Richard Klein: A Regulator's Perspective

FDA staffer Richard Klein says people often underestimate the risks and overestimate the benefits of taking medications that have not been through the full FDA approval process

by Margaret Wahl on July 7, 2014 - 9:09am

Quest Summer 2014

Richard Klein is the director of the Patient Liaison Program at the Office of Health and Constituent Affairs at the U.S. Food and Drug Administration (FDA).

Q: What is the most common misconception that patient communities have about the FDA's accelerated approval mechanism?

A: I think it's that it's that these approvals are "accelerated," or done faster than usual. But actually that's not what accelerated approval means. It means that the approval process is "telescoped," or "condensed," because the FDA is temporarily relying on an endpoint in a clinical trial that it believes is likely to predict clinical benefit but is not in itself a marker of clinical benefit, such as functional improvement or longer survival. This is what is known as a "surrogate" marker or surrogate endpoint.

A surrogate endpoint can be used instead of a "true" endpoint that shows clinical benefit when a drug is being developed for a serious or life-threatening disease. In some diseases, it would take several years to figure out whether there's a true clinical benefit, such as an effect on survival.

The accelerated approval process always comes with a requirement that the drug continue to be studied post-approval to confirm its safety and benefit.

Q: Is expanded access to a drug an automatic consequence when a drug is granted an accelerated approval?

A: In a very broad sense, yes, because patients have access to the drug while clinical trials are still ongoing. You have mandatory continuation of those trials to make sure you have the clinical outcome predicted by the surrogate marker.

The FDA makes a distinction, however, between the accelerated approval process and the expanded access mechanism. Accelerated approval has to do with the use of surrogate endpoints in a trial. Expanded access is permission to offer an unapproved drug to patients outside a clinical trial and can occur at any point during the course of drug development. The expanded access mechanism can be used outside the accelerated approval pathway.

Q: Is compassionate use the same as expanded access?

A: The FDA only uses the term "compassionate use" in reference to a medical device, not a drug. However, it's a colloquial term for expanded access, and it's actually a good description.

Q: Are there factors related to expanded access that are out of the control of the FDA?

A: Yes. Supplying the drug is out of the FDA's control. The FDA provides the pathway, but it's up to the company developing the drug to say if it's willing or able to supply it to patients.

Q: Besides the harm that could occur to a patient who takes a drug that has not been fully approved, are there risks in making a drug available under an expanded access program?

A: Yes. An expanded access program can interfere with the ability to conduct a clinical trial, which usually requires a control group as well as an investigational treatment group. The control might be a placebo, or more likely, the accepted standard of care.  If patients believe an experimental drug will help them, they often don't want to take the chance of being assigned to the placebo group in a trial; they'd rather just get the drug through the expanded access program. However, many drugs that go into clinical trials prove to be too toxic or are found to be ineffective during the trial, and are withdrawn from development.  So, new is not necessarily better.

And, of equal, if not greater, import, you will never know whether a treatment is actually safe and effective without adequate study. A good example is the use of bone marrow transplantation and high-dose chemotherapy to treat advanced breast cancer. However, it turned out that doing a bone marrow transplant, which seriously impairs quality of life, did not improve survival in breast cancer patients.

Q: What would you most like families of seriously ill patients to understand about unapproved drugs?

A: That's a tough question. I think it's that people often have unreasonable expectations of the therapeutic value of an unapproved treatment. I think the biggest misconception is that, if you could only get access to this treatment, everything would be fine. But that's not often the reality. There are some successes, and they're really terrific. But these are not cures, for the most part.

This article is part of a Web-exclusive series titled Four Perspectives on Expanded Access, which includes the following articles:

Be sure to read The FDA Approval Process: Can We Have This Drug Now? for a Q&A about the FDA and its process for approving new drugs.
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