ISPE Hosts a Fireside Chat with FDA Commissioner

Before joining the FDA for the second time, Califf was the Head of Medical Strategy and a senior advisor at Alphabet, Inc. Prior to his time at Alphabet, Inc. he served as a professor of medicine and as Vice Chancellor for clinical and translational research at Duke University. He was also the founding Director of the Duke University Clinical Research Institute.

In the interview, Hartman and Califf discussed the harmonization of pharmaceutical and biologic innovation and manufacturing, improving patient access to drugs for rare diseases and the current global regulatory efforts to achieve this, emerging technologies such as artificial intelligence (AI), FDA and industry cooperation during the COVID-19 pandemic, preventing drug shortages, and maintaining the quality of the industry and regulatory workforce.

Tom Hartman

President & CEO

Hartman: The regulatory harmonization of innovation and manufacturing and the analysis of pharmaceuticals and biologics are critical for meeting the needs of patients now and in the future. The FDA has been a true leader in these areas for a number of years by providing industry with mechanisms to discuss and implement innovation and emerging technologies.

If our industry is to successfully leverage this innovation to positively impact global supply resiliency and patient access, we believe steps are necessary for regulatory alignment and convergence. What can the FDA do to facilitate interactions with health authority peers, such as the Quality Innovation Expert Group in the European Medicines Agency (EMA), the World Health Organization Innovation Hub, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, or similar groups?

Califf: This is an important issue. If we don’t innovate in the manufacturing of drugs, we’re really letting the world down. I was thinking about this during my recent trip to India. There are 1.4 billion people in India. In the US, we tend to think about the Indian generic industry as something that serves the US, but there is a much larger population to be served. There are 7.6 billion people who live outside the US, so we have a lot to do to make manufacturing resilient and to have it serve the needs of so many people. To do that, we have to interact with our fellow regulators. As you are aware, we are harmonizing guidances now with our recent “Q13 Continuous Manufacturing of Drug Substance and Drug Products” guidance coming out.

While working together is important, I don’t think we want total convergence because a lot of what leads to innovation is the ability for smaller units to step up rather than regress to the lowest common denominator of what we all have in common. I think a key part of the US approach is going to be to continue to try to be leaders in innovation, but where there is an establishing technology—as it evolves—we should work with our collaborators around the world.

Hartman: Global patient access to medicines and therapeutic products for rare and ultra rare diseases poses a significant challenge for both industry and regulatory authorities. Is there an opportunity here for leading regulators—such as the FDA, EMA, and others—to develop a globally agreed upon approach for clinical and commercial development and approval of these novel and life-altering therapies?

Robert M. Califf, MD

Commissioner of Food and Drugs

FDA

Califf: We should be able to work together to identify everyone with a rare disease, no matter where they live. And using our aggregate intelligence and technology should make it possible for them to get a diagnosis and to enter clinical trials. There is a cluster that has been formed that involves EMA, FDA, and Health Canada.

We are meeting together and talking, but, as I pointed out in the last question, India has 1.4 billion people, China has 1.5 billion people, and the Association of Southeast Asian Nations and the sub-Indian and sub-Chinese part of Asia add another 1.5 billion people.

So, we have a large portion of the world’s population that we’re not communicating with. That has to be an important part of our strategy as we work together on guidances and accelerating rare disease cures programs. There are differences in resources around the world, of course, and we can’t act as if that’s not the case, so it’s really important—I think—for the US to lead the way.

Hartman: I think that’s a very good perspective, as the industry is constantly evolving and placing significant emphasis on emerging technologies that facilitate faster access to medicines for patients globally. One area of high interest is “model informed drug development,” or MID.

With MID, physiological-based models can improve clinical trial efficiency, optimize drug dosing, and potentially reduce the number of patients in a trial, or even decrease the number of clinical studies to support the approval of a particular medicine. Can you share your thoughts on the potentially beneficial impacts of this program for patients, and do you see an opportunity to extend or even accelerate this initiative for global consideration?

Califf: Early in my career, we worked on predicting outcomes for people with coronary disease, and I learned pretty quickly that if you just depend on raw data, without modeling, you leave out a lot of knowledge that can be gained by looking at how the data fits together.

