been identified, an analysis of the gaps should be performed to determine if there is any information that may be leveraged to mitigate the risks. Sponsors are encouraged to research and leverage, if possible, all available information pertaining to the device and its material composition to assess the toxicity risks. The sponsor is responsible to determine whether sufficient data exists to establish a safety and efficacy profile for the device and, if not, design a testing plan that completes the data set. The entire body of information should then be collated into a biological evaluation demonstrating the safety of the device that can then be reviewed by the FDA during the 510(k) or PMA review process. Information for review includes, but is not limited to, published literature, pre-clinical and clinical data, extractable/leachable testing, materials review, prior manufacturing experience, animal studies, data from previously cleared devices, and device-specific guidance documents.

When not to? There are cases where biocompatibility testing of the medical device may not be needed. If the device is made of materials that have been well characterized both chemically and physically in the published literature in the same type of patient contact and duration and have a long history of safe use, additional testing may not be warranted.

What about Labeling? In an effort to prevent a false sense of security by users with devices that are labeled as “-Free”, the FDA recommends that sponsors use a statement that the device isn’t composed of a specific element and/or a specific chemical is not used in the processing or testing of the device. The FDA cautions that current test methods may not be adequate to ensure the complete absence of a specific allergen or toxic compound; thus, use of “-Free” could be misleading and potentially injurious to the user. Note: if the “-Free” statement is used in a sponsor’s labeling, supporting data must be provided which proves that the device doesn’t include the material at a level that could create an adverse event.

This is the just the start to understanding what the new guidance entails. The next blog will cover considerations for testing to support a biological evaluation. In the meantime, if you need to determine how the FDA recommendations may impact the biocompatibility testing of your medical device, contact Samantha Thrun at or 952-224-2260 at RCRI to set up a call.

Regulatory Strategy – A Useful Business Tool

by Liliana Omar, Senior Regulatory Affairs Specialist

A regulatory strategy can be a useful tool to aid in making knowledgeable business decisions to get a medical device, IVD, or combination product to market. The regulatory requirements in the United States and the rest of the world are constantly changing and not understanding those requirements and changes may result in delays to market, rework costs, and frustration of senior executives and investors. With this in mind, learning and understanding the different regulatory requirements applicable to the medical device in question and advanced planning can provide the needed information to help you make informed business decisions.

What is a Regulatory Strategy
In our experience, medical device manufacturers approach regulatory strategy in a variety of ways. We find that there are still companies that do not know a regulatory strategy can be created, while those that do know may not fully understand or leverage the value it can provide. The value of the regulatory strategy goes beyond following a procedure and generating a document. A good strategy begins with understanding the device’s indication for use as this will help establish project scope and regulatory requirements.

Despite global harmonization efforts, Medical Device Regulations vary depending on the countries where the devices are to be marketed. These regulatory requirements impact everything in product development from design, labeling, marketing, and Quality System to post market surveillance, third party contracts, registrations, licensing, and other items needed for product clearance or approval.

Larger organizations may have identified different countries or geographies as targeted markets in their early business strategy. Medium and small size organizations may focus their efforts in one or two geographies in order to generate sales and then later consider other markets. The latter approach may result in additional costs and time which are precious items for smaller organizations. Planning ahead and having a regulatory strategy which considers different geographies as short-term and medium-term goals will help medium and smaller size organizations to ‘work smarter rather than harder,’ resulting in better use of their resources and therefore reducing medium-term costs.

How Do You Create a Regulatory Strategy?
Regulatory strategies can be created anytime during the product life cycle. A regulatory strategy created during the product development phase is most impactful. It is then that it provides valuable input to the design of the device, risk assessment, testing and labeling. The strategy can include information about the regulatory plan for the premarket regulatory submission, planned interactions with the regulatory authorities and can be combined with clinical and reimbursement strategies. Regulatory strategies often provide inputs to the Quality Management System (QMS) such as identifying geography specific QMS requirements including post market surveillance/vigilance activities that promote timely regulatory compliance.

What Does a Regulatory Strategy Include?
Regulatory strategies use current information. But what is current today may not be current tomorrow. The regulatory landscape is in constant change and regulatory strategies may need to be updated, the purpose and scope may need to be expanded, and the information included may need to be more detailed as the project progresses. A solid regulatory strategy is a critical, contributing element to every medical device product development process. The information contained in the regulatory strategies can be very helpful to the different areas in your organization, thus making them invaluable tools.

To see how RCRI experts can help you creating the regulatory strategy that will provide the information you need, contact Samantha Thrun at or 952-224-2260 to see how RCRI experts can help you create the regulatory strategy that will provide the information you need.

Ensuring Success: Selecting the Best CRO, part 2

by Mary Kay Sobcinski, Senior Principal Advisor, Clinical Sciences

As you’ve read in part one of this blog series, once you’ve laid out your requirements for working with a CRO, selecting the best fit is your next consideration. Asking the right questions can parse the differences between how CROs operate clinical trials. Selecting the best fit is critical to overall trial success – and not all CROs are equal. The following questions and considerations for the CROs can help you make the decision. Developing a grid to record your questions and answers across CROs will help you with an “apples-to-apples” comparison.

What are your experiences with medical device trials? Describe your experience with projects that are similar to ours in terms of therapeutic area, types of services, and study phase? How were they similar and how were they different, what challenges were encountered, and how did you manage them? Can you present some case studies?

It’s imperative to work with a CRO that has experience in your medical product area to help ensure you identify and meet regulatory requirements that might otherwise be missed. It is helpful, but not critical, that they have experience in the actual therapeutic area or with similar devices. A well-established CRO with strong researchers can easily learn the indication and device. It’s unlikely you’ll find an exact match to your study specifics, but understanding the CRO’s experiences with similar projects can be enlightening. As challenges almost always arise in clinical research, hearing about their identification and management of specific issues will illustrate the depth of the CRO’s strengths and understanding of potential pitfalls. Be wary of a CRO that paints too rosy a picture – it’s unrealistic and if you run into trouble, they may not help you recognize it or manage it!

What will the project team look like, i. e., what are the staffing levels you’ll assign to my project? How is staff turnover managed, and how likely is it that the team I start with will stay for the duration of the project? What is the team composition (name and position)? Will biographies/curriculum vitae (CV) be made available?

These questions help you ensure your project will be appropriately staffed throughout the project and avoid costly, time-wasting turnover. It’s very helpful to view potential team members’ profiles on professional social media as well as to review their CVs from the CRO: look carefully at how long the team members have been with the CRO and their longevity at previous positions. If many of the team members have a short duration with the company, such as less than one year, this could foreshadow a high turnover rate within the company as well as raise concerns over the team’s cohesiveness and stability, all of which can be issues for your project downstream. The CRO team should become an integral extension of your team, working synergistically with you to achieve project timelines and goals. Keeping turnover at a minimum is key to ensuring efficiency, and ultimately, project success.

Budget Management
How are changes to project scope and budget managed? When will I be notified that a line item is at risk for a budget overrun? How are changes to budget documented and approved?

CROs may bill certain tasks at a fixed rate, such as a day rate for monitoring, while other tasks are billed hourly or per deliverable. Some CROs ask for approval on line items when the budget limit is reached, but others consolidate overages quarterly or on another basis. Be sure you know how each line item is billed and how/when you’ll be notified as the limit is reached. This will ensure you are fully informed about the budget at all times so there aren’t any surprises for you or your finance officer. Additionally, be wary of a CRO claiming there will be few scope changes. It is unrealistic to expect a study to not have changes throughout the life of the project. Know how and when you will be kept informed before scope creep happens.

Overall Management and Communication
Describe your project management and communications plan for this project.

The CRO should have its own plan for managing the project internally, including meetings and communications among its staff, to ensure they are providing you with the fullest support and counsel for proactive problem identification and solution. Understand how they communicate internally to ensure a smooth, well-managed project as well as how they will communicate with you and your company team members. Discuss the proposed internal and full-team meeting schedules, timeline updates, and the documentation process for decisions.

Provide me with references from companies with projects similar to ours.

Reference checks are vital to ensuring you know the CRO’s reputation, past performance, potential issues, and the sponsor’s view on how well they managed a project because there is no other way to verify performance in advance of working with them. Many of the questions you pose to the CRO, such as those discussed here, should be posed to their references to verify the information received from the CRO and to hear their perspective as a sponsor.

These are foundational questions to ask during your CRO selection process. As you start talking with various firms, refine your questions to hone in on topics pertinent to your project and corporate needs. Selecting the CRO that best fits your goals, timeline, budget, and philosophy will help ensure success for your company, study, and your team, as well as set the stage for further partnership and successes.

Contact Samantha Thrun at or 952-224-2260 to see how RCRI experts can be your CRO partner on your project.

Ensuring Success: Selecting the Best CRO, part 1

by Mary Kay Sobcinski, Senior Principal Advisor, Clinical Sciences

Of all the critical decisions you make as a clinical researcher, CRO selection is paramount. Your CRO can make or break the success of your study and, ultimately, achievement of your business goals. With a solid understanding of key questions to ask and knowing the answers in advance for what you need, you’ll find the right CRO.

I’ve recently returned to the CRO world after 3+ years on the sponsor side. There I vetted multiple CROs that culminated in the selection of firms that best met my changing needs for different study phases and challenges. In this two-part blog series, you’ll find key questions to ask and considerations for evaluating the answers.

What do internal stakeholders need?
The first step in CRO selection is seeking input from your internal stakeholders. This may include educating your upper management staff on the intricacies, challenges, and expense of a clinical trial, especially if they haven’t been involved with the research previously. Once you know the business priorities and goals for the company and how your study(ies) will support their achievement, you can embark on your CRO quest.

