March 10, 2020

How Can a Systematic Literature Review (SLR) Help Prevent Common Pitfalls in Meeting the Elementary Requirements of Clinical Evaluation for MEDDEV 2.7/1 revision 4 Clinical Evaluation Report (CER)?

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Author: Suzanne Broussard

Checking off list on time

Performing a methodologically sound literature review in the early stages of product development, as well as in the later stages, can help reduce most of the inadequacies highlighted by the European Commission in section A6 of MEDDEV 2.7/1 revision 4.  Section A6 provides examples of studies that lack scientific validity for the demonstration of adequate clinical performance and/or safety.

Here are the seven areas highlighted in section A6 of MEDDEV 2.7/1 revision 4 that manufacturers tend to have the most problems in proving scientific validity:

  1. Lack of information on elementary aspects: This includes missing elementary requirements of the clinical evaluation such as methods, results of clinical studies, observed undesirable side effects, and details on the intend-to-treat population.
  2. Numbers too small for statistical significance: This may include publications and reports with “inconclusive preliminary data, inconclusive data from feasibility studies, anecdotal experience, hypothesis papers and unsubscribed opinions.”
  3. Improper statistical methods: The examples given are centered around 3 scenarios. 1) No corrections applied to multiple comparisons. 2) Calculations and test were used that are based on a certain type of distribution data while the distribution is not tested, not plausible, or data were not transformed.
  4. Lack of adequate controls: It is possible to cause bias or confounding in single arm-studies and in other studies that do not include appropriate controls in the following situations: results based on subjective endpoint assessments, endpoints subject to natural fluctuations, studies with subjects that are likely to take effective co-interventions, other influencing factors, or when publications indicate there may be variables and ill controlled factors.
  5. Improper collection of mortality and serious adverse events data: In situations where mortality studies and other studies that may result in serious outcomes, there must be procedures in place to “investigate serious patient outcomes, numbers of subjects lost to follow-up, reasons why subjects leave the study, and the results of sensitivity analysis should be fully disclosed in reports and publications.”
  6. Misinterpretation by the authors: Conclusions must be in line with the results section.
  7. Illegal activities: All clinical investigations must be in compliance with local regulations, as well as designed, conducted, and reported in accordance with EN ISO 14155 or a comparable standard, and the Declaration of Helsinki.

In a recent post, we talked about one of the most challenging areas of the CER: Defining Measurable Safety and Performance Endpoints

The first deficiency listed, “lack of information on elementary aspects,” can obviously be improved using a robust systematic literature review. Defining the evaluation criteria is the first step in performing a methodologically sound systematic literature review, and these sections would then fall into place. For example, one criterion would define the clinical study methods, while other criteria might include clearly defining results to be included, undesirable side effects, and the intended-to-treat population. A scientifically sound approach and well-organized data management plan can bring all the clinical data together and allow for a thorough understanding of where the device is in the process of obtaining an CE marking.

Less obvious is how a methodologically sound systematic literature review can help with some of the other CER deficiencies. Let’s look at the three points in a devices lifecycle in which clinical evaluation is undertaken: development of the medical device (section 6.2.1), initial CE-marking (section 6.2.2), and updating the clinical evaluation (section 6.2.3).

The systematic literature review can be an effective tool early in the development of the medical device for gap analysis and determining State-of-the-Art. Once all the clinical evidence is gathered it is much easier to see if the publications and report documents have conclusive preliminary data or if further clinical data is required before moving forward with CER submissions. And, closely evaluating the complied data makes it easier for manufacturers to note statistical methods in the supporting data, and the potential of bias.

Of course, not all inadequacies can be addressed with a systematic literature review, such as improper collection of mortality and serious events data that rely on a different process for review. It is always important to collaborate with your organization’s regulatory authorities or a regulatory specialist to make sure you are complying in these areas.

Following leading practices and presenting clinical data in a straight-forward manner helps manufacturers be in good position to help regulatory agencies not to have to say No to your CER submission. Lack of organization and transparency can create a cycle of generating responses to regulatory agencies and delays getting devices to market.

