The FDA's Present and Future, with Commissioner Robert Califf, MD

The FDA's plans to expedite and expand regulatory pathways has resulted in a novel drug development boom since 2017. The commissioner discusses the details of their strategy.

Even in an industry rote with buzzwords and poorly translated hyperbole, there may not be a more overused term in health care media than “game-changer.”

What even is a game-changer? From the experiences of HCPLive’s editorial team, it can be really anything new or exciting in medicine. Phase 3 trial results can be a game-changer. Improvements to screening and diagnostics can and have been known to change the game, per our experts. Even a concept as straightforwardly helpful as a new inhaler feature for patients with asthma has been described—no, exclaimed—to be a game-changer. It’s a catch-all description, a verbal crutch for opinion leaders and media members to convey in no scientific terms whatsoever that, “We didn’t have this before, and now things are better because we do.”

Perhaps the overuse comes out of necessity; after all, how many different ways can what’s transpired the last half-decade be described?

For those unaware, the US Food and Drug Administration’s (FDA) role in new drug development and regulation has shifted greatly since the early 2010s, enacting and refining a series of policies and pipeline strategies that has made the application and regulatory pathways more collaborative between the agency and drug developers.

The result? Well, more game-changers.

As of this writing, there has been 243 novel drug approvals from the FDA since 2018—an average of approximately 50 per year. That annual rate is a 25% improvement from the average annual from 2015 – 2017.

A significant portion of this substantial increase of novel drugs to the market is due to an embrace of the FDA’s quartet of expedited development and review pathways: Accelerated Approval, Breakthrough Therapy, Fast Track Designation, and Priority Review. A November 2022 report from a team of FDA investigators found that use of ≥1 of these expedited programs among drug-indication pairs increased by 32.2 percentage points from 2008 to 2021.

What’s more, the study showed that 85.4% of drugs undergoing the Accelerated Approval pathway were orphan drug designations—agents designed to treat conditions for small patient populations with few to no other treatment options available. As such, the orphan drug approved by the FDA pertained to diseases throughout oncology, neurology, hematology and infectious diseases, among others.

Indeed, since 2018, approximately two-thirds of all FDA novel drug approvals have been indicated for rare, cancer, or rare cancer diseases. Another 11% were granted to infectious disease indications, as outbreaks, epidemics and pandemics have become an increasingly prioritized matter of drug development during the COVID-19 era.

Altogether, though, this boom of novel agents to the US health care market appears intermittently robust and labile; as great as it has been to fulfill needs in the many vacancies of pharmacotherapy development, how is it possible for an agency and drug developers to keep this pace.

But there is a plan behind all this; today we feature a discussion with the person behind it.

In an exclusive interview with HCPLive®, FDA Commissioner Robert Califf, MD, discussed the agency’s strategy behind novel drug approvals relevant to trends in use of the expedited pathways, addressing unmet needs in rare and oncologic conditions, the role of COVID-19 in regulatory strategies, challenges in health care inequity relevant to drug research and development, and aspirations for the FDA in 2023 and beyond.

HCPLive: Since 2018, the FDA has averaged approximately 48 novel drug approvals annually—nearly one novel drug introduced to the market for every week. There’s obviously been greater efforts and messaging around streamlined regulatory processes and informed product applications in recent years that coincide with this trend.

Do you anticipate a continued climb in novel drug decision opportunities for the FDA in the next decade?

Califf: The short answer is yes! The science of drug development and our understanding of systems biology are advancing at an amazing rate. Especially for rare diseases with a major genetic component, our understanding of biology and how to compensate for abnormalities continues. We have geared up the regulatory system over the years, and the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) continue to keep their review systems up to date with the latest science. The largest increase in the PDUFA VII agreement is for CBER to gear up its cellular, gene and tissue regeneration therapy effort. We expect to see a major increase in effective products in this arena.

We need to do more to increase the pipeline for some key areas of unmet need, for example: addiction, mental health and long-term chronic diseases like cardiovascular, pulmonary and renal disease. Another area that will need specific focus is maternal-fetal health. We have a dearth of effective therapies despite unacceptable and rising maternal and fetal mortality rates and continuing large numbers of premature births, leading to enormous disability and costs.

A look into the novel drugs approved by the FDA in 2022 show approximately two-thirds are intended to treat a form of cancer, a rare disease, or a rare cancer. As you’ve noted, these are “major priority” conditions, along with chronic disease, for treatment progression and diversification.

Can you speak more to the need for simultaneous progression of needed drug candidates and efforts to continuously assess their benefit-risk profile in real-world patients, and how do you envision those two priorities best coinciding in the future?

Califf: Even with all our advances in biomedical science, drug development remains an enterprise in which failures far exceed successes. The early phases of drug development work well to identify therapies with a reasonable likelihood of clinical benefit, albeit at tremendous expense. As drug development focuses on unmet needs, an increasing proportion of drug candidates qualify for accelerated pathways. By definition these pathways require confirmatory studies, since they are not based on empirical demonstration that benefits outweigh risks from a human population. Furthermore, across the board our system for understanding the evolving benefit-risk profile in clinical practice falls far short of what is needed.

We learned a lot about this in the pandemic. Israel had a far superior system to use EHR data to judge vaccine effectiveness and the UK incorporated simple trials answering essential pragmatic questions about treatment into the healthcare system. This enabled the UK to answer essential questions rapidly at low expense. Simply put, with all the technological prowess in the US, including the ubiquity of EHRs and the rapid spread of digital technologies, we need to do a major upgrade on our evidence generation system.