What services do we want to outsource – both now and potentially in the future?

You can’t assess a CRO’s capabilities adequately if you don’t first identify what tasks you’re going to outsource. Common services include database design/management, data management, statistics, and monitoring, but can include all aspects of trial management. Find a CRO that will be flexible – one that can take tasks on now and is willing assume others in the future, or importantly, is willing to transition them back to you as your needs and staffing levels evolve.

What will we control and what do we give to a CRO?
What is our philosophy on site management? Do we want the CRO to be the primary communicator with sites or do we want to keep it in-house? Who will manage enrollment tactics and milestones? Do we want our clinical department to be the “face” of the study and the company, or are we willing to let the CRO take on this critical marketing role? If keeping control of the study as the sponsor/site manager is important to you, be sure to communicate this during the bid process, as not all CROs are willing to work with sponsors who won’t allow the CRO to be the primary site manager/communicator.

What are site opinions on various CROs and databases?

It is very informative to poll the sites you’ve already worked with on previous studies to learn about what CROs they successfully – and unsuccessfully – worked with and why. You can also learn what database(s) sites prefer for electronic data capture (EDC). You’ll receive a myriad of answers and opinions, but the differences will help refine criteria important to you. For example, site database preferences can then be cross-referenced to match the needs identified during the protocol development process. The list of CROs under consideration can be narrowed to those with experience and expertise specific to that database.

Answering these questions will help set up your selection criteria and identify the CRO with the best match of services and philosophies to your clinical trial needs. But it is just the beginning. Part two in this blog series, coming next week, will cover questions you need to ask every CRO you are evaluating to make the right selection.

Questions? Contact Samantha Thrun at or 952-224-2260 to be put in touch with an RCRI expert today.

Ready to Meet the UDI Rule for Class II Products?

by Carol Ryerson, Senior Principal Advisor

The due date for UDI implementation for Class II medical devices is September 24, 2016.
Navigating through the mountain of FDA guidance and information on the UDI Rule and finding the right information for your company and products is challenging. However, the process can be more manageable if you understand the complexity of the guidance rests on two main aspects; 1) placing the barcode and human readable text on the label, and 2) setting up the information stream for the GUDID submission.

Determine the Team and its Plan
As with any systemic change, planning and incorporating the right team members is the difference between successful implementation and failure. Adding identifiers to medical devices requires the engagement of all aspects of manufacturing, from fundamental quality systems through end user perception and usability. Therefore, when embarking on the journey to implement UDI, set up a team comprised of regulatory, IT, quality, supply chain, procurement, marketing, and legal. Not every stakeholder is needed at each step, but gaining perspective from each area is critical to implementing a process that is integrated from end to end.

Identify Your Issuing Agency
After you’ve identified the team and established a master plan, the next core issue is selecting an Issuing Agency. Agencies have slight variations in expectations and these variations will drive the details of your process for collecting and implementing GUDID elements. Defining these elements helps determine what the barcode content should be as well as determining which labeling will require UDI. When that is complete, manufacturers then need to then review supplier and distribution agreements to determine if they comply with UDI requirements.

That’s just the start. Are you ready? RCRI experts can assist your UDI project team with preparing an implementation plan, training the executive team on the importance of compliance with UDI, and with training for your project team on practical considerations for implementation of UDI.

Review of the 2015 FDA Medical Device Quality System Report

by Lisa M. Olson, President

In compliance with its initiative for transparency, the FDA recently released a report summarizing inspections, FDA form 483 observations, and warning letter citations for the 2015 calendar year. Understanding the types and frequencies of findings is important to maintaining a high-caliber quality system and avoiding spending resources and time on making corrections within your own system.

FDA Activity Increased
Several interesting trends emerge when the 2015 results are reviewed as a whole. While overall inspection findings and actions are holding steady to 2014 levels, activity remains substantially higher than the 2008-2009 levels. Clearly, the FDA remains concerned about manufacturing activities outside of the United States. Further, the FDA has maintained its focus on the systemic processes supporting quality systems.

Foreign Inspections
Since 2008, the FDA has tripled the number of inspections of foreign sites, representing nearly a third of all inspections done annually. Manufacturers of record must ensure that the quality systems of their own plants and those of subcontractors match the same high standards of the U.S. plants. In particular, the FDA is heavily inspecting China, performing nearly 50% more audits there than the next highest target country, Germany.

Cited Actions
Official Action Indicated (OAI) from inspections reached an eight-year high at 11%. This is 2% higher than 2014 and continues the upward trend of these findings. Voluntary actions were 5% higher than 2014 and also at an eight-year high. Looking deeper, foreign inspections are driving 5% higher levels of both voluntary and official actions needed. Looking at the detail of the form 483 citations helps explain these trends. CAPA and Production and Process Controls still lead the observations by nearly double those of Management, Design and Document Controls. The FDA is signaling to manufacturers how seriously they need to take making systemic changes and implementing robust processes to control device quality.

Warning Letters
While the overall number of warning letters remained flat compared to 2014, foreign manufacturers experienced a 31% increase in the number of letters received. As expected, following the trends of the 483 citations, the preponderance of the warning letters contained citations for CAPA and Production and Process Controls. When evaluating the CFR sections cited, a clear focus emerges on process control starting with ensuring material and vendor controls and processes are suitable to clear investigations and resolutions of problems.

483s are Most Cited
In the current environment, over 50% of inspections are resulting in form 483s, many of which are escalated to warning letter status as the FDA puts increased pressure on manufacturers to demonstrate effective and systemic process improvements. Understanding where the FDA is looking can help you prepare and minimize time spent on remediation projects.

To find out what the recent FDA report means for your device development, contact Samantha Thrun at or 952-224-2260 to schedule an appointment with an RCRI regulatory expert.

Utilizing Electronic Patient-Reported Outcomes

by Kelly Haupert, Principal Clinical Data Manager

Advances in technology for electronic data capture (EDC) have led to increased efficiency of data collection, data management, monitoring, time to database closure, and completion of final study reports. These advances have extended to the collection of patient-reported outcomes (PRO) in electronic format, but how do you know if it’s right for your study?

Many clinical database providers and focused PRO vendors offer services for electronic collection of PRO (ePRO) – where the ability to collect any data desired exists. Before you determine whether or not to pursue ePRO for your study, consider:

Benefits to ePRO Data Collection
including, but not limited to:

  • Capturing data directly from the subjects reduces data entry of the PRO by site personnel and the monitoring burden for data entry error review.
  • Reducing potential social stigma perceptions by the subject completing the PRO, especially where responses to questions may be of a sensitive nature, such as sexual health/habits or drug and alcohol use.
  • Providing alerts and reminders to subjects and site personnel for completion of the PRO to collect data within the required timelines.

Considerations before Deciding to Utilize ePRO Data Collection
including, but not limited to:

  • Is the technology suitable for the study’s intended subject population?
  • What is the subject burden for the time it takes to complete the questions (e.g., the length and frequency requirements of the PROs used, and will it introduce compliance issues)?

And, specifically for validated PROs:

  • Is the PRO validated for electronic use?
  • If the PRO is licensed, is it validated for electronic use within a specific ePRO system?
  • If the PRO is validated based on set formats or fixed measurement scales, how could it be impacted by converting to an electronic format?
  • How does built-in quality check functionality (e.g., forced entry flow vs. allowing for missing values) compare to how the PRO was originally validated?

The FDA has clearly announced its interest in this area with the announcement of the FDA’s 2016 Strategic Priorities and the decision to put “Use of Real-World Observational Patient Data to Support Decision Making for Medical Devices” on the FDA’s A-List for draft guidance documents. Patient-reported outcomes need to become more common in our studies because the FDA is considering these outcomes when evaluating products for market approval.

Understanding the considerations for each PRO used in a study and its suitability for the ePRO environment are key components in determining appropriate data collection practices to obtain clean, accurate, and high-quality patient-reported data for submissions. Contact Samantha Thrun at or 952-224-2260 to see how RCRI experts can help, with your PRO and data collection needs.

Preparing for a Notified Body Audit of CE Technical Files

by Carol Ryerson, Senior Principal Advisor
and Liliana Omar, Senior Regulatory Affairs Specialist

As many medical device manufacturers have seen recently, the bar has been raised by Notified Bodies responsible for auditing the content of CE Technical Files specifically with respect to meeting the requirement to demonstrate the device continues to be consistent with “state of the art.”

How Do You Prepare?
Consider this list of items when preparing for your next Notified Body audit:

  1. Update the risk assessment and risk management file in accordance with the current standard, ISO 14971:2012 “Application of Risk Management to Medical Devices.” Ensure that all risks have been included in the risk documentation, all products listed in the file have been incorporated into the risk report, and the report includes the risk-scoring matrix used in the assessment.
  2. The Technical File should include documented evidence that the device design considered human factors and meets usability requirements with reference to ISO EN 62366 “Application of usability engineering to medical devices.”
  3. Review the list of standards referenced in the design documents. Where appropriate, update the reference list with the current version of the harmonized standards and ensure the design meets the requirements of such version of the standards. Where necessary, document a justification for why the current version of the standard is not applicable.
  4. Ensure documentation of biocompatibility testing is consistent with state of the art and was conducted in accordance with ISO 10993-1:2009 “Biological evaluation of medical devices.”
  5. Confirm real-time stability testing was conducted with three lots of product as expected by current state of the art and that the Technical File was updated with documented evidence of the test results.
  6. Update the Clinical Evaluation Report and clinical literature review to ensure documentation is consistent with state of the art as well as the current safety and performance profile for the device. Also have a robust Post Market Clinical Follow-Up Plan or justification for not conducting one.

