By Mark Abdoo
February 24, 2023
(Remarks as prepared for delivery with slide presentation)
Thank you for that introduction. And thank you to the Indian Society for Clinical Research for inviting me to speak this morning and for its work to bring together diverse stakeholders to facilitate ethical and responsible clinical research for better patient outcomes. I’m Mark Abdoo, Associate Commissioner for Global Policy and Strategy at the U.S. Food and Drug Administration. Globalization fundamentally altered the United States’ economic and security landscape and demanded significant changes in the way FDA fulfills its mission to protect and promote the health of the American people. One of those changes was placing FDA staff abroad to be the FDA’s eyes and ears. My office - the Office of Global Policy and Strategy which, among other things, oversees our four foreign offices - is a critical hub where information is collected, analyzed, and transmitted bi-directionally – from our foreign offices back to HQ and our product centers to inform policy and risk-based decision-making, and from HQ to our foreign offices to inform their engagement with stakeholders like you.
But globalization, while very relevant, is not what I’m going to speak about today. Today I’m going to speak about the FDA’s perspective on the current state of medical evidence generation – and what steps the agency and other parts of government are taking to address the issues we’ve identified.
First, some background. The FDA requires and reviews clinical data to determine whether a drug or device is safe and effective for a person to use; to study different applications for current treatments so that they will be more effective, easier to use, or decrease certain side effects; and to learn how to safely use a treatment in population groups that were not part of previous trials, such as children or pregnant and lactating mothers. As you all know, the FDA doesn’t conduct clinical trials. We regulate them and promote what we call good clinical practices, or GCPs. This includes ensuring that clinical trials are adequately designed and well-run, and that the rights and safety of participants are considered and protected. Many offices across the FDA play a role in our oversight of clinical trials – this includes investigators in my office and in the Office of Regulatory Affairs who conduct on-site inspections, data audits, and remote regulatory assessments designed to monitor all aspects of the conduct and reporting of FDA-regulated research, whether it’s conducted in the United States, India, or elsewhere.
The COVID-19 pandemic demonstrated that much more needs to be done to create a clinical trial ecosystem that can conduct critical research needed to respond to a communicable disease outbreak or public health emergency. FDA scientists assessed clinical development efforts worldwide, focusing on data from ongoing interventional clinical trials for potential COVID-19 drugs registered through ClinicalTrials.gov and the World Health Organization International Clinical Trial Registry Platform. The study found that only 5% of the over 2,800 registered COVID-19 clinical trials were randomized and adequately powered to yield actionable results for identifying effective treatments. Of these trials, many failed to enroll sufficient numbers of participants, as the studies were dominated by independent groups running small investigational studies competing for the same patient population, sometimes with overlapping study objectives. The institutions and networks that were conducting these trials tended to implement their own research protocols and captured and stored their own data.
The lack of a coordinated approach slowed the development of actionable information, which in turn delayed the availability of vaccines, therapeutics, and diagnostics, while also impeding efforts to track Coronavirus surges or outbreaks. Without a mechanism to coordinate and organize research on a larger scale, decision-makers were left with a series of relatively small, often inconclusive studies.
I think we can all agree that a trial that fails to address an important health question because of a design flaw is a tragic waste, including the lost time and effort of those who volunteered to participate.
During the FDA’s evaluation, one trial stood out as a successful model – the United Kingdom’s Recovery Trial. In March of 2020, the UK established a nation-wide platform for clinical trials to evaluate repurposed drugs for COVID-19. The trial was designed to include a randomized, multi-arm master protocol and was able to quickly evaluate six treatments in a head-to-head comparison with standard of care as the control arm.
RECOVERY enrolled 7,586 patients across 172 sites within one month of the ethics committee approval. Within three months the study generated data to conclude that dexamethasone was effective in reducing mortality, and that hydroxychloroquine was not. The upshot is that 22,000 lives were saved in the UK alone. The UK trialists had one advantage: A nationalized health system that made it possible to quickly enroll patients using their electronic health records.
COVID-19 was a clarion call for lawmakers and policy leaders, raising alarms about the need to strengthen health data generation systems and improve and modernize our clinical trial infrastructure. But for the FDA it was only the latest, if most striking, example of our current challenges. We’ve known for some time that trials are becoming more costly and complex to administer, that recruitment and enrollment is difficult, and that sponsors are spending billions of dollars each year to address endpoint creep, as a result of a proliferation of non-core or exploratory endpoints in research protocols.
Consider this finding from the Tufts Center for the Study of Drug Development, which reported in 2021 that Phase II and III protocols involved 263 procedures on average per patient, supporting approximately 20 endpoints.
Unnecessary complexity isn’t found only in how trials are operationalized. It equally impacts trial design. Often, we pack trials full of different “ornaments” in the form of trial procedures and data collection. All that complexity burdens participants and sites. And at the end of the day, the protocol itself ends up very distracted from the important question it was intended to address.
