Remarks by Dr. Califf to the 2024 Biannual Conference of the NYU Grossman School of Medicine Working Group on Compassionate Use and Preapproval Access January 30, 2024

Speech | Mixed

• Speech by: Robert M. Califf, M.D., MACC

(Remarks as prepared for delivery)

I’m delighted to be with you today.  I want to thank Allison Bateman-House and John Massarelli for inviting me to speak and for organizing such an impressive conference.  The agenda and the issues you’ve been focusing on these past two days are a virtual smorgasbord of issues in this dynamic and important area of health care, regulatory science, and policy.  

Given that you’ve already addressed so many key topics, I’d like to provide a perspective, including the challenges posed by often overlapping questions relating to public health, clinical care, ethics, philanthropy, business, and most essentially, patient well-being.  I speak from my vantage point as Commissioner, but also as a critical care and outpatient medicine clinician for over three decades and an outcomes researcher, including specific research on issues in patients with a low probability of survival in the near future — the setting of what at the time was called end-of-life care.

At the FDA, our approach to this issue comes from a unique but at times perplexing vantage point.  As an organization charged with applying scientific standards to product assessments, it is our mission and duty to apply the highest quality evidence to our product reviews.  The goal is for patients and their clinicians, provider organizations, and payers to have confidence that when a treatment is prescribed or used, the best estimate of risk-benefit balance for that product is a positive one for the patient.  

And yet, even as this process must always involve a balancing, the scale on which we make these decisions based on aggregate evidence differs to some extent for every individual patient and circumstance.  These estimates are especially difficult when applied to the extraordinary needs of individual patients who might be considered for expanded access. As regulators who are trained and required to apply scientific data to make the most informed decisions about risk and benefit applied to populations who can be identified to label a medical product, it is a challenge to apply this thinking to individual patients, especially when the evidence is not adequate to form a regulatory decision about marketing or claims.

Indeed, I suggest that within the FDA’s wide-ranging responsibilities to carefully review scientific evidence to determine the safety and effectiveness of medical products and whether they should be made available to the public, few areas are more fraught than those involving treatments that may offer the last potential option available to treat a life-threatening condition for which there are no proven effective treatments.  

The determination to provide expanded access, commonly known as “compassionate use,” is specifically designed to focus on patients with serious, life-threatening diseases and to provide them with access to investigational new drugs or therapies outside of clinical trials.  And yet, a decision that may seem straightforward on its face can be thorny when placed against the broader backdrop of what we know about medical products prior to approval and the overall system for drug development and review. 

The saying “medicine is a science of uncertainty and an art of probability” is attributed to William Osler, one of the four founding physicians for Johns Hopkins at the turn of the last century.  Despite all of our remarkable progress in biomedical science, the failure rate of molecules introduced into human clinical trials remains around 90 percent.  That means that 9 out of 10 drugs that have not been approved will never make it to market because of unexpected toxicity or inadequate effectiveness.  So, purely at face value, the probability of net benefit from expanded access is not high.

In the setting of clinical trials we talk about the “therapeutic misconception”.  A situation in which patients believe they will get a benefit despite explicit consent language that the research is being done to create generalizable knowledge without promise of benefit to the research participant.  In the setting of possible expanded access, the issues are related, but not the same—expanded access is not research, but it does have a tendency to elevate the perception of a potential therapy with unproven effectiveness to a status that exceeds its likely benefit.

Against these odds, we have the dire situation of a patient with an otherwise bleak prognosis.  I had the privilege early in my career of participating in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment, the SUPPORT Trial. This trial was a national study to improve decision-making in patients who were considered to be near the end of life.  

While I could talk for hours about what I learned as we intensively communicated with patients and families in the throes of decision-making, including in my own ICU, the overarching point is that views of impending death, risk taking with interventions, understanding of how to weigh options, and the degree to which a person wants to have autonomy relative to their clinicians vary considerably.  The only way to know in each case is to have the conversation, and shared decision-making is crucial, as good decision-making in this situation requires knowledgeable and committed clinicians and well-informed patients and families.   

I worry that the compression of time for clinicians in our health care systems makes it very difficult to review realistic probabilities with the patient and family and is a major limitation on well-informed shared decision making.  This important and complex interaction needs to impart vital information while maintaining appropriate hope that is consistent with the patient’s cultural, religious, and personal values.  Our goal in this situation is for the FDA to be helpful and not an impediment, and also to help provide background information for realistic expectation setting.

One thing that is incontrovertible is that this decision-making process revolves around the perspective and needs of the patient and the family or other carers.  It is an approach and model informed by the FDA’s broader efforts to incorporate the voice, perspective, and experience of the patient across the entire medical product development continuum, from development through review and approval.  In short, our scientific research and other work is increasingly supported by, and linked to what we now call the science of patient input. 

The many programs involving patient input are designed to facilitate the development of medical products in a systematic fashion that is dependent upon adequate and well-controlled trials.  This is the law, but it is also a well- developed science that is essential to avoid harm that would occur from the majority of drugs and devices that enter human clinical trials where the risks are found to outweigh the benefits.  But, as this conference has explored, for many patients there is a reality that there is no time to wait.  For them, this deliberative scientific approach may not be appropriate. And that is why, together with advocates, clinicians, the industry and elected officials, we’ve created programs that allow some patients to use investigational drugs, biologics, or medical devices that are still being tested to determine whether they are safe and effective. 