RCRI has assisted clients with preparing CE Technical Files for new products as well as updating files for products already on the market. Our team has expertise with compliance to the MDD, AIMD, and IVDD directives. Contact MSamantha Thrun at or 952-224-2260 to schedule an appointment with an RCRI expert.

Best Practices for Risk-Based Monitoring

by Kaisa Kivilaid, Senior Biostatistician

Over the last decade, risk-based monitoring has become more widely accepted and implemented in the medical device industry. This is due to the increased pressure on the industry to run clinical studies more efficiently, effectively, and accurately.

With the release of the FDA guidance for Industry “Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring” in August 2013, the International Conference on Harmonisation (ICH, 2005) “Guideline Q9 Quality Risk Management,” and European Medicines Agency (EMA, 2013) “Reflection paper on risk based quality management in clinical trials” sponsors and vendors have been working on the best way to implement risk-based monitoring into their clinical programs.

Risk-Based Monitoring Advantages and Challenges

  • Potential reduction in the overall monitoring budget.
  • Reassignment of resources to areas and study sites with greatest need.
  • Identification and prioritization of data review based on risk mitigation; i.e., data requiring 100% source document verification vs. narrowed review for lower-risk data points, based on pre-determined risk thresholds.
  • Potential to improve sponsor oversight of clinical investigations with focus on risks to the most critical data elements.
  • Critical data elements need to be defined prospectively and risk assessments should be performed on those critical data elements.
  • Monitoring plans need to be designed to fit each specific clinical study, taking into account the complexity of the study, types of endpoints, site experience and expertise, etc.
  • Confidence in the ability to do more with less; i.e., confidence in the risk management and cleanliness of the data.
  • Requires routine review of data trends across sites and more work up front to program data edit checks and create reports.

Utilize SAS Reporting
Based on the type of database that is used to collect and house the clinical study data, the database may not always have robust reporting capabilities to summarize and track the data used for monitoring. As an alternative solution to other add-on software systems, SAS (Statistical Analysis System) can be utilized to assist with risk-based monitoring. SAS reports can be developed just once and set up to run at pre-specified intervals and/or on-demand. Some SAS reports may include:

  1. Metrics related to data queries ­­– number and types of open queries, average time to resolution and protocol deviation counts, and types by investigational site or patient-months.
  2. Safety summaries ­– adverse event counts, types, duration by investigational site, based on enrolled subjects or patient-months.
  3. Subject disposition summaries – number enrolled, treated, discontinued or screen failed by investigational site.
  4. Metrics related to regulatory and operational risks – submission timelines, geography-specific requirements, and vendor management.
  5. Value-range results of selected variables by subject across multiple visits ­– change from baseline in vitals where clinically-significant change could indicate an adverse event.

Establish Risk Thresholds
In addition to the typical study metrics, risk thresholds can be developed for each report so each site can be categorized as “above acceptable or average,”, “acceptable or average,” or “below acceptable or average.” Those thresholds can either be stationary (e.g., no more than 0.1 serious adverse events per randomized subject) or fluctuating with each reporting cycle (e.g., within 10% of median value at all sites).

Overall, Be Flexible and Review
Flexibility in the reporting and review of captured subject data is a key component for successfully implementing a risk-based monitoring approach for your trial. Incorporating SAS programming can allow for greater versatility in reviewing study metrics or thresholds specific to your unique risk parameters. Any reporting limitations inherent in your current database solution can be eliminated through incorporating customized reporting and output from this very powerful statistical software.

To learn how to incorporate SAS into your risk-based monitoring, contact RCRI’s Samantha Thrun at or 952-224-2260.

2016-17 CDRH Strategic Priorities
Transitioning to Meeting Patient Expectations

by Lisa M. Olson, RCRI President

The FDA, in particular CRDH (Center for Devices and Radiological Health), recently published its 2016-2017 strategic priorities in a clear demonstration of their intent to address concerns raised by the public regarding medical device safety and innovation. The language used to describe the priorities for the coming years represent not only an extension of FDA’s prior initiatives, but also signal the intent of CDRH to change their baseline paradigms.

New Priorities Focus on the Patient
The new strategic priorities incorporate CRDH mission, vision and values into three main actionable precepts with specific goals supporting each initiative. Although CDRH has been making smaller, iterative changes to modernize and adopt practices to foster medical device innovation, fundamental operating practices and measurement assessments have prevented meaningful change. Unmistakably, the game is changing now. The FDA, or at least CDRH, is intending on becoming patient-centric. This fundamental shift will impact the medical device industry in a myriad of ways. To successfully address these changes, medical device manufacturers will require an insight into each of the strategic initiatives in addition to an awareness of the more subtle changes in approaches necessary to win and keep approvals.

Three CDRH Strategic Priorities
Of the three areas CDRH has identified for action in 2016-17, two are heavily patient-centric while the third focusses on CDRH itself. Each initiative is supported by CDRH’s rationale for their approach, measurable goals, and overarching action plans intended to support goal achievement. They are:

  • Establish a National Evaluation System for medical devices
  • Partner with patients
  • Promote a culture of quality and organizational excellence

The language used by CDRH in discussing these priorities is indicative of a changed philosophy for supporting medical device development. For example, CDRH uses the concept of a device “ecosystem” in identifying the myriad of stakeholders involved. The inter-relationship and responsibility of each group involved with or using medical devices is imperative to this ecosystem. This is a key differentiator from past positions when the FDA spoke only of stakeholders and in essence removed accountability from anyone outside of the FDA or the manufacturer. The concept underscores and highlights the role of the patient in device development.

What Device Manufacturers Need to Know
Moving ahead, CDRH will not only be engaging patients directly in their daily working activities, but they also will be evaluating millions of electronic patient records. This puts the FDA in a position to have first-hand knowledge of data trends. Furthermore, CDRH is setting the expectation for more patient-reported outcomes (PRO) in studies and in submissions. As a result, device manufacturers will have to ensure trial design and post-market follow-up processes not only generate meaningful patient data, but also use the data in the device lifecycle management.

What does this all mean? CDRH will be generating and collating more of their own data, meaning device manufacturers have to expect the agency will be in a position to know more (or believe it knows more) than a manufacturer. There is a higher likelihood that the agency will have pre-determined positions established based on their data expectations and device manufacturers will have to be prepared to defend against them. These changes are a positive signal that the agency is evolving to address the realities of today’s patient-centric medical device world. And manufacturers will need to be prepared with objective evidence and well-reasoned arguments.

To discuss how the new priorities impact your device development, contact Samantha Thrun at or 952-224-2260 to schedule an appointment with an RCRI expert.

Regulatory Considerations in Mergers and Acquisitions

By Julie Underdahl, Regulatory Affairs Project Manager

Medical device industry mergers and acquisitions present many challenges. Maintaining and obtaining regulatory approvals during these transitions is a critical priority to ensure ongoing market access and revenue. Significant changes due to a merger or acquisition that could impact regulatory approvals are changes in ownership, manufacturer, or legal name, and submitted level of management to regulatory bodies. For some countries, these changes are minor while others may require lengthy, new registrations.

Identify the Changes
Before communication with domestic and global health authorities can begin, it is important to get all the facts in order. There are several questions that should be asked to ensure you’re in compliance:

  • Identify all legal changes and how they may impact regulatory registrations or customs access. Is this a name change that will affect labels, marketing materials, and/or invoicing? If so, when?
  • Are there any required changes in facilities or establishment registrations?
  • For CE-Marked product and product sold in Canada, are all certification changes identified before contacting the Notified Body or Health Canada?
  • Is there an adequate and well-documented Quality System to support all ongoing and new activities?
  • Does the merger/acquisition change impact any of the Quality System documents previously submitted?
  • Are the approvals for all products documented for each country?
  • Will there be any impact to in-country regulatory representation that may void the license in that country?
  • If country licenses are held by distributors or other third parties, are all contracts current to maintain the licenses under the new company configuration?
  • Are there any ongoing clinical trials to support approvals? If so, what transitions are necessary to continue?

Develop a Transition Plan for Each Country
Once the scope of changes is known, a regulatory impact plan can be developed by country. These plans should include the specific changes that are triggering the submission and what documents are required to support it. This information can come from a government agency, in-country license holders, or in-country consultants familiar with that particular health authority and the company’s type of devices.

Recognize a Submission Plan
Another aspect of the regulatory plan should include the estimated cost, length of submission review, and whether or not the previously approved product configuration can be distributed in the country during the review process. This information can be used to determine country-specific inventory plans to limit any product interruptions. And remember, inventory management during the global submission process can be lengthy. Some submissions can take two to four years to meet new registration requirements.

Planning and preparing ahead of communications with health authorities can help identify any gaps in the merger or acquisition transition plan or where outside expertise may be beneficial. With solid information and supporting documentation about the future state of the new company, communication of these changes to health authorities can be open and productive.

RCRI staff can help you plan for a smooth regulatory transition during medical device industry merger and acquisition activities. Please contact Samantha Thrun at or 952-224-2260.

Changes in EU Medical Device Regulations

Are You Ready for the New Regulatory Compliance Responsibilities?

By Liliana Omar, Senior Regulatory Affairs Specialist

The process of updating European medical device regulations (Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009)¹ started in 2012 and the time of adoption is coming soon. Manufacturers that distribute (or plan to distribute) medical devices in the European Union must understand the changes and be ready to address them. The final version of the proposed regulation is expected to be adopted in Q1 or Q2 of 2016. Medical devices will then have a three-year transition period for compliance and in vitro diagnostic devices have five years. The new requirements and responsibilities will apply to both manufacturers and European authorized representatives.

