Continuing the Discussion of “Conditional Approval” and the Accelerating Access/Ensuring Safety and Efficacy Dilemma

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Last week I commented on an excellent New England Journal of Medicine article by Darrow, Avorn and Kesselheim -New FDA Breakthrough-Drug Category- Implications for Patients, 370 New Eng. J. of Med. 1252-1258 (March 27, 2014)- on the problems of accelerated approval. Then today my attention was drawn to another excellent article on the early access dilemma for critically ill patients: Karl Thiel, Did Chimerix, Inc. (CMRX) Set A Bad Example For Biopharma?, available at (visited April 4th 2014). The topic is clearly an extremely important one, and in need of much more serious discussion.

At the end of last week’s post, I suggested that the history of the FDA’s response to the push by AIDS activists could provide lessons for today. Prior to the AIDS crisis of the 1980′s, no patient advocacy group had ever focused their attention on the FDA and on the fact that the FDA process creates a(n inevitable) delay in the ability of desperately ill patients to access potentially life saving new therapies. The patient advocacy groups before AIDS, such as the American Cancer Society and the American Heart Association, focused their efforts on raising money for research and paid virtually no attention to the FDA. With AIDS, and particularly with ACT UP (AIDS Coalition to Unleash Power), the world changed and the pressure on the FDA to do something, anything, to get experimental drugs out to patients was enormous. The FDA responded with a number of efforts to allow expanded early access,1with themost far reaching of those efforts (in concept, not in terms of subsequent history) being the Parallel Track program referred to in my last post. I am not suggesting that Parallel Trackbe resurrectedin its 1992 formand expanded to other diseases, only that there were elements of the Parallel Track program that could be used to construct a program that draws a better balance between access and benefit/risk than the current model of accelerated approval based on questionable surrogate endpoints followed by a post-marketing commitment to do a further study in “Phase IV). In Parallel Track, as it was adopted in 1992,2each physician treating an HIV patient who became part of the Parallel Track program became a clinical investigator, under a protocol that specified the data to be collected and with a data monitoring boardto regularly review the physician/investigator reports. Parallel Track allowed the sponsoring drug company to charge for the drugs at a price to be approved by the FDA. These four core elements- physician investigators, a protocol specifying the safety and efficacy data to be reported by those investigators, a data monitoring board, and an approved distribution price, are at the heart of my proposal to replace, at least in some cases, accelerated approval and Phase IV commitments with a form of “conditional approval”/expanded access to any critically ill patient whose physician is willing to enroll in the distribution program. Let me briefly expand on these.

First- physician investigators. Physicians treating patients with late-stage cancer, ALS, Alzheimer’s, or other diseases with a predictable, terrible prognosis and no real treatment options have to be made aware of the opportunity to use a still experimental drug to treat their patients and they have to be reasonably compensated both for their care and for their participation in the data collection process. For Medicare patients, HHS can establish the appropriate guidelines and rates, but for the private insurance patients the question is more complicated. While a full answer to the private insurance reimbursement problem is beyond the scope of this post, it must be kept in mind that under the current system, private insurors would generally be expected to pay full freight, at extremely high prices, for drugs that are approved under accelerated access where there are no real therapeutic alternatives. So insurors actually come out ahead by coming on board under a system in which the prices are much lower until the benefits and risks are more clearly understood, even with additional compensation to treating physicians

Second, the protocols under which the drugs are to be distributed must necessarily be relatively minimalistic. Ordinarily, physicians treating patients with diseases that would be considered for this expanded access program are well-prepared to regularly assess their patients‘basic disease status. They are also reasonably well-prepared (and already expected) to report potential adverse effects. These two data endpoints, basic disease status (as defined appropriately for a given disease in the protocol) and possible adverse events, are likely to be sufficient to determine the drugs‘real world safety and efficacy,once sufficient patients have been treated for an adequate period of time. Of course,the protocol must alsopre-specify the criteria for evaluating the outcome: what duration of survival, rate of decline in cognitive or physical function, etc., would constitute proof of efficacy. Again, for these types of diseases, the course of disease is known well enough to allow this kind of open label trial to be fairly evaluated for efficacy. In fact, in the Chimerix case discussed in Thiel’s article cited at the beginning of this post, an open label trial was the solution to that particular problem precisely because of the well-established mortality and morbidity outcomes for that indication.

Third, a data monitoring board, that can both review the data and request that either full approval be given or the trial ended and the drug discontinued,is a requirement that really needs no elaboration. The use of data monitoring boards in clinical trials is a well established practice that can easily be adapted to this new use.

Fourth and finally- the price of these still experimental drugs will need to be approved by the FDA, but it has to be enough to justify the additional costs and efforts of drug sponsors. Aaron Kesselheim, a coauthor of the New England Journal article, was kind enough to emphasize this point in a response to my previous post. NOTE- I am not by any means suggesting price controls for pharmaceuticals generally. I am completely in support of drug companies being able to set their own prices for their drugs, and for drug companies reaping significant, market-driven rewards for breakthrough therapies. There is no reason for the pharmaceutical industry, which contributes greatly to our health and welfare, to be singled out for price controls. Gilead can charge whatever the market will bear for Solvadi, which seems to be a truly breakthrough drug. What I am suggesting, however, is that it is inappropriate, almost to enter the market at breakthrough drug prices before it is demonstrated that a drug truly is safe and effective.

The FDA has the power to move forward with this concept. I hope that the discussion I am attempting to initiate here continues, that patient advocacy groups weigh in, and that we can get beyond the current unsatisfactory status quo in the process of approving drugs for seriously ill patients.

1 FDA has taken significant steps, primarily in response to the HIV/AIDS crises, toward making experimental drugs intended to treat life-threatening diseases more widely available to severely ill patients, as well as toward speeding the review and approval of the applications for these products. (visited April 4th, 2014).

2 PHS, HHS, Expanded Availability of Investigational New Drugs Through a Parallel Track Mechanism for People With AIDS and Other HIV-Related Disease, 57 FR 13250-01 (April 15, 1992).

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