FDA approval for marketing is the end of an arduous and effective system to sort out drugs with a positive benefit-risk balance for an intended use, but it is the beginning of another important journey in which use of the drug should generate data enabling us to determine when a drug should be used across the eligible populations, how it should be used alone or in combination with other drugs, devices and behavioral interventions and its value. Much of this is beyond FDA’s remit, but we should be developing better approaches to putting the pieces of the puzzle together that ensures a better continuum between the responsibilities of FDA to fulfill its regulatory and public health mission, and the broader needs of society, including patients, clinicians, health systems and payers. Such a system could also enhance our premarket evidence generation system by enabling less expensive, larger premarket trials when needed.

The COVID-19 pandemic required new investigative practices, diligent disease and drug candidate monitoring and bolstered collaboration between regulatory agencies and would-be vaccine/drug developers to help deliver virus-curbing agents to the market in a timely fashion.

Practices like the Emergency Use Authorization pathway moved from lesser-known option to common knowledge among the public. How do you see the pandemic as having altered our regulatory and drug development strategies?

Califf: The development of safe and effective vaccines for COVID-19 was indeed an astounding success. Years of investment in the mRNA platforms and associated biology set the stage to make it possible, in combination with more traditional approaches, which also proceeded in record time. We saw that when industry, academia and regulators have common goals and the effort is supported by the public, biomedical science can move quickly, at scale and with reliable results.

Another factor that has not been stressed enough is the massive government investment to de-risk the early phases of development and manufacturing so that companies could take on the development in the face of so much uncertainty. This is an area of policy that needs much more discussion and thought. For areas of development with a high rate of return, government’s role is appropriately passive, but in areas where development doesn’t happen because of perceived or actual low rate of financial return, there may be an important role for government.

Another important element is that we should recognize the difference between a pandemic killing thousands of people a day and many other areas of medical product development. There is wisdom in a system that requires companies to generate evidence proving that benefit outweighs risk for an intended use prior to marketing. In the EUA setting, the potential benefits and risks are weighed because waiting for definitive evidence is not tolerable. I’m in awe of the way definitive phase 3 RCT evidence was generated for the vaccines and antivirals by the intense collaboration of all involved, but the EUA’s were granted prior to the usual follow-up required for vaccines.

Your JAMA Viewpoint essay highlights the prevailing need to reverse health outcome inequities through strategies including diverse patient population messaging and improved clinical trial representation. What historically remains as hurdles to better tailoring regulatory strategies to address inequities?

Califf: We must continue to make progress in the manner in which clinical research and information about health have an intentional goal of reducing disparities. The longstanding gaps in health outcomes associated with race, ethnicity, wealth and education remain evident in our latest health outcomes data. Rural America is experiencing a dramatic decline in life expectancy. Between FDA and NIH, we can continue to emphasize inclusion and diversity in trials. And between FDA and CDC, we can emphasize appropriate health education efforts, including issues related to the pandemic, use of medical products, nutritious food consumption and avoidance of tobacco related disease.

However, the “elephant in the room” is the healthcare system in which the research is conducted and information is disseminated.

What are some of the lesser-discussed components of drug development and regulation that play a pivotal role in today’s system?

Califf: I remain in awe of the drug development system. A couple of areas need much more discussion and consideration, however.

First, we need to develop a plan to accelerate development in diseases where outcomes are poor and the pipeline is lacking as discussed above.

Secondly, we need to revamp our evidence generation system, also discussed above.

The third major area where much more discussion and action are needed is in the multiple aspects of the supply chain, including manufacturing and distribution. The move to “just in time” delivery, large, sole source contracts and market consolidation has led to a system that is not resilient and prone to shortages in normal times. But when major stresses like a pandemic or a major war in a country like Ukraine that supplies a lot of our materials, the system cannot compensate. Companies are developing increasingly sophisticated supply chains for their own systems, but for most medical products and food, there is no “central switch”. Specifically for medical products and certain foods, the offshoring trend has created extreme dependance on countries that may not have our best interests in mind. There is not room in this interview to cover the solutions, but I’d refer you to the National Academy of Medicine report.

Do you hold any specific goals for the FDA in 2023?

Califf: As I was going through the nomination process, many people from inside and outside the FDA called to say that the food side of the Agency needed more support and attention. We are moving along with significant reform of the Human Foods Program. I hope to have leadership and structure in place this year and significant progress towards a Human Foods Program that can regulate in a manner that successfully helps the industry through the challenges of climate change, supply chain disruptions and the enormous growth in common, chronic disease, much of which is initiated by poor nutrition.

The area with the most opportunity to save lives in the short term is the Center for Tobacco products.With almost 500,000 American dying from tobacco related disease this year and millions of youth addicted to nicotine through the use of e-cigarettes, a more effective tobacco program will make a big difference. This is not to say that we’re starting from scratch—a lot of progress has been made in CTP’s first 13 years, but this is a great time to reassess and refresh our approach to fulfilling the center’s mission “to make tobacco-related disease and death part of America’s past, not America’s future, and, by doing so, ensure a healthier life for every family”.

As discussed above, we need a more effective system of evidence generation so we can develop more effective health interventions faster and at a lower cost. The system should extend far beyond health care to inform us about nutrition, tobacco and dietary supplements.

I believe that misinformation is now the leading cause of death in the US. For the pandemic alone, since the availability of effective vaccines and antivirals, death should be an uncommon outcome, but unfortunately many people have failed to be up-to-date on vaccination or have not received antivirals despite their high risk status. But this is not limited to the pandemic—all too often nefarious or misled information has been promulgated, leading to bad health decisions, particularly in some segments of our population. I hope by this time next year we’ll have an effective strategy to combat misinformation.