Person Responsible for Regulatory Compliance – a Designated Expert

One significant change to the regulation is having a person specifically responsible for regulatory compliance. That person’s role is to be fully supported by the company. The draft proposal now defines competence, knowledge and responsibilities, all of which focus on demonstrating expertise and authority to adequately control the products and perform regulatory due diligence. The following competence attributes must be considered when assigning responsibility:

  1. Formal qualification in the field of medicine, pharmacy, engineering, or another relevant scientific discipline.
  2. Minimum two years of professional experience in regulatory affairs relating to devices or in quality management systems relating to devices or five years of professional experience in regulatory affairs related to devices including experience in quality management systems.
  3. Manufacturers of custom-made devices may demonstrate their expert knowledge by at least two years of professional experience within the relevant field of manufacture.
  4. Micro and small enterprises within the meaning of Commission Recommendation 2003/361/EC are not required to have the person responsible for regulatory compliance within their organization, but shall have such person permanently and continuously at their disposal.

Regarding the execution of responsibilities, the drafted proposal clearly strengthens the liaison of knowledge of quality systems and medical devices and other applicable regulations such as medicinal substances, REACH, RoHS, software, animal tissues, blood derivatives, etc. Knowledge in risk management, technical documentation, and safety and performance standards will be essential for an adequate execution of such a responsibility. A graphical representation of the responsibilities of the person responsible for regulatory compliance is presented in Figure 1.


Figure 1. Responsibilities of the manufacturer’s person in charge of for regulatory compliance.

The proposed regulation also indicates that the person responsible for regulatory compliance “shall suffer no disadvantage within the manufacturer’s organization in relation to the proper fulfillment of his/her duties”¹ regardless of whether or not he/she is an employee of the organization. In essence, the company must provide resources and systems to support regulatory compliance.

European Authorized Representatives
The draft proposed regulation also requires that authorized representatives have at least one person in charge of regulatory compliance activities who is permanently and continuously at their disposal. This individual should have expert knowledge of the regulations for medical devices and in vitro diagnostic medical devices in the European Union. The competence and knowledge requirements of this person are similar to those requirements of the manufacturer’s person responsible for regulatory compliance.

The Expectation

Once the regulation is finalized and adopted, the manufacturer and authorized representative should expect to demonstrate, with documented evidence, that these requirements are being fulfilled.
RCRI can help you meet the requirements of the proposed regulations. Please contact Samantha Thrun at or 952-224-2260 to get in touch with an RCRI regulatory expert today.

¹COM(2012) 542 final, 2012/0266 (COD). Proposal for a REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009


Five Most Common Pitfalls in Clinical Trial Design

By Susan Wiskow, Clinical Project Manager

We’ve all heard the adage that something can be done fast, right, or cheap – pick two.

The issue, when it comes to clinical trials, is that speed, quality and working within a limited budget are all expected by the shareholders, executive management, and venture capitalists funding your clinical research trial. With these competing demands, it is critical to start your trial off correctly from the very beginning. From what we’ve seen from our industry experience as a medical device CRO working with hundreds of clients from small start-ups to Fortune 500 medical device companies, these are five of the most common and costly (in terms of time, money, and quality) pitfalls in clinical research trial design:

1. Not beginning with the end in mind. What is your objective? How do you plan to market your device, drug, or IVD product? Who will pay for it? What evidence do you need? Who are the Key Opinion Leaders (KOLs)? What value can be demonstrated over current treatments/competing products? And how will it be demonstrated? All these questions need to be addressed early. Other considerations:
Who is the customer? (Patients, Health Care Providers, Insurance Companies, Medicare)
What is standard of care in the geographies where you plan to market?

2. Adding unnecessary complexity in trial design. This is a common pitfall when a focus is to gain information that some may “want” but you won’t use. Streamline your thinking and ask: What are the essential data necessary to demonstrate safety and efficacy? What will demonstrate financial benefit/ improved quality of life to patients, hospitals and payors? FDA’s guidance for industry reveals their current thinking: According to FDA: “The right balance of premarket and post market data collection facilitates timely patient access to important new technology without undermining patient safety.” FDA believes this “will improve patient access to safe and effective medical devices that are important to the public health by improving the predictability, consistency, transparency, and efficiency of the premarket review process.” Consider this:

  • Focusing on critical data can increase quality by allowing for targeted review (less data “noise” to filter) and reduce data monitoring costs by utilizing risk-based Monitoring Plans which combine centralized data review with targeted on-site monitoring reviews, based on pre-established risk levels defined in your Monitoring Plan.
  • Leaving in too much “nice to know” data increases your study timelines, as well as the expense of designing the protocol and Case Report Forms (CRFs) and data collection from clinical sites.

3. Not incorporating Quality into the trial design. Quality systems need to be included in clinical trial designs from the very beginning. These systems then need effective management and monitoring of the key quality components throughout the trial. Consider what is essential to manage the risks before, during, and in completing a clinical trial.

4. Not recognizing areas of weakness and not investing to gain expertise that your organization currently lacks. Avoid this by training internal staff or supplementing with unbiased outside experts. The quickly changing healthcare landscape, new technologies, mobile medical apps, changing of standard of care, and economic viability make it critical for manufacturers to stay ahead.

5. Making the wrong assumptions. Errors in projecting timelines and enrollment based on poor assumptions can negatively impact the trial outcome. Assuming you will enroll subjects on time and not planning for factors that will likely jeopardize your timelines is a risky business. Site selection is critical to finding the right patient population and subject recruitment planning is needed from the start to get and keep momentum.

Our experience says that spending time upfront in thoughtful planning, investing in training your employees, and seeking outside expertise when internal knowledge or resource gaps are identified can help you to avoid these pitfalls and lead to successful completion of your clinical trial.

Contact Samantha Thrun at or 952-224-2260 to see how RCRI can help with your clinical trial design.

Recent Trends in FDA Warning Letters

by Lisa M. Olson, MBA, RCRI President

Understanding the FDA’s current hot buttons is critical to getting and keeping your products on the market. The FDA is not hesitating to let manufacturers know that after the issuance of a warning letter all other pending submissions for approval or clearance can be delayed. Not only do you have all of the costs associated with remediating and addressing the citations in the warning letter, but you also are faced with the losses associated with not having your product out in the market. This can result in millions of dollars lost. Manufacturers should be aware of these recent trends:

Most Submissions Have Multiple Findings
In a survey of all warning letters issued for medical devices from July 1, 2015 to October 16, 2015, some interesting trends emerged. Most warning letters are comprised of multiple findings, averaging five major points with several sub-points under each major category. As has been noted in the past, deficiencies in corrective and preventative action (CAPA) systems are still the leading findings. In many cases, the FDA is citing inadequate root cause evaluation, deficiencies in evaluating all related quality documents and insufficient retrospective reviews. Also amongst the top findings are deficiencies in design validation and controls.

MDR Findings Up
Lack of proper Medical Device Reporting (MDR) now rivals CAPA for the leading finding. After the implementation of the new electronic Medical Device Reporting (eMDR) requirement in early 2014, with an effective implementation date of August 14, 2015, the FDA is now clearly looking to hold manufacturers accountable for compliance with the system. In many cases, the FDA is linking MDR with complaint management. The most common citations include failure to develop and implement written processes for MDR and failures to adequately link corrections made as a result of a complaint to MDR notification.

Guidance is Included

Although the FDA is registering their concern by including the lack of correct compliance in the warning letters, they are also trying to provide guidance to manufacturers. The FDA is giving extensive guidance in the warning letters but also directing manufacturers to the reporting requirements on their website. These can be found at

Get It Right the First Time

The FDA expects detailed procedures that clearly define different reportable criteria, how information will be consistently submitted with all of the required detail, and how complaints will be investigated and assigned to MDR status if needed.

Understanding how the FDA is evaluating medical device manufacturers across the spectrum of products can help you avoid costly 483s and warning letters down the road. Spending the time to create the right regulatory and quality strategy to address emerging trends is critical to minimizing the burden from unfavorable findings. RCRI knows FDA medical device submission requirements and can help ensure yours are right the first time. Contact Samantha Thrun at or 952-224-2260 to get in touch with an RCRI regulatory expert today.

Field Support for Clinical Studies

by David France, Principal Advisor, Clinical Sciences

Field technical specialists employed by the manufacturer often support complex medical devices. When conducting clinical studies, it may be beneficial to rely on these specialists to help manage device-related testing and data collection rather than rely solely on the site personnel who are not as familiar with device operation.

Advantages v. Risks

Involving staff from the manufacturer in clinical trials can create a perception of interference or bias so study Sponsors are sometimes hesitant to use their field specialists in studies or try to quietly involve them. The FDA recognizes the value of using Sponsor personnel in studies, but also feels it is an area of concern. As a result, the FDA issued a document on their current thinking: Guidance for Industry: Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects, Document UCM187772. This document outlines their expectations for the Principal Investigator to oversee and supervise the involvement of the field team in the clinical trial and how to disclose field specialist involvement in the protocol and informed consent, if necessary.

Set Up for Success
While the FDA guidance is helpful to establish the framework of field team involvement, there are other important considerations to ensure proper study conduct and avoid potential issues with the FDA and other government agencies. Training, as well as proper documentation of field team activities and Investigator oversight of these activities, will be closely scrutinized by FDA auditors, so study processes and procedures should be designed to address field personnel involvement and these activities. Alignment of the field team and field management with the clinical team’s expectations, and the importance of conduct in accordance with GCP, will also be critical for successful involvement.

Consider Study Payments

The Department of Justice (DOJ) and Office of the Inspector General (OIG) are also subjecting clinical studies (especially post-market studies) to close scrutiny. Medical device companies have been fined millions for alleged kickbacks, in part because of questions on the amount of work the investigator did versus the field team. So, when using field personnel to conduct activities, the study payment to the investigator must be appropriate for the actual work performed. The payment should not include compensation for the field personnel work as if the site staff performed it. This is a red flag to the DOJ or OIG and may lead to further investigations.