Today we’re in a new era that is extraordinarily exciting. Call it AI. Call it machine learning. But we can now take diverse data sources, with different types of data, and that enables us to create models that include disparate kinds of data. That creates the ability to do things that just couldn’t be done before.

I am pretty excited about using AI to identify targets, then look at the configuration of proteins and molecules in a way that enables us to not only more quickly identify what the real candidates are, but also to use the models to predict where the toxicities might be. I think this might really make a difference.

Hartman: To shift gears around some of the learnings from the pandemic, given the FDA’s leading role in working with industry to expedite development and approval of vaccines, how is the FDA leveraging that experience and translating it to address unmet medical needs and even approval accelerations, particularly with respect to therapeutic and technical innovations domestically as well as globally?

Califf: I don’t like using the term “accelerated approval.” That term may imply that we always approve, but 85% of drugs that get introduced into phase one trials don’t make it. So, it’s really “accelerated evaluation,” and the approval is based on biomarkers, which is another place where modeling is a very important part of the overall effort. We have multiple ways that we can accelerate, depending on the particular circumstance, such as a priority review where we want to make a decision within six months.

I do want to point out one more thing. In the haste to say that we have learned about doing everything fast, as if it’s just a matter of having less bureaucracy, we should not forget the COVID-19 vaccine effort. That effort was, I believe, perhaps one of the most momentous scientific achievements in history, given the speed at which that vaccine was developed and how effective it has been.

The government put in a lot of money, and we shouldn’t lose sight of the fact that it’s not just how fast we go through the regulatory review. It’s about the resources put into the scientific concepts and the articulation of industry, academia, and government—all working toward the same goal.

I don’t want to disappoint people who may hope that we are saying, “now we can go twice as fast, and it’s no problem.” I think the answer to this is mixed. We should go faster where we can but still have confidence that we’re not opening the field up to ineffective or dangerous treatments.

Hartman: That’s an excellent point. Now to shift to drug shortages. On the part of both industry associations and regulators, there have been recent efforts to mitigate drug shortages. As you may know, ISPE has recently issued its Drug Shortages Prevention Model, and I know that the FDA has focused on preventing drug shortages. And, we have seen some legislation in support of enhanced reporting and transparency.

Does the FDA feel the current reporting expectations have been effective to predict and even mitigate shortages? And what other measures can the FDA and industry implement in partnership to reduce shortages significantly and sustainably?

I think AI is going to be a companion to everything we do. Whether it’s a drug, a biologic, or a device. AI should reduce the amount of cutting and pasting that goes on to free up our brains to work on the creative part and the human part— that’s really needed.

Califf: When demand goes up, there is a potential for an impending shortage. You can predict that almost any inexpensive generic drug is at risk of shortage. We can produce probabilities, but what really produces a shortage is when a line goes out in a manufacturing plant, or there’s some problem, like in Ukraine, where there is a shortage of raw material. We need a system that’s resilient to those factors.

So, having said all that, we want to make the best predictions we can, but we need to be able to plug the holes when they occur. But, right now, we’ve got 200–300 impending shortages every year, and it will continue that way until we fix the economics of the industry.

Hartman: And in that regard, there has been a lot of conversation around reshoring manufacturing. Do you feel that the US or other countries have an overreliance on foreign or geographically concentrated sources for either manufacturing the material, the drug, or key starting materials that ultimately result in shortages?

Califf: I do think there’s overreliance. The whole world needs access to generic drugs, so what we need is a balanced geographic distribution. The key starting materials, the raw materials, are far over-concentrated in China. So, I was really pleased when I saw that India is making a good faith effort to do environmentally sound starting-material transformations into active pharmaceutical ingredients. I’m gaining a lot of confidence that we can get a geographic balance. We just have to decide to do it.

We’ve taken this amazing gift of very inexpensive, highly effective drugs, generics, and created a contracting system that guarantees that there will be shortages. So, we have to fix the contracting so that the companies that make generic drugs have adequate security, so that they can attract investors to keep their technology and equipment updated, so that they can manufacture high-quality products with enough in the supply chain to have a reserve on hand. You can predict that almost any inexpensive generic drug is at risk of shortage if one or two bad things happen.

