1. DISCLAIMER: The views and opinions expressed in this presentation are those of the author and do not represent the perspectives of any organization.

2. Presenter: Kanchana Iyer April 1-2, 2019
Integrating critical-to-quality (CTQ) metrics into medical device product and process design
Today I will be discussing with you this topic: Integrating critical to quality metrics into medical device product and process design. And no, I will not be defending a master’s thesis today. I say that because I was looking at the agenda and saw all these really cool titles and mine reads
Presenter: Kanchana Iyer
April 1-2, 2019

3. Summary History of medical technology (in particular medical devices)
Approaches U.S. FDA has used to address scientific and regulatory challenges stemming from medical technology innovation
Integration of quality metrics into FDA oversight of medical products with examples
Conclusion and Final Thoughts
Today I will be discussing with you a history of medical technology over the last two decades. My discussion will be more focused on medical devices, however, there is absolutely applicability across all products. I also want to go over the approaches regulatory agencies, in particular US FDA has used to address some of the scientific and regulatory challenges. I want to go over the evolution of those approaches and how over the last ten years or so the approach has been to push not only regulatory compliance but integrate quality metrics as well. I will give you a couple of very recent examples of these approaches and conclude the presentation with a recap of the main points and some of my own final thoughts.

4. Question: Which amendment to the FD&C Act was unanimously authorized by the House and Senate?
Safe Medical Devices Act of 1990 
Food and Drug Modernization Act of 1997
Medical Device Amendments of 1992
Prescription Drug Amendments of 1992

5. Question: Which amendment to the FD&C Act was unanimously authorized by the House and Senate?
Safe Medical Devices Act of 1990 
Food and Drug Modernization Act of 1997
Medical Device Amendments of 1992
Prescription Drug Amendments of 1992

6. Food and Drug Modernization Act of 1997
Nov 9, 1997: FDAMA signed by unanimous vote
Nov 21, 1997: President Clinton signed bill into law
FDA issued numerous guidance documents to address technical issues
One major goal: Improved collaboration between manufacturers and FDA
In November 1997, Food and Drug Modernization Act of 1997 (FDAMA) was signed by unanimous vote and subsequently put into law. It was truly a formative law that would really set the stage for the regulation of prescription drugs, medical devices, and biologics.
In order to successfully implement FDAMA, the FDA was charged with addressing the technical issues that were covered in the act. You may recall that right around this time FDA had issued numerous reports and guidance documents.
One of the reforms that was introduced as part of FDAMA and that would become a recurring theme in the years and decades to come is this one here:
Improved collaboration between manufacturers and the FDA throughout the approval process;
The intent of this being that by streamlining FDA procedures and expediting the approval process, FDAMA reflects Congress' intention for FDA to work with industry in expanding public access to safe and effective medical products.

7. Next Steps
FDAMA 1997 introduced a very important objective: Improved collaboration between manufacturers and FDA
Medical device technology changes over the last two decades
FDA response to medical device technology changes
So FDAMA was introduced back in What I would like to go over with you next is an assessment of the goal: Improved collaboration between manufacturers and FDA, and the improvements that have taken place.
But in order to do that we really need to look back at the last 20 years. Again I want to reiterative that much of the discussion today will focus on medical devices but there is certainly cross-industry applicability. We’ll be looking at how the landscape of innovation and technology has changed and what kind of impact that has on on FDA actions and its response to this landscape.

8. Quickly evolving technologies
FDAMA exempted most Class I and many Class II devices from premarket requirements
More than 1000 product codes added between
Drug eluting stents (DES) is a good example of a quickly evolving technology
DES presented scientific and regulatory challenges
FDAMA 1997 exempted most Class I and many Class II devices from premarket review. So interestingly enough the volume of submissions, in particular 510ks, had gone down, but FDA was seeing newer and more complex devices. In fact, a CDRH 510(k) working group report from 2010 indicates that more than a thousand product codes were added between
I think one very good example of a technology that has been prevalent over the last 20 years is the drug eluting stent. And with it came very interesting scientific and regulatory challenges.

9. Drug Eluting Stents 1980s: metallic stents
1990s: rapid development of metallic stents
Restenosis rates of metallic stents were high
2000s: introducing a drug to the stent reduced restenosis rates
2002: introduction of FDA Office of Combination Products
The concept of stenting began in the late 70s and early 80s with metallic stents. Then in the 90s improved iterations of metallic stents were being developed very rapidly. However, a major problem persisted with these devices- that being that restenosis were still pretty high. So in the new millennium it was discovered that introducing a pharmacological agent was helpful in reducing restenosis rates. FDA listened to the feedback from industry and worked to develop tools to bring innovative products to market faster. For the review of drug eluting stents, FDA developed the Office of Combination Products in 2002.