In summary, the use of field personnel in clinical trials may be advantageous, but carries some risk that must be managed. When using field personnel, their involvement should be described in study documents, and the Sponsor must carefully consider all the ramifications and put measures in place to address them and ensure compliance while reducing any bias.

Contact Samantha Thrun at or 952-224-2260 to have RCRI help you navigate field personnel in your clinical study.

Don’t Wait to Conduct Your Clinical Audit

by Paula Kamman, Principal Advisor

Your pivotal clinical study is underway. Congratulations! Your company has scheduled product launch. The targeted date of regulatory submission is on the calendar just months after the study is scheduled to finish. There are many activities underway to all make this happen and it‘s important that consideration be given to conducting early audits of in-house clinical processes, contract research organizations, and investigational sites. So why do so many wait until end of study to conduct an audit?

Benefits of Early Clinical Audits
By end of study there is often little or no time to resolve any issues identified during an audit. An internal (or external third-party) clinical audit done early in the clinical trial life cycle lets a project team know what to expect during a formal audit and provides the time to apply what was learned for all their tasks through study end. An early clinical audit also allows the means to catch misinterpretations of study requirements, road-blocks to enrollment, and areas where insufficient documentation is being collected. And finally, an early, fresh pair of eyes will significantly reduce the time and resources required when later preparing for FDA inspections and the submission of a marketing application.

Early Audits are Proven Valuable
If you are not yet convinced an early audit is beneficial, consider FDA’s Bioresearch Monitoring metrics for 2014. Last year’s top four deficiencies noted by their team of inspectors were:¹

  • Inadequate monitoring
  • Failure to bring investigators into compliance
  • Inadequate accountability for the investigational product
  • Failure to obtain FDA and/or IRB approval prior to study initiation

Each of these deficiencies could have been caught in an early audit and stop-gap measures then put into place to stop patterns from continuing.

A review of recent warning letters further, and painfully, demonstrates how an early audit could have helped. Companies are being cited for deficiencies related to inadequate monitoring. Examples of just a few of the many warning letter findings:²

  • The monitoring report for the August 30, 2010 periodic visit was not completed until November 1, 2012, and the report had not been approved by the CPM as of September 2014 when FDA conducted its inspection.
  • Your monitoring failed to identify and correct a clinical investigator’s failure to perform protocol-required laboratory tests…… missed hematologic laboratory tests compromised subject safety.

The project team would have benefited from an early internal (or third party) clinical audit. These, again, are patterns that would have been picked up early and not later have jeopardized product launch..

Contact your internal clinical auditing group sooner than later! Or, if a third party clinical audit is what you want, consider RCRI, Inc. However you decide to move forward, internal audit or third-party audit; make sure the audit is vigorous and gives you peace of mind for your product launch.

1 Data from


Practical Considerations for UDI Implementation

Class II Device Compliance is Fast Approaching

By Carol Ryerson, Senior Regulatory Principal Advisor

The FDA regulation requiring UDI (unique device identifier) for medical devices isn’t just another task for your Regulatory Affairs department to manage. The UDI regulation¹ is changing how medical devices are tracked in the U.S. Implementation of UDI challenges manufacturers to consider labeling content throughout the product lifecycle as well as the global reporting requirements for registration and postmarket surveillance for those products. In addition, the impact of managed buyer groups in today’s healthcare world makes it essential to consider UDI not just as a regulatory project, but as a business improvement project.

The UDI September 24, 2016 compliance date for Class II devices is fast approaching. A fully integrated project team along with a detailed complete project plan are essential to successful implementation of UDI. The team needs to establish best practices to implement a UDI process and maintain it going forward.

The UDI project team should include representatives from regulatory affairs, quality, labeling, supply chain, procurement, IT, marketing, and legal. There are two main aspects to implementing the UDI regulation:

1) placing the barcode and human readable text on the label, and
2) setting up the information stream for the GUDID submission.

Regulatory and IT team members should focus on leading the tasks to meet the GUDID (Global Unique Device Identification Database) requirements. Preparing the plan to design the label, determine what products require UDI, and application of the barcode information during production should include regulatory, quality, labeling, supply chain, procurement and marketing team members. Marketing and legal will need to review contracts for contract manufacturing and supply agreements to ensure the appropriate roles for each party are defined. The entire team will need to determine customer requirements from the healthcare buyer groups who ultimately purchase your products as they will be interested in using the barcode for their own inventory management purposes.

Are you ready? RCRI experts can assist your UDI project team with preparing an implementation plan, training the executive team on the importance of compliance with UDI, and with training for your project team on practical considerations for implementation of UDI.

Contact Todd Anderson at or 952-227-2254 at RCRI for more information.

RCRI will be hosting a free Webinar this September. To receive the event announcement, signup here for RCRI News

¹UDI Final Rule


New FDA eMDR Final Rule. Are You Ready?

by Liliana Omar, Senior Regulatory Affairs Specialist
and Eric Kjellesvig, Regulatory/Quality Project Director

The final rule for the eMDR (Electronic Manufacturer’s Device Reporting) was published on February 14, 2014 and goes into effect on August 14, 2015. It requires manufacturers and importers to submit their Medical Device Reports (MDRs) to the FDA in an electronic format rather than on paper. Electronic submission of MDRs will allow FDA to use less manpower , improving both the processing and the analysis of postmarket medical device adverse event information. The sheer volume of reports submitted to the FDA warrants the use of an electronic system in order to handle reports efficiently and accurately. This change also supports timely and comprehensive data analysis to meet the agency’s efforts of communicating potential problems and ensuring the protection of public welfare.
The regulation has undergone numerous revisions since the FDA regulation governing the medical device adverse event reporting was enacted as part of the Medical Device Amendments of 1976. With the implementation of the eMDR, the agency continues moving towards a transformed postmarket program following the recommendations identified in 2006 by the Postmarket Transformation Leadership Team (PTLT).

How it Works
The implementation of the eMDR is a multistep process that may take up to six weeks before a sponsor can be ready for an eMDR submission. A key step in the process is the selection of submission application:

  • eSubmitter is a free FDA-developed software that allows the low volume reporters to enter the report information onto an electronic version of FDA Form 3500A, which can be submitted through FDA’s Electronic Submissions Gateway (ESG).
  • Health Level 7 (HL7) Individual Case Safety Reports (ISCR) is software developed in conjunction with the HL7 standards development organization to support the exchange of electronic data. This option allows for the extraction of information directly from the reporter’s database to populate an MDR, production of the appropriate data output, and transmission of the MDR to FDA’s ESG. This option allows reporters to submit individual MDRs or batches or MDRs.

In general, after the selection of the submission application, the process includes:

  1. Request of a Web Trader account
  2. Submission of a compliant submission
  3. Receipt of a production account
  4. Submission of eMDRs to the FDA

To comply with the regulation deadline, there are specific requirements for each of the steps mentioned above. Each step requires interaction between multiple parties including the agency’s ESG FDA helpdesk and other outsourced services that must be considered in implementation planning. The receipt of three acknowledgements during the test and real submission process is the indicator of a successful submission. Exceptions to the eMDR may be submitted to the FDA under 21 CFR803.19.

For more information, please contact Todd Anderson at or 952-227-2254.

Understanding the eClinicalOS™ Endpoint Adjudication Module Process

by Kiran Asrani, Senior Programmer Analyst

The adjudication of events by an independent third party, such as a Clinical Events Committee or Medical Monitor, is a common practice in medical device clinical trials. Whether for the classification of adverse events or determination of endpoints, the eClinicalOSTM (eCOS) Endpoint Adjudication Module (EAM) is a tool that can be used to support the collection of additional information on events that are important to study outcomes and analysis through electronic means rather than by a manual paper-driven process.

The EAM allows everyone in the process (sponsors, sites, coordinators, and adjudicators) real-time, online access to the study status, data, documents, and adjudication determinations based on their role. The EAM automatically compiles an electronic dossier of all required event details and source documents while allowing any authorized user to see the original materials.

The eCOS EAM allows for rapid configuration and implementation and is scalable to individual study workflows. When using the eCOS EAM, potential safety risks can be rapidly identified and decisions can be made more proactively.

The steps involved in adjudication with the eCOS EAM include:

  • An event is entered into the EDC system that requires adjudication. An electronic notification that there is an event ready for adjudication is sent to the sponsor or study administrator, as defined for the study.
  • The study administrator ensures all source documentations required for adjudication are uploaded and queries the site if any documents are missing or require clarification. Confidential information is de-identified during the upload process using a mark-up tool.
  • The event coordinator reviews the information submitted and confirms that the event information is complete, querying the site for additional information from the site if needed.
  • An event dossier is created within the EAM. The dossier contains all of the required information for adjudication, is displayed in appropriate order, and contains page labels and a table of contents.
  • The event coordinator reviews the dossier and the event is assigned to the adjudicators based on the study’s established workflow.
  • Adjudicators are notified electronically by the system that there is an event to review. The adjudicator logs into the eCOS system, reviews the online dossier, and completes the outcome form within the EAM.
  • Based on the study’s workflow, the system creates the endpoint outcome as a final record and closes the event or assigns the event to an additional adjudicator or committee for additional review.
  • When the adjudication is considered final, the system generates the endpoint outcome into the full record and the event closes.
  • The final endpoint outcome is accessed by the event coordinator, adjudicator, sponsor and committee based on their roles and rights established for the study.


