Interview with Janet Woodcock

Abstract

Dr Janet Woodcock is the Director of the US FDA’s Center for Drug Evaluation and Research. Dr Woodcock has held various positions within the FDA’s Office of the Commissioner from October 2003 until 1 April 2008, as Deputy Commissioner and Chief Medical Officer, Deputy Commissioner for Operations and Chief Operating Officer and Director of the Critical Path Programs. She oversaw scientific and medical regulatory operations for the FDA. Dr Woodcock served as Director of the Center for Drug Evaluation and Research at the FDA from 1994 to 2005. She previously served in other positions at the FDA, including Director of the Office of Therapeutics Research and Review and Acting Deputy Director of the Center for Biologics Evaluation and Research. Dr Woodcock received her MD from Northwestern Medical School (IL, USA), and completed further training and held teaching appointments at the Pennsylvania State University (PA, USA) and the University of California in San Francisco (CA, USA). She joined the FDA in 1986.

Bioanalysis spoke with Dr Janet Woodcock on 21 June 2010.

What are the top priorities for the Center for Drug Evaluation and Research (CDER) at the US FDA for the next 4 years?

Right now our top priority is to put in place a quality management system. We also have to implement a biosimilars program based on the latest statute that was passed, and we are continuing to work on putting together a more robust drug safety program.

What do you see as the most important actions that you need to take with regard to biosimilars?

We will have to set up regulations and policies and decide how to implement the language in the statute [1]. At the same time, we have to give people advice and review applications. The main thing we need to do is establish a program, similar to that already in place for generic drugs, so that people understand the rules of the game and what they need to do and what procedures they should follow.

What are the major differences between the established pathway for generic drugs and the forthcoming biosimilars pathway?

The major difference is that you can tell whether a generic drug is chemically identical to the innovator product, but you cannot with a large protein molecule. Biosimilars are similar, but not identical, which means a lot more work.

What challenges are posed to the FDA and the public by counterfeit and unapproved drugs, and how does the Agency detect them and remedy this issue?

This has been a problem for over 100 years; one of the reasons the FDA was established was that drugs were contaminated or contained the wrong active ingredients. Now, with globalization, there are many more opportunities for contaminated or unapproved drugs to enter the US market and pose a threat to consumers and the public.

To detect unapproved drugs, we rely on alert members of the healthcare community to tell us when they see subtle differences. Sometimes, for example with heparin, it gets to the point of adverse reactions in patients before the contamination can be detected. We also collaborate with law enforcement agencies and other international authorities who inform us of their findings, and we have a group that works on criminal investigations.

How do counterfeit drugs appear in the marketplace?

It is not just counterfeit drugs; we often see products marketed as dietary supplements that contain unapproved drugs labeled as products for weight loss or erectile dysfunction, but they contain unapproved pharmaceuticals which can be very dangerous. We also see a lot of anabolic steroids for bodybuilding that purport to be dietary supplements, but are in reality unapproved drugs. We see frank counterfeits that imitate an approved product, and these may or may not contain the real drug.

The approval of suitable vaccines and diagnostic tests by the FDA less than 6 months after the first appearance of H1N1 was a great success. What lessons were learned from the H1N1 outbreak?

It underscored the fact that we need new production technologies for vaccines and drugs. The manufacturing process should be modernized so that we have the surge capacity for a pandemic, as you can never predict what emergency is going to come about. I think that everyone learned how to respond better in a health emergency like this.

How prepared is the FDA to deal with future pandemics?

With influenza there is a huge ongoing effort; however, we do not know what the next pandemic will be; it could be some other organism, so obviously there is a lot of work that still needs to be done. The entire biomedical research community are trying to identify organisms that could emerge into pandemic status and develop therapies and other interventions or preventatives that could be used to counter these organisms. At the FDA, we have pathways to release unapproved drugs quickly and get them into the hands of the healthcare professionals in an emergency, as we did with peramavir for the recent influenza episode.

Pharmaceutical development, clinical trials and food production are increasingly globalized. How do you see the role of the FDA evolving in light of this?

It is changing from a domestically focused agency to a globally focused agency that expends a lot of effort collaborating with our regulatory counterparts around the world. We have to work with regulators in other regions extremely closely because nothing stays within a national border. The concept of a global regulatory network is now starting to emerge.

What part do you envisage the FDA playing in moving towards global harmonization in areas such as bioanalytical method validation?

We have made a huge effort with the International Conference on Harmonisation (ICH) and the pharmaceutical industry has helped make that work. We have a tremendous amount of technical standard harmonization. I will have to plead ignorance as to the progress of the specific bioanalytical regulations, but the ICH model has been extremely successful in other areas.

As the ICH does not cover all countries worldwide, do you think we need to consider other options for international cooperation?

Our lead at the ICH, Justina Molzon, is working very hard with regulatory bodies around the world. Clearly they need to participate in different ways in regulatory standard-setting and figure out how those technical standards will be applied in their country or region. Regional representatives from developing countries are invited into the FDA and work with the agency to establish appropriate guidelines.

It can be difficult to assess the bioequivalence of locally acting drug products, which presents a challenge to the approval of generic products. How do you propose to address this problem?

Unfortunately, the FDA is not funded to perform much research so we do not have the capacity to carry out the program that would be needed to set up new technical standards to assess the bioequivalence of different locally acting drugs. It is a big problem and we have tried to get others, for example the generic industry, to fund the research that needs to be done to set up the technical standards. Meanwhile, people are paying a lot more for certain dosage forms or the generic companies have to carry out full-scale clinical trials.

There is a large potential benefit to making biosimilars available to patients in the USA. Could you explain the science behind creating a regulatory framework for the approval of biosimilars, and the current legal status?