Hartman: From the FDA’s perspective, what are the big, enduring lessons learned from the pandemic and what is the FDA currently planning, implementing, or preparing for the next pandemic? Also, how can industry and the FDA have a partnership in preparation for the next pandemic?

Califf: As I mentioned before, I think one of the big lessons learned is that when we all agree on a problem, we decide we’re going to go all out to fix it, and the government pumps money into the system, we can accomplish miracles.

A second lesson was the investment in platform development that happened with mRNA over the course of 15–20 years. We need to keep working together on platforms so that we can be ready to deliver when the need occurs. We also learned a good bit about the steps and where you can take a calculated risk in terms of FDA review. If you have a situation where people are dying, and there’s no effective treatment, well that’s different. We know the calculated risk that we can take.

I also would mention the dedication and resilience of the FDA workforce. I was on the outside when this all started. I came in in the middle of it, and it was amazing to see how strong people really were, considering all the night and weekend work that had to be done. I think that’s just an attribute of all the elements involved—FDA, industry, and, of course, academia going night and day.

Hartman: From your perspective, what topics could be best leveraged by AI? Or, what activities could be leveraged by AI in terms of medicines development, manufacturing, or, ultimately, product licensure?

Califf: I think AI is going to be a companion to everything we do. Whether it’s a drug, a biologic, or a device. AI should reduce the amount of cutting and pasting that goes on to free up our brains to work on the creative part and the human part—that’s really needed. I think generative AI could also open a window into something that can be terribly biased and lead to really bad results. Or it can free us up from bias, depending on how we use it.

What should the guardrails be on the use of AI, particularly as it becomes more generative across all these things? How do we police it? How do we turn it in the right direction? I know an evolutionary biologist who says, “There is no invisible hand of justice in an AI algorithm.” So, we must keep that in mind. It’s important not just for us, as regulators, but for industry to look at AI very carefully and highlight the need for a robust control framework to keep AI within the guardrails.

Hartman: You spoke earlier regarding the Center for Biologics Evaluation and Research hiring a number of individuals. One of the industry’s challenges, which I think has been exacerbated post-pandemic, is the availability of a capable workforce to fill critical medicines development manufacturing and related roles.

Many companies have established internal programs where they look to organizations like ISPE to implement programs similar to our student travel grant program that enlists students to participate in conferences and gets them introduced to the industry. Does the FDA have similar challenges in this space and, if yes, how are you addressing workforce issues?

Califf: We are constantly worried about the workforce, especially in scientific areas. There must be a constant infusion of new people who are recently trained at the cutting edge or have been out in industry working at the cutting edge. We have to compete for those people, but we also need to grow them, so we have an extensive program for students of all types, from high schools and colleges to postdocs. There are over 1,000 students, and about half of those students come back and begin working at the FDA.

We also have something called the ORISE Fellowship. It is run out of the Department of Energy, and we’re one of the major users of that program, particularly for postdocs who can come in and work at the FDA. I feel like we play our role in developing the workforce of the future, some of which stays at the FDA. Many go into the industry with a knowledge and appreciation for the regulatory side—something that academia traditionally doesn’t teach very well.

Hartman: Yes, it’s a big issue and we also are trying to address it as part of ISPE’s remit. Now, with the fourth quarter of 2023 upon us, a lot of organizations—and I’m sure the FDA as well—are preparing their budgets and activities for 2024. What are the big challenges and what do you see as the leading priorities for the FDA as we head into 2024?

Califf: We’re facing a very tough financial situation in 2024. The budget—at best—is flat. I would say our number one challenge is just surviving the financial situation that we’re going to be in and, of course, dealing with the Congress and the election year, particularly one that’s so dramatically frustrating as this one, where people just aren’t working together. That’s a challenge.

On the other hand, I’ve never seen an explosion of biotechnology like we have now. I think the medical products side of the FDA is doing great, and it will continue to be able to respond to what’s needed. The biggest emphasis for me is the food side of the FDA, where we’re doing a complete reorganization of the human foods program. Biotechnology applied to agriculture is, I think, going to turn out to be one of the most important things. We must have resilient plants and animals and production of protein independently of polluting the atmosphere. And that’s dependent on smart regulation to help the industry get to where it needs to go.