1. eClinical: Endpoint Adjudication(Document version number: (Authored by Emily Malok, 22-August-2014)
2. Achieving Cost and Process Efficiencies, A Merge eClinical White Paper


The Value of Feasibility Studies – for Pivotal Studies and Beyond

by Peggy Pereda, MS, Vice President of Biostatistics and Information Management

Medical device clinical trials present unique challenges not found in other types of clinical trials. Devices have different operational issues driven by regulations and the products themselves. The challenges can include smaller sample sizes, identification of appropriate control groups, and blinding and randomization that are more difficult to handle than in a pharmaceutical trial. Furthermore, due to the nature of product development and regulatory requirements, fewer trials are performed. And when they are, they’re typically performed at much later stages in product development than in pharmaceutical trials. This means that studies have to deliver the first time.

So how does a device manufacturer ensure their study will be valuable? First, depending on the complexity and stage of the device, one, two or all three types of trials may be appropriate: feasibility, pivotal, and post-market. Manufacturers determine a trial type based on their desired goals.

  • Feasibility studies include first-in-human and pilot studies and drive iterative learning and product development. Although feasibility studies aren’t a requirement, their exploratory-stage evaluation helps to better understand how the device may perform, its intended use, and how to design an appropriate pivotal study design.
  • Pivotal trials are performed as the definitive study to support the safety and effectiveness evaluation of the medical device for its intended use. Both feasibility studies and pivotal trials support regulatory submissions,
  • Post-market trials include studies intended to better understand the long-term effectiveness and safety of the device including assessment of the occurrence of rare adverse events after regulatory clearance was given.

Feasibility Study Benefits
Feasibility studies serve an important purpose in the development lifecycle. The research nature of these studies means that additional studies can be done to explore issues and define protocols further to minimize complications with recruitment, drop-out, protocol deviations, or study variability. Because these studies don’t bear the same regulatory burden as a pivotal study, designs can be created to focus on broader areas of interest rather than on a specific safety endpoint. Generally, formal hypothesis testing is inappropriate in feasibility studies because the design of the study generates general information rather than fully-powered evaluations. Nevertheless, these studies can be used to help refine the device design or clarify the procedures necessary in training on and using the device.

A feasibility study can also offer an indication of device safety and effectiveness if the right endpoints are collected. The insights developed in a feasibility study can show where outcomes can be better measured to drive down variability and improve outcome measurement. These early assessments of outcome can also be used to guide a better design for the pivotal study. Additionally, because the feasibility study mirrors many of the same operational issues of a pivotal study, important metrics can be gathered on recruitment and drop-out rates. All of this information means that clearer protocols and operational approaches can be designed into the pivotal study from the start.

Another benefit of a feasibility study is the early performance evaluation of clinical sites and investigators. Low performing sites can be excluded avoiding problems with slow enrollment, compliance and poor data that could confound a pivotal trial. In many cases, deliverables such as clinical protocols, documents (e.g. ICF, CTA and CRFs), and databases that are generated for a feasibility study can be reused in the pivotal study with some minor refinements. This can help jump start the pivotal study kick-off and minimize expense. Later in the study, the SAS programming and structure of datasets and statistical outputs (tables, listings, and figures) may be able to be leveraged from the feasibility to the pivotal study.

With careful planning and design, feasibility studies can offer numerous efficiencies and critical information in support of later pivotal studies. A well-planned feasibility study improves the chance of a successful pivotal study when there is a lack of information available or too many unanswered questions. Spending sufficient time on designing and executing feasibility studies can speed the clinical trials process overall, saving money, and getting the product to market faster.


FDA Release Draft Guidance on Adaptive Design for Medical Device Clinical Studies

On May 15, 2015, FDA released for comment a draft guidance on Adaptive Design for Medical Device Clinical Studies. The guidance aims to provide clarity on the design and use of adaptive designs for clinical studies of medical devices.

An adaptive design is a design that allows for prospectively planned modifications based on accumulating study data without undermining the trial’s integrity or validity. Adaptive designs, when properly implemented, can reduce resource requirements and/or increase the chance of study success. The document provides sponsors and FDA with guidance on how to plan and implement adaptive designs for clinical studies when used in medical device development programs and is applicable to premarket medical device submissions including Premarket Approval Applications (PMA), premarket notification (510(k)) submissions, de novo submissions, Humanitarian Device Exemption (HDE) applications, and Investigational Device Exemption (IDE) submissions. This guidance can be applied throughout the clinical development program of a medical device, from feasibility studies to pivotal clinical trials.

The draft guidance document is available at

The comment period is open for 90 days.

To discuss how this draft guidance document may streamline or expedite your medical device Regulatory strategy and Clinical development plans, contact Samantha Thrun at or 952-224-2260 at RCRI to set up a call.

I Need to Write a CER, Where Do I Start?

Imagine sitting at a conference table with your colleagues, quietly minding your own business, when your manager looked directly at you and said, “You need to write a Clinical Evaluation Report.” Can you do it? Should you do it? Maybe…but you need to be honest about your experience, capabilities and, just as importantly, your available time.

While having some background on CERs will help you toward success, one thing to keep in mind is that having read a CER is not the same as being ready to write a CER.  Before putting pen to paper, consider the following:

  • Is there a company SOP and a CER Template? (If so, GREAT! You are ahead of the game!)
  • Do I know the intent of the CER?
  • Do I know the audience?
  • Am I familiar with the current EU guidance on CERs¹?
  • Do I understand the intended use, contraindications, risk profile, Essential Requirements, and history of the device?
  • What is an appropriate timeframe for the CER to cover?
  • Should I include information about equivalent devices? What ARE equivalent devices?
  • Do I know how to properly select key terms and run a literature search?
  • What rules should I use when I am assessing literature for inclusion and exclusion?
  • What kinds of information am I looking for in the selected articles?
  • What internal data is pertinent to the CER?
  • How about CAPAs or trends in complaints and sales?
  • How do I find out about any recent regulatory activity or significant issues in the therapeutic area that should be considered?
  • Do I understand how all of the information should be arranged, discussed, and synthesized for the assessment of clinical safety and performance AND to allow for a meaningful conclusion?
  • What is the timeline for completion? Is it reasonable?
  • Do I have enough time to complete this task?

The end goal for a CER is that it demonstrates the device complies with relevant Essential Requirements covering safety and performance and is accepted by a Notified Body. This means all of the pertinent and required information and conclusions must be presented in a full, unbiased, coherent manner informing the reader on the clinical safety and performance of the product.

Seem daunting? We can help. Through the years, RCRI has worked with many clients (big and small) to produce CERs covering a wide range of medical specialties. As can be expected, the methods and requirements of some companies are mature and detailed, while others may be in need of additional assistance and guidance. These varied experiences have provided RCRI with the vantage point to view best practices for your CER needs. We understand the power of a well-defined template in conjunction with strong and static rules and guidelines. Our team can help to interpret the MEDDEV requirements, implement strategies, and achieve the end goal of a quality CER…and a happy manager. Contact Samantha Thrun at or 952-224-2260 to have RCRI help on your CER(s) today.

¹MEDDEV 2.7.1 rev 3 (2009): Guidelines on Medical Devices – Clinical Evaluation: A Guide for Manufacturers and Notified Bodies.


FDA Releases Draft Guidance on Acceptance of Foreign Data for Medical Devices

On April 22, FDA released for comment a draft guidance document. The document is intended to articulate FDA’s policy of accepting scientifically valid clinical data from foreign clinical studies in support of premarket submissions for medical devices. It describes special considerations that apply when using such data; such as applicability of the data to the intended US patient populations and study design issues. It also provides recommendations to assist sponsors in developing data to support approval or clearance of the device in the US that are adequate under applicable FDA standards.

The document, titled “Acceptance of Medical Device Clinical Data from Studies Conducted Outside the United States,” focuses on considerations sponsors of device submissions should consider when initiating or relying on previously collected data from an OUS clinical study to support an IDE, 510(k), De Novo Petition, HDE, or PMA.

The draft guidance document is available at:

FDA is accepting comments on the draft guidance for the next 90 days. Details on how to submit comments can be found on the cover page of the draft guidance document.

To discuss how this draft guidance document may impact your medical device Regulatory strategy and Clinical development plans, contact Samantha Thrun at or 952-224-2260 at RCRI to set up a call.

Two New FDA Guidance Documents Released

FDA released two new final guidance documents on April 8th. The documents are intended to facilitate timely access to important new technology without compromising FDA’s high standards for safety and effectiveness.

The first, Balancing Premarket and Postmarket Data Collection for Devices Subject to Premarket Approval, which was written by CDRH and CBER was originally issued in draft in April, 2014. This guidance clarifies FDA’s current policy on balancing premarket and postmarket data collection during FDA review of premarket approval applications (PMAs). The guidance discusses the least burdensome approach to data collection; the consideration of benefit-risk in determining reasonable assurance of safety and effectiveness; and the role of post-market data and the factors FDA considers in determining whether it is appropriate to collect certain data in the post-market, rather than the pre-market phase. The guidance also addresses the different types of studies that may be required as a condition of approval and post-market actions. The guidance document is available at

The second, Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions, was also issued in draft in April, 2014 and written by CDRH and CBER. This guidance introduces a new, voluntary program for certain medical devices that demonstrate the potential to address unmet medical needs for life threatening or irreversibly debilitating diseases or conditions and are subject to premarket approval applications (PMAs) or de novo requests. The guidance discusses the Innovation Pathway, the role of post-market data for Expedited Access for Premarket (EAP) devices subject to PMA, and the expedited access pathway. The guidance also discusses how to request expedited access, the criteria for expedited designation, and FDA’s possible responses. The guidance document is available at

To discuss how these new guidance documents may streamline or expedite your medical device Regulatory strategy and Clinical development plans, contact Samantha Thrun at or 952-224-2260 at RCRI to set up a call.