Systematic literature reviews can help you find gaps in information that may be needed for inclusion in the CER, as well as putting your best foot forward by strongly providing sufficient clinical evidence for the evaluation of safety and performance of the device. Regulatory agencies expect this level of compliance. We can help you meet the challenge. We are experts in this area. Check out our recent webinars to better understand the process.

Systematic Literature Review to Help Meet MDR Requirements

Systematic Literature Review to Empower Data-Driven Decision-Making

At Criterion Edge, we are experts at generating methodologically sound systematic literature reviews and state-of-the-art reports to ensure your CER is ready for review by notified bodies. And, we can help ensure the scientific validity is adequate and document the methods we use for data collection. Talk to us about running a systematic literature review for you. 

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February 19, 2020

Clearly Defining Measurable Safety and Performance Endpoints in Clinical Evaluation Reports (CER) is a Real Challenge for Medical Device Manufacturers

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Author: Suzanne Broussard 

All medical devices sold in Europe must have a Clinical Evaluation Report (CER), and specific and measurable safety and performance endpoints are paramount for an acceptable CER. However, many small medical device manufacturers are struggling to adequately define and subsequently document measurable safety and performance endpoints, especially in the literature review, to support an evidence-based evaluation.  

The newest regulations for medical devices, Medical Device Regulation (MDR) 2017/745 and MEDDEV 2.7/1 revision 4, set high standards for confirming safety and performance when using the device according to the manufacturer’s Instructions for Use. Regulations under the old MDR and MEDDEV were not as demanding, and manufacturers are not accustomed to the current systematic process of CER evaluations.  

These relatively new requirements for clinical evaluation extend to manufacturers trying to get new products into the European market, as well as those that are already selling medical devices. Safety and performance are central components of the evidence-based evaluation process for obtaining and maintaining CE Marking for MDR 2017/745 and MEDDEV 2.7/1 rev 4, and medical device manufacturers are expected to be in full compliance by May 26, 2020. For manufacturers that already have products on the market, the CER must be updated throughout the product lifecycle.  

For more information on the role of CERs in obtaining CE Marking for legal marketing in the European Union (EU), see Criterion Edge’s article What role does the CER play in getting a Medical Device Approved for Marketing in the EU? 

Systematic literature reviews (SLRs) are a big part of the CER. The ultimate goal of the CER is to provide sufficient clinical evidence that the device achieves its intended purpose and is safe and effective. MEDDEV 2.7/1 rev 4 Section 4 defines evidence-based as: 

  • Clinical studies: clinical data from clinical investigations of the device concerned; or 
  • Existing data: clinical investigation(s) or other studies reported in the scientific literature, or a similar device for which equivalence to the device in question can be demonstrated, or 
  • Clinical experience: published and/or unpublished reports on other clinical experience of either the device in question or a similar device for which equivalent to the device in question or a similar device for which equivalence to the device in question can be demonstrated.  

Note that this list is comprised primarily of endpoints that need to be generated by performing methodologically sound systematic literature reviews.

Clearly setting safety and performance objectives in the review of scientific literature proves to have its own special challenges. Conducting systematic literature reviews requires expertise, people, and time.  

  • The individual or team of evaluators should possess knowledge and expertise of research methodologies (including clinical investigation design and biostatistics), information management, regulatory requirements, and degree and experience equivalence (MEDEV 2.7/1 rev 4 Section 6.4).  
  • It is often difficult to find experienced personnel that meet all the requirements to perform the clinical evaluation. 
  • Performing systematic literature reviews takes time, lots of time! 

A systematic literature review is much different than an internet–based literature review for a scientific manuscript. It requires a clear and methodologically sound search strategy coupled with a robust literature search. Every decision needs to be documented. 

There are many circumstances in which using experts in some areas of CER preparation can fill in gaps where expertise may be needed, or time is of the essence. To determine if hiring a consulting expert to facilitate timely and expert CER development, ask your organization these questions. 