We know that these products may or may not be effective in the treatment of a particular condition.  They also come with the understanding that their use may cause serious toxicity or side effects.  But because they are intended for patients with life threatening illnesses with no options for treatments that are already proven to be effective, the risk-benefit assessment is based on a different calculation.  Thus, we provide this earlier use of unapproved products AND we do not want to undermine the broader scientific and regulatory goals essential to the FDA’s work and mission and that are a critical underpinning of the public health.

I want to focus for a moment on the word “access” in expanded access.  We recognize that this approach currently reaches a limited number of people, and accordingly we are working on ways to address the broader need.  One challenge, for example, is that many requests for expanded access come from academic medical centers, where primary research is being done.  But what this means is that the applications are limited to those geographic areas where, say, a major cancer center operates.  That’s why we are working to increase awareness about the expanded access process and the procedures for getting access to investigational medical products. We have a goal for patients and their doctors to be aware of the process and ensure that they are able to effectively navigate and implement it. 

We must also recognize that in addition to a patient who wants to pursue this issue and a clinician who is able and willing to administer the treatment, provide supportive care and contribute the needed information for FDA consideration, we must have a drug development company that will make the product available.  The requirement for posting expanded access policies has made a difference, as more and more firms are participating in expanded access.

And we have ethical issues that we need to continue to consider.  Who should pay for expanded access treatment?  The current system clearly creates inequities that are difficult to justify.   What does it mean when we collect data to inform the regulatory process without explicit consent for research?  We all recognize the value of real world evidence from deidentified, reused clinical data, but this is a bit different.  We recognize that these are dilemmas that require collaboration across the clinical care, product development, and legal ecosystem.

A special area of emerging concern is the use of expanded access for cell and regenerative therapy, a situation with extensive ancillary care that is often covered by payers, resulting in profitable activity even when there may be no intent to eventually file for approval of the product.

Earlier in the conference, the staff of the Reagan Udall Foundation for the FDA distributed a pamphlet that outlines the expanded access process and directs you to various resources on the FDA website as well as the website of the Foundation.  RUF has developed a tool called the EA Navigator that is designed to help patients and their doctors identify investigational drugs, provide links to clinical trials, and search for EA policies, company contact info, and program listings as well as the ERequest.  I want to express deep appreciation for the Reagan Udall Foundation’s work.

You also heard from the FDA’s Tamy Kim about the Oncology Center of Excellence’s Project Facilitate, which is designed to assist Healthcare Providers with Expanded Access Requests for Investigational Oncology Products. This is another successful way we’re working to expand opportunities for expanded access by providing outreach to healthcare providers and making efforts to provide equitable access to patients in need of an investigational cancer drug..  

The FDA grants the vast majority of EA requests, but only after considering whether the patient is eligible for an ongoing clinical trial.  Scientifically speaking, the first choice for these patients would be for them to enroll in high quality clinical trials designed to define the balance of risk and benefit with proper counterfactual comparisons, using randomized controlled groups when suitable.  This enables us to acquire important data about new drugs so that all future patients can benefit. However, if it is not possible for a patient to be a part of a clinical trial, either because there are no ongoing trials, a patient may lack access to them or may not be eligible for them, or the logistics of ongoing trials may be impossible for a patient or family to navigate, then we have the case for expanded access.  

To aid in this process we need to do everything we can to support increased understanding by reviewers and clinicians of the specific disease and needs of the patient. Patient advocates often play an important role in this regard, both in terms of communicating symptoms and result of treatment, but also by sharing a sense of urgency.  

The ultimate goal of gathering any data and evidence is to better inform our knowledge about the benefits and risks of health interventions, and for us at FDA — specifically for medical products used in health interventions -- and to assure that that patients and clinicians have the best information available to inform hard, probabilistic decisions to improve the likelihood that health can be improved relative to the risk of harm.  A program such as Expanded Access may seem like an end around the traditional approach to data gathering and medical product review, but ultimately, we may benefit from other patient-centered activities and information that is gathered.  

To do this successfully and to combine the rapid availability of these products with the essential societal need to have evidence to inform clinical decision making in the long-term will require each of the various parties – patients, medical product developers, regulators, and others to focus on creative approaches.  Like all of the work we do in this area which can have life and death consequences, it involves a balancing.  Your voices and your actions can help shape that balance and ensure the best outcomes for patients and for science. 

Before closing, and at the risk of joining the crowd running up the expectations for artificial intelligence, we need to start envisioning how this new world could revolutionize both access and the degree to which clinicians and patients are informed.   Like many areas of medicine where the work far exceeds the available personnel, the integration of electronic health records with systems of artificial intelligence could stimulate a much more effective ability for patients and clinicians to identify appropriate situations for expanded access and to optimize the complex clinical situation and the ingestion of information to inform further policy.  

I commend you for tackling these tough issues and I look forward to your questions.