Organizing and Managing Clinical Events Committees

by Jill Cernohous, Senior Principal Advisor, Clinical Affairs

A Clinical Events Committee (CEC) is established to provide a standard, systematic, independent assessment of clinical endpoints for a study. This is especially important for studies that cross multiple geographical regions with varying clinical practices. For maximum effectiveness, the committee should consist of at least three practicing physicians with expertise in the therapeutic area of the study. It has been demonstrated that adjudication decisions can vary among individual CEC members; however, when utilizing a full committee of at least three members, greater consistency can be obtained and the need for intra and inter-observer variability assessments is minimized.¹,² Preferably, the selection of members and the management of the committee should be delegated by the sponsor to an independent academic research organization or contract research organization to maintain the independence of the committee and reduce bias.² If these responsibilities are retained by the sponsor, a detailed pre-specified procedure addressing these issues should be created and implemented.²

CEC members should not be involved in the clinical study (including the Data Safety Monitoring Board or Steering Committee) and the process for reviewing events should be clearly outlined in the CEC Charter.² Every attempt should be made to provide the CEC with all data critical for the adjudication of the event in a timely manner but when conclusive evidence cannot be obtained, decisions may be based on medical expertise. Thus, the processes of the CEC should be continuously monitored to ensure the basis for all decisions is documented and consistently applied throughout the study or program.² Untimely adjudications and/or events in which the CEC was presented with insufficient information have been cited in Form FDA 483s.

1. Petersen JL, Haque G, Hellkamp AS, Flaker GC, Mark Estes NA 3rd, Marchlinski FE, McAnulty JH, Greenspon AJ, Marinchak RA, Lee KL, Lamas GA, Mahaffey KW; MOST Clinical Events Committee. Comparing classifications of death in the Mode Selection Trial: agreement and disagreement among site investigators and a clinical events committee. Contemp Clin Trials. 2006 Jun;27(3):260-8.
2. Vranckx P, McFadden E, Mehran R, Cutlip DE. Clinical event committees in coronary stent trials: insights and recommendations based on experience in an unselected study population. Eurointervention. 2012 Jul 20;8(3):368-74.


Transferring Responsibility to a CRO – Medical Device Trials in the U.S.
What Do You Need to Know?

Companies initiating medical device trials in the U.S. face unique challenges compared to pharmaceutical trials when working with contract research organizations (CROs): the medical device Code of Federal Regulations (21 CFR Part 812)1 do not define or delineate responsibilities for CROs. Therefore, medical device companies are held responsible for any regulatory noncompliance by a CRO2. In addition, the ICH Guideline for Good Clinical Practice (ICH-E6 Section 5.2A)3 indicates that even though a medical device company may transfer trial-related duties to a CRO, the ultimate responsibility for the quality and integrity of work product resides with the medical device company.

Because of this, it is extremely important to select a CRO that implements quality assurance and quality control systems and practices

In addition, ISO 14155:2011(E)4 section 8.3, outlines further details regarding the medical device company’s responsibilities. These responsibilities include verification of existing standard operating procedures (SOPs) as well as adherence to written SOPs at the external organization (e.g., CRO).

But mere SOPs are not enough to guarantee a successful study or project. The goal is to select a qualified CRO with an experienced project manager that can proactively manage and communicate risk. The CRO and project manager must have the ability to walk in the company’s shoes at each decision point and process involving the company’s product and trial. Ultimately, the company is responsible and hence this requirement is crucial.

If the CRO is not providing options or solutions while identifying the risks of each option, one needs to consider if the right vendor was selected. Confirm that the CRO has a quality system that gives freedom to efficiently manage the company’s trial(s) without burdensome activities that add cost but no value. Consider where your cost efficiencies or “bang for your buck” lie-is it performing low priority/low risk tasks or is the effort towards high risk/high priority items? Engage the CRO to collaborate and build quality into processes from the beginning of a project. An external set of eyes trained in ISO 149715, can help conduct a proper risk assessment that includes all aspects of risk-from device failure to risk-based monitoring, managing external data sources from devices or software systems, or safety data review and documentation.

Engaging a CRO in trial planning and implementation early is prudent. A CRO involved during the protocol development stage can help determine feasibility of the study design and can help identify what data are critical to test the hypothesis. Furthermore, the CRO can identify processes upfront at this stage to insure audit readiness.

It is important to accept the CRO as part of company team to insure a successful working relationship.

At RCRI, we always welcome “get to know you” sessions and even mock scenarios (e.g., tell me how you would go about this, if I were to work with you). Open your mind to building trust with us as your CRO to make everyone successful. Your success is our success!

For more information, please contact Patrice Horwath at RCRI or 952-595-5585.


  1. FDA Protection of Human Subjects, 21 CFR Part 812 (2014).
  2. FDA Compliance Program Guidance Manual, Chapter 48: Bioresearch Monitoring (2011). Retrieved January 21, 2015 from
  3. International Conference on Harmonisation, Guideline for Good Clinical Practice (1997).
  4. International Organization for Standardization, Clinical Investigation of Medical Devices for Human Subjects (2011).
  5. International Organization for Standardization, Application of Risk Management to Medical Devices (2007).

Top Deficiency Reasons Resulting in FDA 483s

The FDA recently published it’s FY 2014 Inspectional Observation Studies which lists the top reasons for deficiencies cited in 483s.

Here is the list you don’t want to be on. Lack of or inadequate:

  • Procedures
  • Complaint procedures
  • Purchasing controls
  • Process validation
  • Written MDR Procedures
  • Documentation
  • Nonconforming product procedures
  • Design changes
  • Quality audits
  • Investigation of device failures
  • Training
  • Management review
  • Device Master Record (MDR)
  • Final acceptance procedures
  • Environmental control
  • Design history file
  • Device History Record (DHR)

All medical device manufacturers should know that these are major areas of concern and should have a comprehensive Quality Management System and corresponding workflow processes in place to avoid having to respond to a FDA Form 483, post-inspection. You only have 15 days to respond to a 483, but often the follow-up activities can require significant additional time and resources to effectively address the 483 concerns.

RCRI can help evaluate your risk for a 483, create appropriate corrective action plans, and help respond to 483s.

Contact Todd Anderson at to speak with regulatory and quality experts who can help to keep you off this list and catapult your manufacturing success.

Is Your Clinical Study BIMO Ready?

The Bioresearch Monitoring Program (BIMO) is FDA’s inspection program designed to ensure the protection of human subjects and the quality and integrity of data submitted to the agency. Because FDA’s BIMO inspections can occur at any time during a clinical trial, it is imperative for biotech manufacturers to be prepared from the very beginning of a clinical study.

Below is an overview of common FDA’s BIMO inspection findings as well as our top 10 recommended tips on how to best prepare for a sponsor BIMO inspection AND for BIMO inspection at a clinical research site.

FDA’s most common BIMO inspection findings: (Metrics provided on FDA’s website, available to the public):

Sponsor/ Monitor/ CRO Findings:

  1. Inadequate monitoring
  2. Failure to bring investigators into compliance
  3. Inadequate accountability for the investigational product
  4. Failure to obtain FDA and/or IRB approval prior to study initiation

Site Investigator Findings:

  1. Failure to follow the investigational plan and/or regulations
  2. Protocol Deviations
  3. Inadequate recordkeeping
  4. Inadequate accountability for the investigational product
  5. Inadequate communication with the IRB
  6. Inadequate subject protection- failure to report AEs and informed consent issues

Being prepared before an inspection occurs is the best thing you can do to reduce your regulatory risk. How do we do this?

Top 10 Ways to Prepare for Sponsor Inspections:

  1. Develop strong SOPS that are realistic to adhere to and support compliance with regulations and Good Clinical Practices (GCP).
  2. Hire qualified monitors and train them well on study medications, the device, and follow-up tests. Also, ensure adequate time is allocated for monitoring.
  3. Start with the end in mind. Set up a Clinical Trial Master File structure to include and track all essential documents.
  4. Don’t “allow” protocol exceptions, except where required for subject safety. Update the protocol, where appropriate.
  5. Timely review and response to study documents: monitoring reports, EDC, IRB/ EC approvals and conditions, Regulatory body letters, etc.
  6. Conduct internal audits of site monitoring, core labs, and the sponsor early in the study and promptly address any issues that are identified.
  7. Consider processes to secure compliance such as a Corrective and Preventive Action (CAPA) plan.
  8. Maintain and disseminate Decision Log or FAQ from start of trial to document questions about protocol requirements.
  9. Manage device accountability from the beginning of the trial through study completion.
  10. Upon notice of inspection: Train involved staff on BIMO audits before the inspector arrives, notify upper management, notify all sponsor employees about the BIMO inspection and provide behavior expectations.

Top 10 Ways to Help Sites Prepare for Inspections:

  1. Have a team of well-trained monitors to identify issues early-escalate as needed- and support the sites. Conduct internal audits of monitors early in the study and at points throughout time. Stratify findings by risk and address appropriately.
  2. Review 100 % of original Informed Consent Forms/ HIPAA: approved version used, and all pages present, signed by real subjects and investigators prior to any study procedures.
  3. Review Regulatory Binder checklists to identify and collect missing documents.
  4. Corrective and Preventive actions- secure prompt compliance. Document all communications and steps to resolution.
  5. Provide thorough training and tools to sites on the protocol and retrain as needed.
  6. Verify that all annual study renewals were sent to the IRB / EC prior to expiration, and there was no lapse in approval.
  7. Ensure the investigator followed the protocol and subjects and can medically justify reasons for deviations in best interest of subject. For example, “had to hold a study medication to prevent bleeding.”
  8. Verify serious adverse events are reported per the protocol and applicable regulations.
  9. Ensure monitors verify investigational product accountability at every on-site monitoring visit to identify and resolve issues early.
  10. Upon notification of BIMO inspection, offer to send a team for on-site support or provide remote support for site during the entire inspection.