FDA has been working for many years to facilitate innovative trial designs and promote patient-centered endpoints that can make clinical trials more agile. We’ve introduced a variety of innovative processes to facilitate clinical trial innovations and we are looking at novel ways to generate data. These have included master clinical trial protocols, seamless trials, decentralized trials, and trials which rely on real world data. Since 2007 we’ve been looking more broadly at clinical trial modernization as part of our public-private partnership with Duke University called the Clinical Trial Transformation Initiative, initially chaired by Duke’s then Chancellor for Clinical Research, Dr. Robert Califf, who today is our FDA Commissioner. Over the years, CTTI, as it is called, has focused on the design and conduct of clinical trials that can address the challenges I’ve cited without compromising our gold standard for medical product evaluations. Fundamental to CTTI’s work is the concept of Quality by Design - or QbD - which allows industry to enhance trial design, in a way that consistently and efficiently generates results that FDA can have confidence in.
We recognize that some of the complexity industry confronts in navigating the FDA’s clinical trial requirements stems from how the FDA has talked in the past about quality expectations. If you think about it, advocating for the highest level of quality has little practical meaning and may lead to ever escalating activities in search of incremental improvements. As you can see on the graph here, there is an exponential increase in costs associated with incremental improvements in quality, to the point at which the costs are disproportionate to any new benefits achieved.
Quality by Design reframes the concept of quality in a practical way. It describes a systems approach in which quality is a key consideration during trial design. Those responsible for the overall conduct of a trial identify the critical aspects that would threaten the protection of patients or the integrity of the results if not performed correctly. They draw up a quality management plan and prospectively identify and periodically review those factors that are critical to quality. But importantly, rather than striving for the absence of error – i.e, the thought that any error, no matter how far remote from an impact on participant safety or data quality, has to be prevented – trial sponsors need to consider quality as the absence of errors that matter to decision making.
To illustrate the issues discussed in the previous slide, let us discuss a cardiovascular outcomes trial with a MACE endpoint – that is, a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. For a trial such as this we’d want to make sure to capture when any of these events occur for all participants. That’s the evidence that is critical to quality. But in such a trial, a trivial error such as a failure to obtain a patient’s temperature wouldn’t impact the trial conclusions and wouldn’t merit using limited resources to identify and correct.
Quality by Design concepts have now made their way into internationally harmonized guidance. In early 2022, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) updated its E8 guideline, General Considerations for Clinical Studies. Designing quality into clinical trials is a core element of this revision.
The ICH E8 guideline provides useful tools and advice on trial design so that attention can be focused both on the scientific soundness of the trial and on developing trials that meaningfully measure what is relevant to patient outcomes. ICH E8 dovetails on the ICH E6 guideline, which continues to be a global benchmark for good clinical practice, serving as an international ethical and scientific set of quality considerations for designing, conducting, and recording clinical trials. Together, these guidelines and their subsequent revisions guide us in enabling safer, more ethical and effective trials. From a practical perspective, we need to better consider the burden of study procedures for participants and study sites, particularly when many procedures and data collected don’t link to primary or key secondary trial endpoints. Another big issue we see in industry is the failure to consider differences in medical practice across regions/sites and how these differences may impact an objective assessment of the study’s endpoints. Prospective attention to these details can improve trial efficiency, subject recruitment, and ultimately, the ability to complete a trial and use trial data to support product evaluation.
The concept of quality is a key feature of ICH E8. It asks those designing a trial to engage within and outside their organization to align on what is truly “critical to quality” for a trial, and then use that information to design a trial which avoid challenges. This coordination across functions is vital. Those designing a trial may not be attuned to the issues that design choices can create, and those operationalizing a trial, such as a Contract Research Organization or (CRO), may not fully appreciate design elements such as the nuances of randomization strategies that can reduce opportunities for bias if implemented appropriately.
Study design should aim to eliminate nonessential activities and data collection, to reduce burden and unforeseen errors brought on by excessive activities.
Finally, study designers should verify that the study you’ve designed will, at the end of the day, answer the important scientific question to be addressed.
If Quality by Design has such benefits, and is encouraged in internationally harmonized guidelines, why hasn’t it yet been applied broadly, to all trials? In interviews conducted by CTTI stakeholders across the clinical trials enterprise, those interviewed reportedly saw value in QbD but struggled to translate principles to practice. They wanted additional tools and resources to help them obtain organizational buy-in, train others, and support change management efforts.
To aid adoption, in 2014, CTTI developed a QbD toolkit that includes resources for researchers first learning about QbD concepts, to those who are ready to fully implement QbD into a clinical trial. Components of the toolkit include 1) an introduction to QbD concepts, 2) tools for teaching others in your organization about QbD and its use, and 3) tools for operationalizing QbD in your next clinical trial.
Most recently, CTTI has developed additional tools to further accelerate adoption of a QbD approach. These include:
- Detailed case studies on implementation of QbD (both retrospective and prospective) across a range of different organization types and sizes. These include commercial sponsors, academic units, and patient advocacy groups to illustrate that Quality by Design is not “one size fits all”, and that a variety of approaches have been successful in embedding QbD principles.
- Also included are tools to help organizations benchmark their current practices against Quality by Design principles, and to make decisions about what, if any, aspects of Quality by Design the organization might need to implement. For example, an organization might look at their trial design to better incorporate patient perspectives and processes or to allow more diverse participation.