Does your team meet all the criteria for preparing the clinical evaluation?  

Does your team know how to document the methods used to generate systematic literature reviews?  

Are they familiar with what aspects to consider when determining relevance? 

Do they have the time to perform systematic literature reviews? 

Criterion Edge is an expert at CER preparation, generating a systematic literature review, and determining state of the art of medical devices based on systematic literature reviews. As leaders in this area, we have given 3 webinars for our customers; one we sponsored for the Regulatory Affairs and Professional Society (RAPS) community. These webinars can be accessed on our main page or by following these links:

Systematic Literature Review To Help Meet MDR Requirements 

Systematic Literature Review: How to Empower Data-Driven Decision Making 

State of the Art Literature Review for EU MDR Compliance: How to Get It Right 

In addition, our whitepaper State of the Art: Best Practices and Literature Review Using DistillerSR provides detail on how we perform systematic literature reviews and document all processes.  

We share these resources to help medical device manufacturers develop strong CERs with measurable endpoints that ultimately make the review process smoother and get products to market faster.

“These rigorous principles for performing systematic literature reviews are now mandated by global regulatory authorities.”

Laurie Mitchell, President Criterion Edge

At Criterion Edge, we are experts at preparing CERs and can ensure your reports and systematic literature reviews are methodologically sound, and safety and performance are measurable.  Our medical writers are experienced at setting measurable objectives for safety and performance and performing methodologically sound systematic literature reviews. Contact us for more information on how we can help your organization with preparing CERs and systematic literature reviews.  

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January 24, 2020

Systematic Literature Review to Help Meet MDR Requirements

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Get a copy of the slides from this webinar or click to watch the recording.

Companies face constant pressure to meet the increasing regulatory expectations and demands for information. Data identification through Systematic Literature Review (SLR) supports critical regulatory functions throughout the company, from MDR requirements through IND submissions.

In this session, we review:

  • How the use of published data can support regulatory expectations
  • When to conduct a systematic literature review
  • Best practices for conducting a methodologically-sound SLR
  • The tools and technology available for SLR
  • Real world case studies about leveraging SLR

Sign up for future webinars here.

This webinar is co-hosted by Criterion Edge and RAPS.

Criterion Edge has the expertise and resources to do literature reviews for many types of documents. Ready for a free consult?

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January 14, 2020

High-level Overview of the 4 510(k) Guidance Documents for Premarket Notification by the FDA that Benefit Both FDA Reviewers and Device Sponsors

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Author: Suzanne Broussard, PhD

The Premarket Notification 510(k) Program is the pathway used by manufacturers of low- to moderate-risk devices that are substantially equivalent (SE) to a device already on the market in order to begin the process of legally marketing in the United States. The Food and Drug Administration’s (FDA) release of 4 updated 510(k) guidance documents on September 13, 2019 was intended to both help streamline the FDA reviewer process and help sponsors save time and resources.  

The 510(k) Program is required for any device that does not need a Premarket Approval Application (PMA) and does not meet the specified exceptions. The sponsor must demonstrate that a device is at least as safe and effective, e.g. SE, to a legally marketed device that is not subject to PMA. The 510(k) submitters must receive a SE order from the FDA in order to market the device in the U.S. The SE determination typically takes 90 days, although that time is decreasing. Indeed, faster response times are one of FDA’s anticipated outcomes of these 4 guidance documents. The FDA hopes another outcome will be more guidance for the sponsors to streamline their submission process which will save time and resources. These outcomes are prevalent throughout the document and summarized in the FDA statement that 510(k) submissions “address the recommendations of an FDA guidance document should be easier to prepare by manufacturers and for FDA to review.” 

FDA Definition of a Legally Marketed Device 

Legally marketing a device based on a claim of substantially equivalent to devices legally marketed prior to May 28, 1976 (preamendments devices) requires the manufacturer to submit a Premarket Notification 510(k). The majority of premarket devices use the 510(k) program; hence, it is important to clarify FDA’s definition of a legally marketed device.  