10. Drug Eluting Stents 2002 and 2003: first DES approved by FDA
Use of DES over time led to blood clots
Number of DES-related product recalls were rising
2007: FDA advisory panel to focus on late stage thrombosis caused by DES
the first DES were approved in 2003 and 2004.
Then over time it was revealed that new safety concerns were emerging related to the development of life threatening blood clots that were linked to DES. Other manufacturers were also developing newer DES technologies. The number of DES product recalls were going up.
Then in 2007 an FDA advisory panel convened that focused on safety issues related to late stage thrombosis.

11. Drug Eluting Stents
Advisory panel found more than 60% off-label usage of DES
Advisory panel concluded that benefits do outweigh risks- especially against bare metal stents
Future of DES is promising
Their review of the data determined that more than 60% of the uses of Drug Eluting Stents were off-label. The panel concluded that when drug-eluting stents are used within their approved indications, the benefits do outweigh the risks. especially in comparison with bare metal stents.
Despite these scientific and regulatory challenges, the future for drug eluting stents looks promising even today. We will come back to this shortly.

12. Precision Medicine
1990: Human Genome project began- sequencing of all genes in human beings
2003: full human genome sequence published
Precision medicine: tailoring treatments based on individual’s genetic makeup and lifestyle
2017: FDA approved record number of “personalized” medicine products
2018: FDA issued two draft guidances on Next Generation Sequencing and IVD standards
Let’s take a look at a couple of more quick examples of cutting-edge technologies and the Agency’s response to these:
The Human Genome Project (HGP) started in 1990 was an international, collaborative research program whose goal was the complete mapping and understanding of all the genes of human beings. A Nature paper published in February 2001 with the sequence of the entire genome's three billion base pairs some 90 percent complete. The full sequence was completed and published in April 2003.
Since then, we’ve seen tremendous progress in the area of precision medicine, or “personalized” medicine, which is tailoring of treatments based on an individual’s genetic makeup and lifestyle. In 2017 FDA approved a record number personalized medicines from drug products, direct-to-consumer genetic tests, and companion diagnostics.
FDA has issued two draft guidances on next generation sequencing-based IVDs and use of standards for these diagnostics. Although more understanding and definition of the regulatory oversight of these novel technologies is required, these are certainly leaps and bounds.

13. Medical Software
2006: more than half of medical devices on U.S. market contained software
Software development presents new challenges for regulators
Applicable standards
Human factors
Software updates/maintenance
FDA published guidance over the last decade to provide recommendations for industry
FDA has increased its focus on integrating cybersecurity measures into premarket requirements
A functionality that was integrated into more and more medical device technologies into the new millennium was software. In 2006, it was reported that over half the medical devices on the US market involved software in their function. Innovation in the information technology (IT) industry has led to digital solutions in every industry from healthcare to business and beyond. FDA recognized that the development of software comes with its own unique set of challenges such as product risks, use of and types of standards, human factors, and software updates and versioning. These then impact the way in which these products are regulated. FDA partnered international regulators and has published numerous guidance to help industry address the challenges that encountered during medical software development. In recent months FDA has focused more on providing recommendations to industry on methods to address cybersecurity, especially during early design and development stages.

14. Recap…
Medical technologies quickly evolving over the last 20 years have led to scientific and regulatory challenges
FDA has analyzed data and listened to feedback from the public and devised methods to address these challenges
These approaches have required collaboration between FDA and industry
FDA has recognizes that these approaches could be better defined
We’ve just taken a look at the evolution of some key technologies over the last 20 years. We’ve also taken a look at some of the ways that FDA has responded to these technologies. FDA has collected and reviewed data from cleared and approved devices, they’ve listened to feedback from the public and industry, and have devised methods to address regulatory challenges, streamline processes, and have a better overall understanding of the innovative technologies. Do these examples, however, represent the reform as described in FDAMA that is, improved collaboration between manufacturers and FDA? I would say that that, indeed, collaboration between FDA and industry took place. And that communication was probably more frequent than in the past due to the increased complexities of the technologies. But I think we can all agree that the processes used by both FDA and industry were iterative in nature, where each iteration was a result of a previous learning. I also believe that although this collaboration is a step in the right direction, it could be further improved. And I believe FDA, too, has been cognizant of this. I will next discuss with you a few examples of these improvements. But first, let’s take a few moments to ponder over this situation.

