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Proposals to Speed-Up Drug Approvals: Not Created Equal

An important part of the 2012 user fee reauthorization cycle is Congressional efforts to push FDA toward approving drugs and biologics more rapidly. Most of industry and a large number of patient groups agree. Proposals to speed up FDA are already in play.

Since these proposals have a common purpose, it is easy to think of them as alike. However, most are different from each other—in focus, intent, and likely impact on the agency’s existing decisionmaking process. This is FDA Matters’ analysis of why proposals to speed up drug approvals can’t be lumped together and why FDA may support some, but not others.

Is FDA really too slow? Efforts to speed up drug approvals start with an implicit assumption: FDA is approving drugs too slowly. The conventional wisdom is that FDA’s positioning swings over time like a pendulum. FDA allegedly gets "too easy" with its approvals, but then a few years later is faced with a major product recall over safety issues.

The FDA then hunkers down and the pendulum swings toward being slow and rigid. Finally, the bad experience becomes less immediate in the agency's mind and the pendulum swings back toward “too easy” and the cycle starts again.  

The FDA mindset. FDA hates this metaphor, but secretly fears it might be true. As a result, the agency has been working toward being more consistent….and less prone to the alleged pendulum swing. Among other things, the agency is trying to publish more official guidances and handle perceived blockages proactively (e.g. prospects for obesity drugs seem to have improved since the failure of three such drugs to gain approval in 2010).

Some of this spirit of change is reflected in the agency’s October 2011 white paper, Driving Biomedical Innovation:  Initiatives to Improve Products for Patients. Likewise, as part of the new user fee workplans, FDA and industry agreed to work together, particularly earlier in the development process, so that there are fewer surprises and more approvals. 

Proposals for speeding up drug approvals.  Improving the existing accelerated approval process is the goal of the Faster Access to Specialized Treatments or FAST Act (HR 4132) and section 301 of the Transforming the Regulatory Environment to Accelerate Access to Treatments or TREAT Act (S. 2113).

Accelerated approval allows surrogate endpoints as the basis for demonstrating efficacy. FDA uses this example: “instead of having to wait to learn if a drug actually can extend the survival of cancer patients, the FDA might now approve a drug based on evidence that the drug shrinks tumors because tumor shrinkage is considered reasonably likely to predict a real clinical benefit.”

The two bills would broaden the means to demonstrate clinical benefit by encouraging use of emerging scientific methods and tools and allowing a wider range of surrogate and clinical endpoints. The bills would explicitly codify the accelerated pathway in law.

A different approach is taken in the Advancing Breakthrough Therapies for Patients Act or the Breakthrough Act (S. 2236).  This bill would “provide more flexibility when a drug or treatment shows dramatic responses early in development, while still ensuring drug safety and efficacy. For patients, this proposal would allow FDA the ability to move towards more innovative clinical trials, such as minimizing the number of patients enrolled in trials and shortening the duration of trials, when scientifically appropriate.”

This reflects a reality: FDA often feels constrained in situations where common sense dictates special handling. An example might be a new melanoma treatment that was approved in August 2012, after receiving significant assistance from FDA to move the drug forward rapidly. However, after reading an earlier NY Times article, it is easy to imagine that FDA might have been even more flexible, but felt constrained.

Finally, some commentators have included former FDA Commissioner Andrew von Eschenbach recent Wall Street Journal article in their discussion of “speeding up FDA approvals.” He advocated “creating FDA pilot programs to bring promising therapies to patients more quickly by allowing them to be approved based on safety, with efficacy to be proven in later trials.”

Speculation on FDA’s position. FDA is certain to oppose Dr. von Eschenbach’s proposal if offered as a legislative amendment. However, FDA is still deciding its position on FAST/TREAT and the Breakthrough Act.

In response to a Congressional question, FDA spoke favorably of the Breakthrough Act.  The key is that FDA is given discretion to provide more rapid and higher level process, but is not directed to change the standard of proof or the meaning of efficacy or safety.

FDA has been more hesitant about FAST/TREAT. Informally, it opposed a prior iteration because, among other things, it lowered standards by not requiring prior validation of a surrogate endpoint.  My understanding is that FDA is considering whether its concerns have been addressed by these later versions of the bills.


2 Responses to “Proposals to Speed-Up Drug Approvals: Not Created Equal”

  1. Steve Walker says:

    I really liked your analysis of what is going on with the various proposals to speed up drug approvals. I think you are right on target with respect to the effect FDA is having.

    I also think you were a little too charitable by describing what OODP (now OHOP) did with Zelboraf (then PLX4032). If they felt constrained, it was because of the regressive policies put in place by Dr. Pazdur, Director of the FDA’s cancer drug review office, and his senior staff. FDAMA created a clear path to rapid approval by the end of a single arm Phase II for a drug like Zelboraf, and an even earlier path to patient access through a Treatment IND, had the leadership of that office not been engaged in a long term, aggressively enforced campaign to effectively eliminate Accelerated Approval for most cancer drugs. The existing statute is quite clear that a drug like Zelboraf should have moved through the system much faster than it did, without there ever having been a requirement imposed by FDA for a pre-approval Phase III RCT. The statute is also exceedingly clear that Phase IV trial requirements are discretionary. The text of the law is “may” require, not “shall” require. This leaves broad discretion to FDA to decide whether a Phase IV trial is needed, and what the design of that trial should be. For example, the FDA could have required no Phase IV trial, or Phase IV trials that could actually be enrolled and ethical in a Phase IV setting (e.g., single arm safety and targeting trials).

