The introduction of MDR caused a major transformation in the medical device industry. Manufacturers continue to grapple with all elements of compliance, but clinical evaluation presents unique challenges. RQM+ is committed to helping clients navigate these challenges with former notified body leaders who understand what reviewers are looking for when evaluating clinical evidence.
We interviewed one of our team members to get a behind-the-scenes look at the review process to help you gain a better understanding of what an MDR clinical evaluation roadmap is, the steps involved in creating a thorough roadmap, and the top challenges the roadmap addresses.
Introduction to Dr. Jaishankar Kutty
Dr. Jaishankar Kutty, known as “Jai” among his colleagues, is the Vice President of Clinical Regulatory Services at RQM+. He joined the team from BSI, where he spent seven years in CE marking technical and clinical leadership roles with specific expertise in cardiovascular product development.
While at BSI, Jai trained and developed a structural heart team of multiple technical experts that have successfully CE marked some of the most innovative cardiovascular technologies. His comprehensive cardiovascular device experience spans:
- Product development
- Advanced biomechanical testing
- Preclinical model development
- Biological safety evaluations
- Physician training
- FDA interactions
- Implantable device commercialization
Throughout the transition to MDR, the RQM+ Clinical Regulatory Services team, with the recent addition of Jai, has refined the processes we use to help clients tell the whole clinical story, leading to a faster review process. In this interview, Jai shares the challenges he’s seeing with manufacturers’ presentation of clinical evaluation data, along with advice for increasing success of notified body reviews including clear documentation of a “clinical evaluation roadmap.”
Interview with Dr. Jaishankar Kutty
What is a clinical evaluation roadmap?
When a notified body reviewer starts the review process, before diving into the details, they create a mental roadmap of the big picture based on a clear understanding of the:
- Context of the ongoing review
- Market (and regulatory) history of the device
- State of the art (SOTA), prior device review experience
- Prior relevant industry experience
By evaluating the instructions for use, intended target patient population, and goal of the CER (new CE marking, design change, etc.), they can create boundaries of the review and set an internal calibration for the expectations regarding risk and areas of interest within the clinical evaluation.
Why should manufacturers proactively provide a clinical evaluation roadmap?
The first round of reviews is an opportunity for manufacturers to build trust with their reviewers. Including a clear roadmap is an excellent way to start that relationship on the right note and avoid discrepancies between the reviewer's perceived roadmap and what you intended. If you have a clear roadmap, you will build a solid rapport with the reviewer in terms of calibrating him or her to [the] expected quantity and quality of clinical evidence within the first 15 minutes of review. This enhances your chances of a positive recommendation with minimal questions.
Additionally, although it is essential to follow the primary guidance documents, if this is all you do, it’s not enough. If you start with those documents and try to fill in all those sections, you are neglecting to tell the overall story, and it is easy to get lost in the weeds and focus on too many details.
What you need is the high-level summary upfront to tell that story: the clinical evaluation roadmap. It is this story that will greatly help the reviewer draft their positive recommendation toward new or continued CE marking.
For example, if there are any specific promotional claims being made for the device, make sure they are clearly stated. Most reviewers cannot readily find this information and have to dig for it. By having a roadmap clearly spelled out, you can traverse the journey from claims to objectives to the quantity of the data to gaps in the clinical evidence to a PMCF plan, and so on. It’s important for manufacturers to know that reviews under MDR are not the same as they used to be. If there are any gaps, the reviewer will most certainly find them, so it’s most efficient to acknowledge them upfront and describe your plan for addressing them.
→ Notified body expectations for biological equivalence is another area that still has a lot of uncertainty surrounding it. Need help with your biological equivalence strategy? Read Dr. Kutty’s white paper, Biological Equivalence & the EU MDR.
From a notified body perspective, how does the roadmap help?
The clinical evaluation roadmap basically helps align with the reviewer's thought process and builds trust and confidence in the reviewer's mind about the overall quantity and quality of data within the first 15 minutes of the review. If drafted correctly, the roadmap not only builds confidence but also provides all the items necessary to draft a positive recommendation for certification right at the onset of the review. This is critical since reviewers have limited time available to understand the entire story, draft relevant questions, and most importantly, draft a positive recommendation for new or continued CE certification.
Submissions are often thousands or even hundreds of thousands of pages long.
With a clear roadmap, a reviewer can start with a high-level overview of the content and follow a path that makes it easier to determine whether the device meets that intended use with an acceptable benefit-risk. No reviewer ever reads the CER from cover to cover.
They jump around in an effort to help build a cogent story based on the GPS in their mind that's based on an understanding of SOTA, prior device review knowledge, and previous industry experience. A roadmap also helps identify gaps and show how the manufacturer intends to address them.
What is the best way to tell a compelling story to a notified body when it comes to clinical evidence?
Reviewers have limited time, so it’s important to tell your clinical story as clearly and succinctly as possible. The executive summary should be one or two pages that tell the clinical story of the device.
Limit the use of jargon and connect as many dots as possible so the reviewers don’t have to do it on their own.
Try to read your executive summary through the eyes of the reviewer and include anything that will make their job easier. Reviewers are looking for an unambiguous story and clear objective evidence of why they should approve your device—so give it to them.
What are some of the most common mistakes you see?
Many manufacturers include a boilerplate summary section in their CERs. It might provide a high-level overview, but it doesn’t connect with the reader as the reviewer has most likely read something like this every day of the week. The key is to think like a reviewer and tell a story that will resonate with them.
A clear definition of the target patient population is a critical starting point that many submissions lack. Additionally:
Many manufacturers do not provide a quantified benefit-risk analysis covering every indication and target patient population, which is a requirement under MDR.
