February 19, 2020

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

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 UseRegulations 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, 2020For 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 effectiveMEDDEV 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  • Clinical experience: published and/or unpublished reports on other clinical experience of either the device in question or a similar device for which equivalent to the device in question or a similar device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 expertisepeople, 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 internetbased 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 bneeded, or time is of the essenceTo 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

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

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. 


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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December 17, 2019

What is the Role of the Quality Overall Summary (QOS) in BLA and NDA applications?

Author: Suzanne Broussard, PhD 

The Food and Drug Administration (FDA) is promoting the Quality Overall Summary (QOS) as a powerful tool to promote effective communication between regulators and sponsors of drugs as well as a tool that can substantially impact the efficiency and quality of the regulator’s assessment. The QOS is required for all New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs) and Biologics License Applications (BLAs), thus the QOS has significant potential to impact the regulatory review process for getting marketing approval. 

The QOS summarizes all quality-related information in the application. As part of Module 2 of the electronic Common Technical Document (eCTD), the QOS links to the sponsor’s larger body of data in Module 3. The QOS is expected to provide the regulator with sufficient information to understand the contents of Module 3 in a high-level overview. However, FDA suggests that many sponsors are falling short of these expectations and are not fully utilizing this powerful tool as an effective guide for regulators to assess the application.  

In order to help sponsors prepare a QOS that facilitates the regulators’ understanding of the product’s risks as outlined in the NDA, ANDA, or BLA applications, the FDA’s Office of Pharmaceutical Quality (OPQ) published a white paper that provides practical tips for putting the quality pieces together and explaining what regulators would like to see in the QOS: A Regulators Perspective on the Quality Overall Summary: Putting the Pieces Together.

The QOS provides the sponsor with an opportunity to summarize the key aspects of the new drug or biologics application, explain specific items for the regulators to consider, and extend to post-approval comments. Yet, a poorly written QOS requires regulators to spend significant effort to “understand, summarize, collate, and interpret quality data from module 3 (Figure 1).  

Figure 1. There can be a disconnect between applicants and regulators regarding the communication of quality data and its impact on the assessment. Currently, it takes time and/or communications (e.g., information requests) to fully understand the quality of data and its significance in an application.  

The FDA’s white paper describes key considerations for creating a highquality QOS to ensure regulators have a good idea of the potential risk to the patient and the control of this risk in the commercially manufactured product. The 3 key considerations are: 

  1. Identifying the main risks to the patient from a product quality perspective. 
  2. Understanding how the proposed overall control strategy controls and/or mitigates the identified failure modes of the manufacturing process or products.
  3. Acknowledging potential considerations for the quality assessment of the submission.

These key considerations are designed to help regulators evaluate the potential risks related to quality, and their potential impact on the patients, in a summarized benefit and risk assessment. Indeed, the FDA is encouraging sponsors to explain important aspects of the new drug or biologic such as how the product was formulated, and how the risk might impact the patients. Further clarifications on the 3 key considerations are provided in the FDA’s white paper.

Writing these technical documents to concisely convey information is challenging and you might want to consider these project management and quality control tips when putting you QOS together. These tips might just help improve your QOS, which will reduce the number of information requests from the FDA and thus decrease your NDA / BLA review time.

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December 3, 2019

Manufacturing and Immunogenicity are Key Considerations for Approval of Biological Products: BLA vs NDA


Author: Suzanne Broussard, PhD 

Biological products warrant special regulatory consideration because of their complex nature and susceptibility to variation during manufacturing. Biologics are not only complex in their physical structure, they are produced from living organisms and thus pose a myriad of potential issues in the manufacturing and isolation processes that all have the potential to induce immunogenicity. Regulations for developing a biological product take these potential risks into consideration 

In this second piece evaluating BLA and NDA, we focus on understanding some of the nuances between biologic and drug development. See the first BLA vs NDA blog for a more focused look at regulations.   

Manufacturing of Biological Products is Inherently Riskier than Production of Drugs. 

The manufacturing processes for biological products are different than processes for pharmaceuticals. Traditional drug products are typically manufactured using pure chemical substances that are sterile, and the end products can be relatively easily analyzed. On the other hand, biological products are made from living organisms and are much more complex in nature — making product analysis very difficult. Indeed, most biological products are defined by the manufacturing processes used for production. The manufacturing process and manufacturing facilities are so crucial to biologics that “purity” is part of the agency’s requirements for licensing. 

The FDA strictly controls changes to the manufacturing processes that evolve during the development of the biologic, as well as after licensing. Biologics are much more sensitive to process changes than are drugs – even a small change in the manufacturing process can result in an adverse change in the biological product. This is why biological products are regulated under the PHS Act. Initial manufacturing procedures are detailed in the IND application and then modified as needed throughout the IND phase of clinical evaluation and through the final BLA submission. 

Modification to manufacturing may be needed to scale up from pilot to full-scale production or to improve efficiency; this can include any changes in equipment, facilities, handling, or storage and testing of cell substrates that may be required.  

Changes to the biologic’s manufacturing process, equipment, facilities, or handling have the potential to affect the products identity, safety, purity, and potency. Therefore, any changes to production must be brought to the attention of the regulatory authorities, and the FDA will use its “comparability” ruler to determine if additional studies are required to support the license application 

Comparability Testing 

FDA issued two guidance documents to help manufacturers understand the concept of comparability and gracefully jump through the hoops to achieve a license to sell their therapeutic biologics.  

The Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products “describes those steps that manufacturers may perform and which FDA may evaluate to allow manufacturers to make manufacturing changes without performing additional clinical studies to demonstrate safety and efficacy.”  

The Q5 Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process is “intended to assist manufacturers in the collection of relevant technical information that serves as evidence that the manufacturing process changes will not have an adverse impact on the quality, safety, and efficacy of the drug product.” 

If changes are needed to an approved license, the Changes to an Approved Application: Biological Products Guidance for Industry is available on the FDA website.  

For any situation, the FDA encourages sponsors to consult with them prior to implementing changes.  

Clinical Development of Biologics Must Include Assessment of Immunogenicity 

There are unique clinical considerations for biologics since they are derived from living organisms. Either the biologic itself or impurities from manufacturing could trigger an immune response with potentially disastrous consequences. Therefore, the clinical development of biologics must include the assessment of immunogenicity. This differs from manufacturing and isolation of drug molecules which do not typically pose an immunogenicity threat.  

In January 2019, FDA announced that the final industry guidance on immunogenicity testing is available: Immunogenicity Testing of Therapeutic Protein Products–Developing and Validating Assays for Anti-Drug Antibody Detection.  

This guidance provides: 

  • Recommendations to facilitate industry’s development and validation of assays for assessment of the immunogenicity of therapeutic protein products during clinical trials 
  • Applies to assays for the detection of anti-drug antibodies (ADAs) and may also apply to some peptides, oligonucleotides, and combination products on a case-by-case basis 
  • Includes recommendations regarding the development and validation of screening assays, confirmatory assays, titration assays, and neutralization assays 
  • Finalizes the revised draft guidance for industry entitled “Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products” issued in April 2016 and includes a revised title 


The biggest differences between the approval of therapeutic biological products or drug compounds center around the complex nature of biologics and the many challenges that occur in their manufacturing. Because biologics come from living organisms, immunogenicity is always a concern. The FDA’s regulatory landscape is complicated and always changing. We are happy to help your organization stay abreast of the current regulations and ensure your BLA and NDA applications are on target and on time. 

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