15. Manufacturers Response
Manufacturers face competition and increased pressure to obtain regulatory approvals
Quality management systems (QMS) are in place to address product and process improvements
Improvement of processing and production are foundations of Quality Assurance and Quality Control
As a manufacturer, what must it be like when technology is developing so rapidly? They are faced with increased competition and increased pressure to deliver a finished medical product that can be submitted for regulatory approval. Product and process improvements are part of the and are inherent in the quality management systems that we put into place.
We’re all familiar with the terms lean, six sigma, continuous improvement, value stream mapping. These philosophies have historically been used in the context of improvement to processing and production. And these serve as the foundation for the engineering and management disciplines of Quality Assurance and Quality Control found in most organizations today- including the medical device industry.

16. Question: What concept is demonstrated by the accompanying figure?
Failure mode and effects analysis 
Optimization
Root cause analysis
Critical-to-quality

17. Question: What concept is demonstrated by the accompanying figure?
Failure mode and effects analysis 
Optimization
Root cause analysis
Critical-to-quality

18. Critical-to-Quality Developed as part of Six Sigma
Customer requirements are translated to critical-to-quality elements
Critical-to-quality elements: elements considered to be critical to determining success of a project/product/process
Identification of these elements is part of quality assurance
Due to difficulty in identification of these elements, manufacturers often use controls to catch product defects
Specifically the tool is a critical to quality tree and they are used to identify critical to quality elements. The concept of critical to quality is not a new concept. CTQ trees were originally developed as part of six sigma. It starts with customer requirements, which are translated to CTQ elements, which are elements considered critical in determining the success of the project/product/process. by using a tool such as a CTQ tree, you can drill-down specific and measurable requirements that you can use to improve performance.
Identifying these elements can be extremely tedious and more often than not it is difficult to capture all of these within the first several iterations. Therefore, manufacturers often rely on controls such as inspection to catch product defects. And because inspections can be quite costly and onerous, it’s often done as one of the final steps in a process.

19. Critical-to-Quality
2011: FDA reported 70% of device recalls were due to design, material, or process failures
Utilize a proactive, CTQ management approach- this is challenging
FDA recognized that a mechanism for addressing quality requirements should be implemented
FDA reported in 2011 that 70% of medical device recalls were traced to failures in product design, supplied materials, or manufacturing processes. The costs in correcting defects can be high and often, the approach to correcting these defects tends to be reactive. A better alternative would be for the manufacturer to be proactive- for example, rather than depending on periodic inspection steps throughout the process, utilize CTQ management to identify critical elements of the device during the design phase. This can, however, become a very cumbersome task, especially when in addition to meeting design and quality requirements, a manufacturer is also concerned with meeting all regulatory and compliance requirements. FDA has recognized this and has developed mechanisms for addressing quality requirements. These mechanisms are examples of how FDA has made further progress toward improving collaboration between FDA and industry.

20. Case for Quality
2011: FDA launched Case for Quality to focus more on quality
2017: CDRH launched Voluntary Medical Device Manufacturing and product Quality Program Pilot
Uses model initially developed by Capability Maturity Model Integration (CMMI) Institute
Medical device manufacturers are able to measure their capability to product high quality, safe, and effective devices
Major objective is so FDA can modify its submission and inspection requirements based on these quality metrics
In 2011 FDA launched the Case for Quality, an initiative to shift the medical device industry from a focus on regulatory compliance to a focus on quality maturity. Following an in-depth review of device quality data and feedback from FDA and industry stakeholders, it became clear to FDA that compliance was not enough to ensure quality. Since then, FDA has established mechanisms for increased stakeholder engagement In December 2017, CDRH launched the Voluntary Medical Device Manufacturing and Product Quality Program Pilot. This program utilizes a maturity model refined in collaboration with the Capability Maturity Model Integration (CMMI) Institute, MDIC, and regulatory and industry partners. This maturity model is leveraged as a resource for medical device manufacturers to measure their capability to produce high quality, safe and effective devices. This measurement can then be used by to drive targeted continuous improvement activities. The objective of the model is so that FDA can modify their submission requirements and routine inspection plans as needed based on these quality metrics of the organization.

21. Case for Quality Premarket Approval Critical-to-Quality Program
Goal: streamline premarket approval process while assuring the firm’s quality management system includes controls and critical-to-quality characteristics
Promoting quality in device design and manufacturing
Another pilot program that is part of FDA’s case for quality is the premarket approval critical-to-quality program. The goal of this voluntary program is to streamline premarket approval process while assuring the firm’s quality management system includes controls for features and characteristics considered to be critical to S&E of the device. FDA believes that proactive engagement with PMA applicants on development of critical-to-quality characteristics and controls for their device and a focused inspectional approach will promote quality in device design and manufacturing.