When it comes to performance objectives, using the right methods to set appropriate acceptance criteria tends to leave a lot to be desired. In the case of multiple indications and device variants, there are always challenges with data stratification to cover all bases.
Finally, we continue to see that most people in regulatory affairs positions have been trained to give as little information as possible. With the transition to MDR and the true need for parts of the design history file and clinical development plan to be part of the technical documentation, the days of providing the bare minimum are gone.
What should manufacturers know about reviewers?
Notified body reviewer competency requirements, competency maintenance, and competency assessment requirements are very rigorous and an assiduously ongoing process. The person reviewing your device will have relevant technical and clinical experience and an appropriate level of expertise that qualifies them to review a certain device type. You should assume that they have deep knowledge of the subject matter. It’s possible that they have already reviewed several other similar devices and are therefore familiar with the literature, and they will likely know if something is missing or omitted. However, at the same time, they can make decisions only on the basis of what is clearly presented to them for review.
Many reviewers do not read a submission from beginning to end but bounce around various sections to help fill in their mental roadmap. To do this, reviewers want to know the quantity and quality of the clinical evidence presented. There is an incredible amount of information for them to review and very limited time. It also takes two to four times longer to review than previously under MDD.
The more you can do to make it easier for reviewers to understand your clinical story, the faster and more successful your review will be.
What are the top questions you get from clients related to the MDR clinical evaluation process?
There are three key areas that manufacturers find challenging when it comes to clinical evaluation under MDR: state of the art, defining clinical benefits, and literature appraisal.
State of the Art
Manufacturers often mistake state of the art for being the gold standard.
It is actually what is commonly accepted as the standard for providing adequate care and an acceptable balance of benefit and risk to the patient population.
The primary factors that inform decisions around the state of the art include:
- The risk assessment and biological safety evaluation
- Safety and performance outcomes from all therapies and from the same device technology/clinical condition
- The ability to show compliance with the most updated versions of the horizontal and vertical standards
- The ability to align with standard of care requirements in terms of the latest physician guidelines
If your SOTA is shaky, your whole CER is shaky, so take the time to get a good understanding of this when starting the submission process.
Defining Clinical Benefits
Under MDR, there is a laser focus on clinical benefits. This is the starting point for the benefit-risk analysis and will be used as the basis for evaluating all future device changes.
You have to consider both the direct and indirect benefits—we recommend creating a table to outline these.
From there, drive all of the data analysis to an actual quantified benefit-risk ratio.
It’s also important to remember that clinical benefits do not only include clinical-related patient measures—they could also refer to devices that enable better diagnosis and patient management per Article 2, definition numbers 52 and 53. For example, an imaging device that helps place a stent delivers a clinical benefit that should be included in the benefit-risk analysis in terms of enabling successful completion of the index procedure. Notified bodies are also pushing for a specification of clinical benefits in the IFU per GSPR 23.4 (c).
Literature Appraisal Best Practices
Many manufacturers copy and paste abstracts from publications that meet their search criteria. Unfortunately, this is not enough.
Reviewers want an understanding of the quality of clinical evidence that has been reviewed from each publication and an assessment of its relevance to your clinical evaluation and the target patient population. They want to see a critical analysis of the literature—covering aspects of regulatory and legal compliance of the studies reported, statistical considerations, scientific validity of the conclusions, and impact to the S&P objs of the subject device—along with a summary of the data appraisal and data evaluation process, not just a presentation of the content.
Do you have any examples to share?
In general, biological equivalence is one of the most challenging aspects of MDR for many manufacturers because they assume that the FDA’s 510(k) model for substantial equivalence is applicable. However, it is quite different from the definition in the EU regulations.
Manufacturers often provide a table comparing the subject device to the equivalent device, indicating a range of the same or similar parameters. While this might be sufficient for a 510(k) review in the U.S., it is not enough information for notified body reviewers to make a determination for equivalence in the EU. This table is where an EU reviewer’s process might start, but it is not where it ends. For the parameters that are deemed similar, a notified body reviewer wants to understand everything that is nonidentical. Therefore, the reviewer focuses a majority of their time on understanding items that are not identical but [are] similar and items that are different in terms of the potential risk and the impact of the same on the clinical data leveraged from the equivalent device.
To reiterate, a good equivalence rationale will go beyond the factors that are the same or similar and also focus significantly on what is different—and the associated risks of those differences—because this is what is most important to a reviewer, especially when determining biological equivalence and aspects of clinical equivalence. This requires detailed engineering drawings of the two devices, which are often missing from submissions. This omission prompts a round of questions that could have been avoided if the drawings had been included in the first place.
For manufacturers of cardiovascular devices, one of the most common pitfalls is the assumption that accessory devices—guide catheters, guide wires, balloons for stents, and so on—that have achieved CE marking in the past based on equivalence will be quickly accepted under MDR. Although reviewers know that these devices have been on the market for a long time, they still want to see relevant clinical data for these devices, and there is no grandfathering under the MDR.
Many manufacturers have been relying too heavily on literature that does not directly address the subject device, which is resulting in more rounds of questions and longer review times—even for cardiovascular accessory devices that have been on the market for decades.
How RQM+ Can Help
The RQM+ clinical regulatory services team supports our clients through a unique combination of clinical and regulatory expertise. Led by Dr. Amie Smirthwaite, former global head of clinical compliance at BSI, the team provides an accurate assessment of sufficient clinical data and effective strategies for filling the gaps to enable CE marking to MDR.
When we create CERs, we focus on balancing regulatory and business objectives and providing notified bodies with a cohesive story and relevant data to support it. The results are fewer questions from reviewers, less investment of resources, and faster time to market.
If biological equivalence is one of the stumbling blocks you have encountered, read our Biological Equivalence & the EU MDR white paper to learn more about strategies you can use with your devices.