- Finally, there are CTTI tools to help apply Quality by Design at the trial level and to translate these design discussions to risk-adapted oversight plans.
These tools can support organizations in moving to a Quality by Design approach, in keeping with the recommendations in ICH E8. I think that the most important step is the first one – just starting.
The FDA has issued a variety of guidance documents that provide valuable insights on the agency’s thinking about the conduct of clinical trials and that explain the agency’s interpretation of, or policy on, a related regulatory issue.
Let me explain what I mean when I refer to an FDA guidance document. FDA guidances are not legally binding but do provide those we regulate with the FDAs current best thinking about how to demonstrate their compliance with an FDA regulation.
You can find a list of all the FDA’s current guidance documents on our website, fda.gov. The agency has issued 17 guidance documents since 2020 that contain at least some mention of clinical trials. That’s too many for me to mention them all. But I do want to highlight a few, beginning with the guidance on the conduct of clinical trials during the COVID-19 public health emergency, first issued by the FDA in March 2020 and later updated in August of 2021. It clarified that, where appropriate, FDA regulations can accommodate the adoption of methods to facilitate trial decentralization through the remote collection of trial data outside of a standard in-person clinical trial site. These methods include patient-centric trial flexibilities such as electronic informed consent, virtual clinical visits, delivery of investigational product to the home and obtaining laboratory or imaging assessments locally.
I’d like to flag a few of the FDA’s most recent guidance documents as well.
First, the FDA issued a final guidance in October 2022 about the problems posed by multiple endpoints in the analysis and interpretation of study results. Second, the agency issued a draft guidance in September 2022 that, when finalized, will provide the agency’s perspective on the ethical considerations for including and protecting children in clinical trials. Historically children have not been included in trials resulting in many FDA approved products lacking pediatric specific labeling information.
And just last month, the FDA issued a draft guidance on the design and conduct of externally controlled trials for drug and biological products, this involves the use of real-world data/real-world evidence.
FDA isn’t the only U.S. government entity involved in clinical trial modernization. In October of last year, the White House Office of Science and Technology Policy released the National Biodefense Strategy and Implementation Plan, a whole-of-government framework that organizes how the U.S. Government manages its activities to more effectively assess, prevent, prepare for, respond to, and recover from biological threats. Among other things, the plan called for the U.S. Government to maintain and build upon our domestic clinical trials infrastructure, inclusive of international sites as appropriate, to ensure readiness. The goal is to be able to administer candidate countermeasures to participants within 14 days of the identification of a viable countermeasure.
In October 2022, the Office of Science Technology and Policy issued a request for information to help in the implementation of the plan. It asked about appropriate clinical trial governance, including best practices for designing trials, such as Quality by Design, what could be done to identify and incentivize institutions and networks to participate in trials, how to ensure diversity and equity, and how to develop a master agreement. The RFI included a question on international coordination and capacity, including methods for identifying international sites, overcoming regulatory barriers and the best way to track clinical trial initiatives being pursued by multinational organizations. Comments were due in late December.
There are also a number of international initiatives to harmonize and advance clinical trials underway. In June 2021, the G7 Health Ministers signed the Therapeutics and Vaccines Clinical Trials Charter, designed to speed up the sharing of results from clinical trials for vaccines and therapeutics for COVID-19 and other future health threats. The G7 intent behind this workstream is to strengthen citizens trust in medical science. This pledge prioritized support for well-designed randomized controlled trials that address key public health and clinical needs and supported trials that are consistent with good clinical practices and ethical principles. G7 Health Ministers committed to working with regulators and other bodies to promote more harmonization in clinical trials and streamline regulatory processes, working through existing forums such as the International Coalition of Medicines Regulatory Authorities, the WHO and the ICH.
Last May, as an outgrowth of activities in the G7, the World Health Assembly adopted a resolution calling on Member States to promote and prioritize the development of a sound research infrastructure with strong regulatory oversight systems for national clinical trials that meet internationally recognized standards of design, conduct, regulatory, regulatory oversight, assessment and communication. The resolution focused extensively on the importance of ensuring that such research addresses the needs of diverse populations. One of the underlying principles articulated in the document was the importance of public health transparency, including timely sharing of positive and negative clinical trial results with regulators locally and internationally. The WHO Director General was asked to review existing guidance and develop, with standard WHO processes, new guidance as needed on best practices for clinical trials and report back on progress at the WHA in May of 2023.
Also, last May, at the QUAD Leaders Summit - Australia, India, Japan and the United States - pledged to support QUAD countries capacity to undertake scientifically sound clinical research and collaborate on current and future clinical trials, such as launching additional sites for the international Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) trials, which can expedite investigation of promising new vaccines and therapeutics.
In closing, the FDA, as a regulatory, scientific and public health agency, has a critical role to play in modernizing the clinical trials enterprise. However, confronting the broader issues impeding evidence generation will require collaboration across many sectors. A good place to start is by reminding ourselves that applying Quality by Design isn’t about adding more complexity on top of existing process. It’s about focus, about understanding what really matters to credible, reliable evidence generation, and that “perfection is achieved, not when there is nothing more to add, but when there is nothing left to take away.”