22. 21st Century Cures 2016: Signed into law by President Obama
Objective: accelerate development, innovation, and market activities for medical products
Digital Health Innovation Action Plan- reimagining of FDA’s approach to regulating digital health products
Pre-certification program: potentially replace premarket submission for certain products
FDA completed its first version of the program- will be tested by the pre-certification program participants in 2019
A recent piece of legislation further builds upon the facet from FDAMA on improving collaboration between industry and FDA such that its design will accelerate the development, innovation, and market to the public of medical products. This is the 21st century cures act and was signed into law on Dec 13, 2016.
I am going to highlight two major initiatives that resulted from this law. We’ll see their relevance to what we’ve already discussed.
Here is the first: certain medical software were down classified. FDA has since reimagined its approach to regulating digital health technologies. The Digital Health Innovation Action Plan outlines its plans for fostering digital health innovation while continuing to protect and promote the public health. FDA intends to develop a pre-certification program that would replace the need for a premarket submission for certain products and allow for decreased submission content and faster review of the submission. A pilot program was initiated that allowed participants to become pre-certified based on demonstration of a culture of quality and organizational excellence based on objective criteria such as exceling in software design, development, and validation. Out of the initial data collection phase of the pilot program, FDA developed the first version of the program that will be tested by the pre-cert pilot participants in the first version will assess SAMD de novo requests against quality scorecard criteria and compare these request with previously reviewed software submissions. The goal is to a have a more tailored, streamlined regulatory pathway that leverages organizational quality and product performance across the entire lifecycle of the software product.

23. 21st Century Cures
Breakthrough Devices Program- provide patients and health care providers timely access to breakthrough devices
Speed up development, assessment, and review of these devices while preserving the requirements for premarket approval
Manufacturers can interact with FDA experts and receive feedback in a timely manner
Feb 2019: Drug eluting balloon catheter received breakthrough device designation
The second initiative is the breakthrough devices program.
The goal of the Breakthrough Devices Program is to provide patients and health care providers with timely access to these breakthrough devices by speeding up their development, assessment, and review, while preserving the statutory standards for premarket approval.
The Program offers manufacturers an opportunity to interact with the FDA's experts through several different program options to efficiently address topics as they arise during the premarket review phase, which can help manufacturers receive feedback from the FDA and identify areas of agreement in a timely way.
A manufacturer may request Breakthrough Device designation by submitting a "Designation Request for Breakthrough Device" Q-Submission.
And falling in line with our discussion on drug eluting technologies an innovative drug eluting balloon catheter received breakthrough device designation just a month ago.

24. Conclusion
FDAMA 1997 introduced a goal for improving collaboration between FDA and industry
Since then, medical technology has greatly evolved leading to scientific and regulatory challenges
FDA has been cognizant of these challenges and have devised mechanisms for clarity and more recently, integrating quality metrics into assessments
Manufacturers already integrate quality metrics as part of continuous improvement activities, but should work towards integrating into design and development activities
I have just presented to you some examples of technologies that have come about since the implementation of FDAMA back in one of its key objectives was improved collaboration between FDA and industry throughout the approval process. We have seen examples of the type of responses and interactions that took place as a result of the regulatory challenges brought about by these innovative technologies. Many of these interactions involved FDA providing clarity to industry in the form of guidance or providing recommendations based on certain scientific challenges that were observed. More recently FDA has devised initiatives that integrate quality metrics into the assessments in addition to the meeting regulatory requirements. Manufacturers already utilize quality metrics into their process and product improvements, but there is certainly a need for integrating these into the initial design and development processes

25. Final Thoughts We are in a very exciting time right now
Regulatory affairs professionals are being challenged by the new technologies they will have to submit to FDA
Industry needs to be responsive and proactive to keep the momentum going
From the beginning of development activities, keep regulatory requirements, quality metrics for product and processes at the forefront
I think this is a very exciting time to be a part of medical product development and innovation. I think it’s particularly exciting for someone like myself in the RA profession because of all the regulatory challenges that come with these innovations. And as an RA professional I believe it is critical now, more than ever, for people like me to work closely with the developers of these technologies and really understand the science and intricacies of the technology. This is the only way we can better communicate this back to FDA and other regulatory bodies. With the programs and initiatives that FDA has going on, I think FDA is encouraging this. They want to improve collaboration and want us to engage more with them as the subject matter experts. But in order to prevent stagnation of these initiatives and delays in getting innovative products to market, things that are constantly in the backs of our minds, then we need to be more responsive to these calls for participation in pilot programs, for input into developing scorecards. We need to be more engaging with the divisions and branches we work with. And now with changes to a TPLC organization across all FDA offices, there is that potential for better and more consistent communication that I think we feel is missing at times. If we as the manufacturers keep the regulatory requirements and quality metrics of the products and processes at the forefront from the beginning, then I believe this approach will set us up for success in the long run.

26. Thank you!
Questions?