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Cancer patients are paying for the FDA's caution.
Why narrowing accelerated approval costs lives.

Dr. Scott Gottlieb
Medical Progress Today
May 27, 2005

Accelerated approval for cancer drugs at the Food and Drug Administration just got a lot slower.

Accelerated approval regulations essentially allows the FDA to approve drugs that treat unmet medical conditions (such as many advanced stages of cancer, for which there are currently no effective therapies) based on the results of early stage (Phase II) data.

This gives cancer patients access to new drugs based on their ability to improve a “surrogate” endpoint (like shrinking tumors or arresting their growth), rather than a clinical endpoint (like reduced mortality), which can take years longer to verify.

The policy goal behind “accelerated” approval is to get drugs that treated life-threatening problems to patients as quickly as possible.

In return for early market access, the drug’s developer must promise to study the drug after it is approved and confirm that it does, in fact, extend the lives of patients, or improve their symptoms.

Over the past year, however, the Food and Drug Administration’s cancer division has taken a series of policy positions that has effectively hamstrung accelerated approval.

These new policies mean that accelerated approval is closed to all cancer treatments except for the rare compound — like the leukemia drug Gleevec — that represent a true paradigm shift in chemotherapy. This is the equivalent of a baseball manager demanding that every hitter swing for a grand-slam before they are allowed to bat.

It’s a recipe for increasing the cost and uncertainty of cancer drug development, with no real pay-off for cancer patients, who depend on incremental scientific advances — bunts, singles and doubles — to keep their disease at bay until the next grand slam comes along. Over time, the accumulation of small, incremental improvements in cancer drugs have led to many of the dramatic gains in life expectancy that many cancers now enjoy.

The grand-slam mentality has been codified in a series of decisions by the agency’s Office of Oncology Drug Products. It has also been reflected publicly by the agency’s Oncology Drugs Advisory Committee (ODAC). This outside panel advises the FDA on cancer drug approval decisions, and is comprised of top cancer doctors drawn from the ranks of academic medicine.

ODAC’s new chair, Dr. Silvana Martino, believes that drug companies are developing too many marginally effective cancer drugs. At one recent meeting, Dr. Martino said that “I wish someone would excite me,” referring to her desire to see more drugs with overwhelming efficacy brought before the panel.

Dr. Martino made this remark despite the fact that incremental improvements through new medicines have been the hallmark of gains in cancer survival and quality of life — drugs that dramatically change treatment paradigms are very few and far between.

ODAC’s endorsement of the FDA’s new “go slow” cancer policies gives them added weight and permanency. This means that they are likely to remain in place, at least for a while, until a backlash erupts among cancer doctors and patient advocates who see their chance to explore new treatment options increasingly limited by the FDA.

The recent policy changes by FDA’s cancer division are threefold.

The most recent policy change came this month, in the cancer division’s review of Zarnestra, a drug developed by Johnson & Johnson for treatment of aggressive acute myeloid leukemia (a type of blood cancer). Zarnestra was the farthest along among a new class of cancer compounds called farnesyl transferase inhibitors. ODAC ultimately rejected the drug, following the cancer division’s advice. Their decision reflected a concern that a “confirmatory” study promised by J&J was “not likely” to demonstrate that the drug extended patients lives.

This was the first time that ODAC used the structure of the confirmatory study as a rationale to deny accelerated approval to an otherwise effective drug. If this precedent holds, it means that companies are only going to get one shot at doing a confirmatory study. Moreover, ODAC needs to feel reasonably sure that a new drug will yield favorable results when they approve it under the accelerated pathway. In essence, they have to impute an outcome into a study that hasn’t taken place yet.

Good luck.

Another policy change is that, going forward, ODAC and the FDA cancer division will be interpreting “existing therapy” broadly when they consider whether a new drug provides an improvement over current treatments. Current treatments, or “existing” or “available” therapy as it is defined in regulatory parlance, will now include all of the medicines that doctors might be using off-label to treat the same type of cancer.

Finally, FDA’s cancer division has made it clear that a new cancer drug will not be eligible for accelerated approval based on data that leaves only a presumption of benefit. Unfortunately, the kind of preliminary trial data that has historically been available at the time of accelerated approval rarely reveals the full scope of its eventual benefits.

The policy also focuses on a new drug’s efficacy to the exclusion of all of the other reasons a patient may be driven to choose one treatment over another. In the real world, the patients I see on my medical rounds make tradeoffs like these every day — opting for slightly less effective medical regimens if it means they will suffer fewer side effects from their treatments.

Taken together, the cancer division’s new policy direction is likely to frustrate companies trying to bring new products to the agency for accelerated approval.

FDA’s cancer specialists, in other recent public meetings, have also openly bemoaned what they call a “race to the bottom,” wherein biotech companies opt for the shortest possible clinical trials in order to get their drugs to market as soon as possible. The FDA wants cancer companies to spend more time to generate more data about the ultimate effectiveness of their new drugs.

Delaying new treatments for the sake of generating more rigorous and complete medical evidence helps patients, to a point. But in the field of cancer, where practicing oncologists already do a good job of developing their own medical evidence, and prescribing new medicines based closely on the results of these scientific studies, the FDA’s strict posture is probably overkill.

More rigid standards might make sense for routine medicines like blood pressure pills and antihistamines, because medical options already exist for these conditions. The same is not true of cancer, however. Despite recent success, many cancers still have few effective treatments. Even diseases like breast and colon cancer, which have benefited from recent innovations, still claim too many victims, especially when these diseases reach advanced stages.

The FDA is trying to save patients from the harmful effects of new medicines that have not fully proved their mettle. But regulatory delays make drug development more expensive, closing out the market to small biotech firms with good ideas, and keep new drugs from dying patients.

Under current FDA cancer policies, many more patients will die waiting for the “home-run” drugs than would be harmed by mediocre ones.

Scott Gottlieb, a practicing Internist, is a resident fellow at the American Enterprise Institute and a former senior official at the Food and Drug Administration. His FDA policy blog can be found at

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