BioWorld Today Columnist

FDA's hardening stance on accelerated approvals has been much in the news lately. Not only have several past accelerated approvals been revisited lately – Roche AG's Avastin for breast cancer, Pfizer Inc.'s Mylotarg for acute myeloid leukemia, and Shire plc's ProAmatine for orthostatic hypotension – but the agency seems to be getting more conservative in an effort to avoid potential future controversies. (See BioWorld Insight, Sept. 27, 2010.)

The agency's refusal to consider Roche and Immunogen Inc.'s trastuzumab-DM1 for accelerated approval, for example, despite the fact that it has shown activity in HER-2 positive breast cancer patients who have failed multiple courses of prior therapy, has caused a lot of bewildered head-shaking in the industry. And in a recent New York Times article, Roche was taken to task for not even seeking accelerated approval for PLX4032, a promising melanoma drug.

While the implication in that piece was that the company is seeking to put together the best possible marketing package against potential future competitors, it is likely that the company is considering how to meet FDA's stricter stance on accelerated approval and subsequent data collection.

And the program seemed to be going so smoothly for the past 17 years. How did we get here?

The debate over accelerated approvals has been framed in largely black-and-white terms: On the one side, the need to speed the availability of new medicines to patients with few other options; on the other side, the desire to maintain scientific rigor and public safety. It sometimes seems as if these two goals lie at opposite poles, with a move in one direction a compromise for the other side. But that needn't be the case, and the real misfortune is that neither the FDA nor the industry seems to be moving toward a path that will mean better drugs for patients.

FDA's Office of Oncology Drug Products has a good reason to be cautious about accelerated approvals. The most commonly used surrogate market to support an early approval for a cancer drug is tumor regression, and it's just not that great an endpoint. There are lots of reasons why a drug might shrink a tumor and yet not really improve that patient's survival or quality of life. Among them is that accelerated approval focuses on drugs for very sick patients whose cancers have often metastasized, and it is these metastases rather than primary tumors that more often kill patients.

Frankly, the track record with accelerated approvals has been pretty good when you consider this. Some expectation of subsequent failure should be built into the system by definition – after all, if tumor regression was 100 percent predictive of improved survival, spending the time and money necessary to do actual survival studies would be unethical.

It is rightly assumed that there will be times when tumor regression doesn't predict survival, and when this happens it isn't a failure on the part of either the sponsor or the FDA. Thus, the recent spate of reevaluations doesn't by itself signal a problem with the system.

The real issue is making companies come up with the follow-up data to support accelerated approvals in a timely manner. Mylotarg was approved in 2000, for instance, but Pfizer (then Wyeth) didn't even start the confirmatory studies until 2004. Once a drug is on the market, companies have little incentive to gather data that could undermine an approval, particularly if there are no competitive products to deal with.

The FDA's Risk Evaluation and Mitigation Strategy (REMS) authority should do a lot to force companies to go to market with plans already in hand for following up on surrogate endpoints, but that also means companies have to think ahead more seriously about how that data will be gathered. Thus, you see cases like PLX4032, when a drug that looks like a shoo-in for accelerated approval may have to complete a traditional survival trial because no one will be willing to risk not getting an effective therapy by enrolling in a clinical trial after approval.

That small piece of perversity, however, pales in comparison to other distortions created by the current system. Looming large among these is the fact that companies now deliberately pursue tumor regression in very sick patients as an end unto itself. If FDA shakes the industry out of that tendency, it's doing a good thing.

Here's a test: Try explaining to someone with no connection to the industry that extending a patient's life for four months pretty much counts as a cancer breakthrough. They'll look at you like your nuts. How about curing someone's cancer? How about preventing it? Now that would be a breakthrough.

The problem with accelerated approval isn't that drugs sometimes get approved that shouldn't be – that's part of the system.

The problem is that it fails to incentivize the kinds of drugs we really need. It creates incentives to use relatively cheap, quick trials to get drugs that may have marginal benefits on the market so that companies can slug it out with marketing instead of science.

Of course, this cuts both ways. By getting stricter about accelerated approvals, the FDA may guide the industry back toward a focus on survival. But that's all stick and no carrot. The agency also needs to make it feasible to create the kinds of drugs that will make major differences in more people's lives.

One step would be to make it easier to test and approve combination therapies. Back in March, the FDA announced it was devising guidelines to ease the regulatory pathway for drug cocktails, which have proven crucial in controlling HIV and could undoubtedly play a greater role in improving cancer care. On June 8, the FDA published a Federal Register notice asking for comments on "co-development of investigational drugs," but so far there's been no other formal action.

Nevertheless, this has the potential to be the carrot that can coax drugmakers into creating more innovative products.

The FDA has said that its aim is to address sponsors "co-developing two or more distinct, novel investigational drugs intended to be used in combination . . ." That's a far cry from its current approach to combination therapies, which generally allows only one novel product to be combined with an already-approved agent, and won't consider an accelerated approval unless the novel agent has shown efficacy as a monotherapy. And notice the wording: Two or more distinct, novel investigational drugs.

That doesn't mean a new agent with some standard chemo thrown in; it means a chance to try treatments involving multiple new approaches. Like maybe going after cancer's rapid mutagenesis much the same way virologists went after HIV.

And who knows what might be next? Maybe the FDA will make it easier to test and approve drugs aimed at cancer prevention.

With these kinds of changes, patients may be more willing to give the agency the benefit of the doubt the next time it moves to take an approved cancer drug off the market.

Karl Thiel, an analyst for the Motley Fool, can be reached at kthiel@qwest.net. His opinions do not necessarily reflect those of BioWorld Today.