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By Malorye Branca
Senior Informatics Editor

June 12, 2002 | One reason pharmaceutical companies have been slow to embrace pharmacogenomics is the fear that it will be difficult to get such products through the FDA. Earlier this year, Lawrence J. Lesko, director of the FDA's Office of clinical pharmacology and biopharmaceutics at the Center for Drug Evaluation and Research (CDER), and Janet Woodcock, CDER director, sought to alleviate these concerns in an article entitled "Pharmacogenomic-guided drug development: regulatory perspective," published in The Pharmacogenomics Journal. The article outlines the FDA's position on the use of pharmacogenomics and pharmacogenetics in the drug approval process. Some researchers believe this article opens the door for this nascent field, while others are waiting to see how the FDA will treat the next pharmacogenomic products in line for approval.

Q: Why did you and Dr. Woodcock publish this article in The Pharmacogenomics Journal?
A: The paper is one of three steps towards encouraging pharmacogenomic submissions, which is one of the FDA's goals. The agency wants to assume the role of a driver of integration of this technology into drug development.

A second step we are taking is an aggressive educational initiative within the center to raise the awareness of the medical and scientific staff about pharmacogenetics, including a course on the basic aspects of pharmacogenetics and its use in drug development. I don't want to see a company come to the FDA with this kind of information and not be able to converse with someone in the agency who is an expert in the field.

The third step was to co-sponsor a public workshop on pharmacogenomics with PhRMA [Pharmaceutical Research and Manufacturers of America]. We had a capacity for 300 registrants for that workshop, and over 600 people from the industry wanted to come. We could not accommodate that number, so we are hoping to repeat the workshop.

Q: Has the FDA successfully played this role before?
A: One good precedent is that in 1997 we published a guidance (i.e., a backgrounder with specific recommendations) for in vitro drug metabolism and drug interaction studies. At the time, that was an evolving area in drug development. We encouraged companies to use the technology, and now it is routine and a part of every application.

Q: How have people reacted to the article?
A: There has been a tremendous response. People have called and said that this is something they can show to their CEO that proves the agency has expressed interest in the field and willingness to work with companies. The field is at a turning point, and this article has enabled leaders in industry who want to use this technology to get it done.

I know there has been a lot of concern about the agency's position, which is usually the case in new and evolving areas. People were wondering, "What will happen when we bring it to the FDA?" With this article, we have tried to overcome that fear with an honest appraisal of where we are and what we see as the obstacles that we need to work through.

Our article did not answer all the questions. But we put a lot of questions in the article as a stimulus for further thought and discussion. The main goal was to show a positive stance on this field, and that we are looking at pharmacogenomics in a way that will not penalize the companies involved in it.

Q: Why do many researchers think it will be tough to get pharmacogenomic products approved by the FDA?
A: I think that there are many misconceptions about pharmacogenomics and pharmacogenetics. One reason people may think it will be difficult to get a test approved is because of what happened with Herceptin (the Genentech drug used to treat breast cancer). That was the first time the agency ever looked at a drug and a diagnostic test together, and there may have been some rough edges with that one. But we have learned a lot of from that experience, and now, we expect some submissions will require co-review of a drug and kit. We've worked it out between the agencies so that those co-approvals will not be delayed. We are just waiting for another case, which we will review in an expeditious way.

Q: How many pharmacogenomic studies are you seeing applications for?
A: We did an informal survey of the INDs [Investigational New Drugs] and NDAs [New Drug Applications] that we currently have in the FDA, and we identified 50 submissions that incorporated pharmacogenomics or pharmacogenetics. Between 1995 and 2000, we found 15 such studies, and we mentioned those in the article. Since the paper's publication, we've continued the survey, and found 35 more submissions from 2000 to 2002.

Among those 50 examples, about two-thirds of them involved testing cytochrome P450 enzyme polymorphisms in clinical trials, to identify poor metabolizers (people who are at risk of side effects because of how they metabolize drugs). Some of the other submissions focus on drug target transporters. We haven't seen a prospective pharmacogenetics trial on a new chemical entity [drug], and that is what people are anticipating.

We believe other types of testing will happen. We've been talking to companies about these other types of tests, and we have heard that a lot of the major pharmaceutical companies are collecting samples for testing.

Q: What types of studies do you expect to see in the future?
A: We anticipate that companies will use pharmacogenomics to rescue drugs that might otherwise fail because of an outlier (a large effect seen in a small number of patients). If the drug is working well, but one or a few patients show high blood levels, the company may be able to go back, do either a whole genome scan of those individuals or a candidate gene polymorphism study, and provide a genetic explanation that would satisfy a reviewer.

You could also rescue drugs that have been withdrawn. Let's say a drug gets approved, but it experiences adverse events in the marketplace. If pharmacogenetics is used as a surveillance tool, it can then also be used in a prospective way to better target the drug. Also, you may be able to apply pharmacogenetic information to the next drug that the company is developing in that same drug class.

Q: What will the agency be looking for in these products?
A: We'd like to have meetings with sponsors early on, to get on the table what the regulatory expectations will be. In principal we all agree what is needed: We need a drug that is effective, and a diagnostic test that has real clinical value in identifying patients who should get the drug, or a test that can predict who is predisposed to toxicity. The agency is very concerned about analytical performance of these tests — what is their sensitivity, specificity, and accuracy. The predictive value of the test has to be very high.

Q: What are the next steps for the FDA regarding pharmacogenomics?
A: I think that once we have the public dialogue between industry and the agency, we will have removed some of the fear that something bad will come out of trying to do pharmacogenetics. In the next year or so, I expect to see more pre-Phase II trial meetings, and companies using pharmacogenomics post-approval. The agency also plans to develop a guidance on pharmacogenomics and pharmacogenetics by early next year.

In planning the workshop we have worked with a committee including many of these companies. I found the process of coming together around this workshop signaled a new openness and a new era. This field has tremendous impact on public health, and that is an important goal to strive for. The question now is, "How do we make this happen?"


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