The new legislation allows us to approve a biosimilar product with an abbreviated application, as with generic products, if the product is highly similar. Now, of course, that is the US$64,000 question; the statute that was passed leaves a lot of discretion for the FDA to determine what those parameters might be.

We have to set up how we determine something to be ‘highly similar’ and how much work the follow-on biologic applicant has to do. That will vary with how easily characterized the molecule under question is: with a small, nonglycosylated protein, it is a lot easier than large, complicated monoclonal antibodies. How much work the applicants have to do will depend on how easy, or hard, it is to determine the degree of similarity.

Following the Critical Path Initiative, how significant has the impact of the use of biomarkers in the drug development process been?

It is really taking off. Having a good pharmacodynamic biomarker will stimulate whole areas of drug development. For example, in HIV, having viral load measurements has enabled the development of highly active antiretroviral therapy. A pharmaceutical company will move into an area where they have good pharmacodynamic markers that they can use. What we are trying to do under the Critical Path Initiative is to develop that new generation of markers and also to develop safety markers [2]. There is beginning to be some success with safety markers, which Nature Biotechnology has just published in a recent issue [3]. I would say that it is going to be the world of diagnostic tests and biomarkers in the future, because that is how we are going to apply the new science to drug therapy. We are starting to see the application of new diagnostic markers in the cancer area; targeted therapy trials using biomarkers and looking at mutations in the cancers are really taking off now, which is exciting a lot of people.

What regulatory framework is needed to quantify biomarkers for diagnostic tests?

There has been a long history of laboratory-developed diagnostic tests, alongside FDA-approved test kits that are sold. This will create some policy issues moving forward because diagnostic tests need to be used with newly approved drugs to decide who will get the treatment. The FDA’s position on this is that these assays should be approved by the FDA and should be of a sufficiently robust quality that we can approve them.

You have spoken about the importance of advancing regulatory science to keep pace with the advances in biomedical sciences. What do you see as the main areas in regulatory science in need of improvement?

Every area! Unfortunately, we just don’t have the resources, but it does not mean that the regulators are not good scientists. What it means is, as we discussed with bioequivalence of locally acting products, we just do not have the science base to understand, for example, adaptive trials or how to apply biomarkers. We are obviously working on establishing a good science base on how to do comparability or similarity assessments between protein molecules. That is the kind of science that needs to be continually generated and I think we are behind in that.

How do you envisage advances in the ‘omics’ and systems biology changing the way we develop therapies and assess their safety and efficacy?

They have already rapidly changed how we discover new drugs because we have identified new drug targets. Hopefully, systems biology will give us more insight into off-target effects so we will be able to make better safety predictions. Right now, drug development is very risky as you cannot predict all the effects of the drug and there are a lot of nasty surprises.

As far as assessing efficacy, that is another big gap in regulatory science. There is a need to figure out how to use genomics and other related technologies in assessments of safety and efficacy. We hear people saying everything from “Oh, well, here is a genomics test, we understand everything” to “No, we have to do randomized controlled clinical trials and see whether drug metabolism is important”. There has to be a happy mean there.

What form do you see personalized or precision medicine taking in the short and medium term, in light of current scientific research?

For drug therapy, which is what I can mainly talk about, what we are going to see is the emergence of new biomarkers that will distinguish patients’ response to drugs, because people vary wildly in their response to drugs due to a whole range of factors that we are only now starting to understand. We have markers that indicate, “you are at high risk of a side effect – you shouldn’t take this drug” and others that show “you should start at this dose because your drug metabolizing enzymes indicate that this will be near your final dose” or even, “only people with this genetic mutation in their tumor should get this drug.” We are seeing this now on drug labels, and it is only going to grow over the next 5 years.

What do you think about the costs associated with personalized medicine?

I would say that we are going through a transition phase right now, but actually you have to look at the total cost. What is the cost of treating somebody with an expensive cancer drug that has no chance of working on them? It is very high and we have seen cases where about half the patients being given a cancer drug had no chance of the drug working. With personalized medicine, all of a sudden you have saved 50% of your drug costs; furthermore, the side effects people experience are reduced, so the total cost benefit is huge. Warfarin is almost the number one drug for sending patients to the emergency room; they have bleeds, thromboses and all kinds of terrible side effects because they are under- or over-anticoagulated. You have to look at the total healthcare costs, rather than the cost of the drug or the assay. You begin to see that there is a benefit to using these assays.

To what extent has risk–benefit analysis been applied to the drug development process?

The regulators apply it routinely to judge whether a product is safe and effective, whether the benefits outweigh the risks. What we need to do is make this more explicit. We are developing an explicit risk–benefit template where we write it all down and explain our reasoning more clearly.

President Obama’s healthcare plan promises to lower the cost of healthcare and provide medical insurance for those without, as well as stability and security for those who already have insurance. What impact do you see this having on the FDA and pharmaceutical industry?

I think there will be more scrutiny into the value of pharmaceutical intervention. There will not be too many developments of ‘me too’ drugs with slight modifications because there is going to be less and less interest in getting those paid for. There will also be greater interest in generics and biosimilars in terms of lowering the costs of pharmaceuticals.

What are the key areas that should be addressed by the FDA to do the best for patients, doctors and the pharmaceutical industry in the future?

I think we have to keep the balance between innovation and information. As we seek more and more certainty, and more and more information about a drug, we have to ensure that we don’t squelch innovation. Innovation is the engine that brings hope and new treatment to patients.

How would you encourage innovation?

For developers, regulatory clarity is important so that they understand what they need to do to get their products on the market.

How do you see your role, and the nature of the FDA, evolving over time?

I think the future is going to be very interesting as payers and technology assessors play a greater and greater part in determining what products or services are reimbursed. The role of the FDA, and regulators around the world, will change to reflect this.