A Legally Marketed Device must fit one of these 4 criteria: 

  • A Device that was legally marketed prior to May 28, 1976 (preadmendments device), or 
  • A device which has been reclassified from Class III to Class II or I 
  • A device which has been found SE through the 510(k) process 
  • A device that was granted marketing authorization via the De Novo classification process under section 513(f)(2) of the FD&C  

Note that the legally marketed device(s) used for equivalence is commonly referred to as the “predicate.”  

Here is a summary of the four 510(k) guidance documents FDA released to streamline the process and a bonus FDA webinar on Special 510(k)s. 

Refuse to Accept Policy for 510(k)s

The Refuse to Accept Policy for 510(k) Final Guidance Document contains nonbinding recommendations and supersedes the “Refuse to Accept Policy for 510(k)s” issued early in the same year (February 21, 2019). The newest Refuse to Accept (RTA) policy includes an early review that will inform the submitter within the first 15 calendar days after receipt of the 510(k) submission of issues against specific acceptance criteria with information as to the administrative completeness and if not, includes identification of missing element(s). This guidance includes checklists of which items a sponsor should include in their 510(k) submission if they want to ensure their application is reviewed in a timely fashion.  

Abbreviated 510(k) Program Final Guidance Document

The Abbreviated 510(k) Program is used by the FDA as an optional approach to the traditional 510(k) Program to demonstrate SE in premarket notifications by using guidance documents, special controls, and/or voluntary consensus standards to facilitate review of 510(k) submissions. This review relies on summary reports that “briefly describe and summarize the testing performed to support the submission as recommended in relevant guidance document(s).” 

Device manufacturers can choose the Abbreviated 510(k) pathway if the submission relies on one or more of the following: 

  • FDA guidance document 
  • Demonstration of compliance with special controls for the device type, either in a device-specific classification or a special controls guidance document; and/or 
  • Voluntary consensus standard(s) 

Format for Traditional and Abbreviated 510(k)s

The FDA provides specific guidance for the general framework of Traditional 510(k)s and Abbreviated 510(k)s in the Final Guidance Document. These formatting guidelines do not apply to Special or other premarket 510(k) submissions. FDA believes that using this Formatting Guidance will conserve both FDA and industry resources as well as facilitate timely 510(k) review. 

Special 510(k) Program

The Special 510(k) Program is designed to provide an optional and potentially expedited pathway to legally market “well-defined device modifications where a manufacturer modified its own legally marketed device and design control procedures produce reliable results that can form, in addition to other 510(k) content requirements, the basis for substantial equivalence (SE).” 

The Special 510(k) Program: Guidance for Industry and Food and Drug Administration Staff provides the FDA’s current thinking and intent on premarket notifications that are appropriate for review as a Special 510(k). This Final Guidance Document describes an optimal pathway for certain well-defined device modification for manufacturers that modify their own legally marketed device and clarifies the types of technological changes that are appropriate for review including changes to design, labeling, and indications for use. 

Bonus! 

To further help clarify the Special 510(k) Program, the FDA recently held a webinar to discuss the Special 510(k) Program Final Guidance, and to answer questions. It is packed with useful information for those considering filing for the Special 510(k) Program including eligibility factors and examples of devices appropriate and those not appropriate for a Special 510(k). The recording of the webinar can be accessed here. 

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[WEBINAR] How to Assess Your CER for MDR Readiness Part 1: State of the Art, Safety & Performance Criteria, Equivalence and Systematic Literature Review

Join our President, Laurie Mitchell, on April 29, 2020, at 11AM PST / 2PM EST to align your CER with some key MDR requirements. This live webinar will help you assess your CER and identify possible gaps for mitigation before submission.

Attendees are eligible for a free consultation and scan of their CER (or CER template). Spots are limited – click to register for this free webinar.