RCRI recently presented a Webinar on BIMO Readiness. Content is available here: RCRI Resources.  Click on Past Webinar to access the BIMO Webinar resources.  Each tip stated above is discussed.

For more information on how to prepare your clinical study to be BIMO inspection ready, contact RCRI at 952-746-8080. RCRI offers a variety of consultation services to meet your needs including SOP development, trial monitoring, training, auditing and inspection support.

When Should You Begin Preparing for an FDA Inspection?

As soon as your clinical trial has begun enrolling subjects. Conducting early audits of in-house clinical processes, contract research organizations and investigational sites allow issues to be identified and resolved real-time. Addressing issues real-time can significantly reduce the time and resources required at the conclusion of a trial when preparing for upcoming FDA inspections and the submission of a marketing application. In addition, early audits demonstrate to FDA due diligence in ensuring data integrity and the adequacy of human subject protection, and may identify systemic issues that could jeopardize the outcomes of your clinical trial if not detected and corrected in a timely fashion. Such systemic issues may include misinterpretations of study requirements, road-blocks to enrollment, and areas where insufficient documentation is being collected. Lastly, FDA has proposed the implementation of early inspections, conducted during the IDE stage, of select clinical studies. While still considered in the early planning phase, FDA has conducted a limited number of early inspections to obtain an assessment of the over-all conduct of the clinical trial, including the adequacy of human subject protection. Contact Todd at to begin your preparations.

When Should You Update a Clinical Evaluation Report (CER)?

Clinical Evaluation Reports (CERs) should be considered for updating whenever a change is made to the Risk File, new clinical information becomes available, or routinely (as per your internal SOP). For example a design change, a newly identified use risk, an expanded indication for use leading to new/expanded use population, or updated label content all represent situations in which an update to the device CER may be required. Contact Todd at to find out how to make your CER updates.

The Final Regulation is Out! FDA’s Unique Device Identification (UDI) System

September 22, 2013
On September 20, 2013, FDA released the UDI final rule and the Draft Guidance on the Global Unique Device Identification Database (GUDID). The medical device industry needs to be aware this final rule has many significant changes from the proposed rule: For starters:

  • Direct marking is not required for implantable medical devices.
  • Devices within a kit are now exempt from bearing a UDI.
  • Existing inventory, where the finished device is labeled prior to the compliance date, does not have to be destroyed or relabeled.

Many other details of the 160-page final UDI rule and the 59-page guidance document will greatly impact medical device and combination product manufacturer practices.

How will the final rule influence your organization and your devices? Do you know which deadlines will apply to different devices within your portfolio? Do you know the exceptions you can use? For more information, please contact Todd Anderson at

Are you ready for UDI? Or is your UDI plan on summer vacation?

August 13, 2013
The Unique Device Identification System final rule was expected to be published several weeks ago. Don’t let your organization think that rule delay means rule death! Use this bonus time to educate your organization, finalize your plan, look at label stock forecasts, and set up a smooth transition. Once the rule is published in the coming weeks, the deadline clock starts ticking. If your UDI plan is sipping lemonade in the shade get it back on track!

RCRI has Experts in Unique Device Identifier Regulations
RCRI can help you meet the new FDA rule for Unique Device Identification System. You need to know how and when to change your device labeling and how to submit required information to the Global Unique Device Identification Database (GUDID). This FDA initiative is focused toward decreasing medical errors, facilitating recalls, and providing an easy source of device identification information. Contact Todd Anderson at to help you navigate the UDI requirements.

Understand EMC Compliance and its Coming Changes

August 1, 2013
The Importance of EMC Compliance
Electromagnetic Compatibility (EMC) is a concern for medical devices that utilize electronics for all or part of their functions. But with recent advancements in wireless technologies, assuring safety has not been as straightforward as it was in the past. One standard often used to evaluate EMC is IEC 60601-1-2 which is typically used for CE Marking of devices. Additionally, FDA has its own scientific basis for EMC compliance that can include different requirements than IEC 60601-1-2. Typically manufacturers are required to demonstrate compliance to IEC 60601-1-2, other IEC standards and/or FDA requirements before their devices can be placed on the market or used in clinical studies.

EMC is a regulatory concern because of documented injuries and deaths related to medical devices acting abnormally when they’re used in the presence of various radiated and conducted electronic emissions. While compliance to IEC 60601-1-2, and other electrical safety standards, does not assure full safety in all conditions, these standards have been used as a basis for device design and regulatory approvals.

Now the EMC Landscape is Changing
Recently FDA and other regulatory bodies have expressed concern that the current standards have not kept pace with changes in technology and scientific understanding of EMC. Current EMC testing is based on the nature of devices and subjects them to known radiated and conducted emissions to simulate exposures that may occur when the devices are being used.

There is growing interest in revising standards used for regulatory approvals based on experience with many types of devices and research in EMC environments. One proposed change is in process for IEC 60601-1-2 scheduled for publication later this year. Additionally, FDA has recently started using additional information requests for EMC data provided in device submissions that go beyond the requirements of IEC 60601-1-2 3rd Edition.

The types of changes that are coming to manufacturers and designers include: increased field strengths, basing field strengths on the basis of use environments, changes in expectations for how devices must perform in the presence of electromagnetic interference, increased expectations for EMC risk analysis, and changes to how EMC risks or controls are described in labeling.

Medical device designers and manufactures are strongly encouraged to monitor these changes when developing new or revising devices. For more information on how EMC Compliance affects you, contact Russell Olson, Senior Principal Advisor, at or 952-224-2251.

FDA Holds Stakeholder’s Meeting to Discuss 510(k) Device Modification:
Deciding When to Submit a 510(k) for a Change to an Existing Device.

June 18, 2013
In response to a Congressional request, FDA held a meeting 13 June 2013 to discuss circumstances under which a new 510(k) needs to be filed for a change to an existing device. FDA, Health Canada, a notified body (BSI), as well as industry (AdvaMed) and consumer (National Research Center for Women and Families) representatives presented arguments for or against changes in the 1997 guidance for when to file a new 510(k).

The discussion focused on the value of risk-based or design control-based decisions, the need for clinical data, and the need to establish what constitutes a significant change. Unfortunately, the question was asked repeatedly as to what problem(s) the FDA has identified in the current process to justify changing the 1997 guidance. Frequently the discussion shifted from deciding when to submit a 510(k) for a change to an existing device to alternative topics FDA would like discussed.

Ultimately, FDA proposed the use of critical specification as a method to determine when a change would require a new 510(k). A straw poll taken during the meeting indicated that industry was not in favor of the critical specification approach to decision making. FDA also proposed a risk-based stratification and potential periodic reporting to substitute for a 510(k) submission for a change to an existing device. Although the discussion was informative, no conclusions were reached between FDA, non-industry stakeholders, and industry stakeholders as a result of the meeting. For more information, contact Mary Beth Henderson, Vice President of Regulatory Affairs and Quality Systems and Senior Principal Advisor, at

FDA Submission Stalled? What Do You Do Now?

May 23, 2013
Getting a ‘Not Substantially Equivalent’ letter or other disappointing response from FDA is a little like a getting a flat tire on the highway. One minute, you’re cruising along, expecting to get to market on time. The next minute you’re facing a new challenge. You can watch competitors speed by or take action.

One tool you might use to get yourself back on the road is the new FDA guidance document entitled, ‘Center for Devices and Radiological Health Appeals Processes.’ It was issued on May 17, 2013, along with draft guidance ‘Center for Devices and Radiological health Appeals Processes: Questions and Answers About 517A.’ You’ll find them both at

Just as you wouldn’t put the spare tire on before the lug nuts are taken off, there are certain steps in the process that need to happen. If you are in dispute with your lead reviewer, first try to resolve it with that individual before taking it to the next level. You may wish to utilize a 10.75 appeal, which is a request for supervisory review under 21 CFR 10.75. Keep in mind that time is of the essence. An appeal should be made within 30 days after the significant decision is made. What is a ‘Significant Decision?’ The draft guidance of ‘Questions and Answers’ proposes the term include not substantially equivalent decisions, IDE disapproval, and other key decisions.

Second, a petition could be the best tool for the job. There are a variety of types of petitions discussed in the guidance document, including a Citizen Petition, Petition for Administrative Reconsideration of Action, and Petition for Administrative Stay of Action.

Third, hearings are another option. See the new guidance document or give RCRI a call for roadside assistance. Contact at Todd Anderson at

RCRI Innovation Spotlight

April 3, 2013
RCRI recently participated in FDA’s first Industry Day for its FDA Broad Agency Announcement (BAA) held at the Agency’s White Oak Campus in Silver Spring, MD on March 25th. The purpose of the industry day was to explain to interested parties the purpose and mechanics of FDA’s new BAA contracting mechanism. Used by NIH for many years, this is the first time FDA has used this mechanism. FDA’s intent is to encourage participation by science and technology based firms and educational institutions in meeting FDA goals for innovative ideas and approaches for regulatory science.

Kicked off by Dr. Frank Weichold from FDA’s Office of Critical Path and Regulatory Science and Innovation, the day included presentations by nearly all FDA Centers, introducing the key topic areas for which the FDA hopes to solicit project proposals. As explained by Dr. Weichold, FDA needs to become an agency that “engages.” FDA believes that collaboration through partnerships can promote innovation through synergistic problem solving.
Contact Todd Anderson, RCRI Director of Business Development at 952-224-2254 or

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