    The problem with FDA’s handling of this cancer drug, and many others in recent years, has not been statutory constraints, but rather FDA’s use of the discretion it has under the FDCA; discretion it has used to decide for itself that it isn’t going to use that discretion to make good decisions for the public health and patients. Instead it has used its discretion (especially in oncology) to establish rigid policies, and then to enforce them, whether they make any sense or not. I know why OODP backed off their requirements for Zelboraf (too late by the way). It happened as a result of the outrage that surfaced when what they were doing became known to the patient and physician community. Some people in OODP, including its director and the senior staff overseeing the handling of Zelboraf, should have been fired for how the drug was handled. Instead, they were allowed to try to “fix” the problems they precipitated, which they actually failed to do. All the people who died prematurely in the control arm of the medically and scientifically meaningless BRIM3 trial remained dead, and availability of the drug was delayed by about two years beyond the point where it should have started to become available through an access program – an outcome devastating to thousands of additional patients with metastatic melanoma.

    There really isn’t any valid excuse for what OODP did with that drug, including your premise that they felt “constrained.” They weren’t constrained by law or regulation. They were “constrained” by ill-considered policies. Policies have no legal or regulatory force, and should not be followed when doing so will cause regulation that runs counter to the agency’s mission, the public health and the best interests of patients, especially when those patients suffer from a terminal (in the near term) disease like metastatic melanoma. Tragically, the concept that the public health outcome matters most doesn’t seem to be part of the OODP regulatory and policy paradigm; a reality that seems to exist in similar form in some of the other review offices at FDA..

    The Phase III BRIM3 trial for Zelboraf was required by FDA before they decided to try to unrequire it – after it was fully enrolled, or nearly so, and reaching maturity in terms of deaths in the control arm. From the start, the trial crossed the line from the marginally ethical human clinical testing routinely required by OODP, to clearly unethical, unnecessary regulation pursued in conformance with a set of ill-considered policies.

    Dr. Janet Woodcock, Director of CDER with oversight responsibilities for OODP, used the FDA’s belated approval of Zelboraf as an “example” of how FDA can move quickly last week in her testimony to the HELP committee, failing to mention any of the serious problems with OODP’s handling of the drug. I think that fact alone makes it clear that Dr. Woodcock and her senior staff still don’t fully “get” just how awful OODP’s handling of that drug actually was. By trying to spin the agency’s handling of Zelboraf as a positive, I think it shows how far the FDA still has to go before it can begin the process of improvement and cultural change that is so much needed.

    I have thought for several years now that the change needed at FDA cannot begin with the agency’s existing career senior leadership. They created the mess, and they still don’t seem to recognize the magnitude, or even fully the existence, of the mess. Last year, I proposed a change to the text of the FDCA (http://abigail-alliance.org/docs/FDLISteveWalker.pdf) to allow the agency to escape its relative frequentist approval standard straitjacket (which is what OODP’s rigid policies are based on). FDAMA already created a pathway to faster approvals, but was not clear enough about the intent that FDA should develop policies to make Accelerated Approval work. Congress also didn’t make it clear, and still isn’t making clear in my opinion, that FDA should begin to look at more modern clinical trial and approval endpoints, which would have be facilitated by changing the text of the FDCA as proposed in my article cited above.

    Unfortunately, it appears no one inside the FDA is willing to start considering the level of change now needed.

    So where does that leave us? It leaves us (at least some of us) wondering why FDA is presently being allowed so much weight in deciding what level of reform Congress should impose to get the agency moving. If FDA is allowed to set the limits of that change, whatever happens won’t be enough. FDA needs a very hard and prescriptive push from Congress, and if we have to wait another 5 years for that push to come, we will end up that much farther behind where the agency needs to be, with all the consequences that entails for patients and progress.

    I like your column. I also think some straight talk about FDA’s failures is very much needed right now, and I don’t think sugar-coating those failures is helping the public to understand why strong, prescriptive measures from Congress are also very much needed – right now.

    Some will no doubt be offended or angered by this post because it violates the unwritten rule that names should not be named, and mistakes made by FDA are no one’s fault, but that would be the kind of non-accountability that caused the mishandling of Zelboraf in the first place, and if not addressed honestly and openly, will lead to its repetition.

    Steven Walker

    Co-Founder, Abigail Alliance for Better Access to Developmental Drugs

  2. kpetrak says:

    Surrogate endpoints need to be validated for the purpose. Remember bisphosphonates? Increased bone density did not decrease, but in fact increased the bone propensity to fracture, it made it more fragile.

    “FDA and industry agreed to work together, particularly earlier in the development process, so that there are fewer surprises and more approvals.” This may not help much since it is the result of end-stage of the process, i.e., clinical studies that are all important, time consuming and most costly.

    …“creating FDA pilot programs to bring promising therapies to patients more quickly by allowing them to be approved based on safety, with efficacy to be proven in later trials.” How do you identify “promising therapies”? How much do you charge the customer/patient for a product that is safe but has not been shown to work. Might as well sell placebo since, depending on the disease/condition, placebos have been shown to be effective, typically some 30% but on occasion as much as 50%. This approach would bring drugs to the level of nutritional supplements and alternative medicine where the marketing angle is that “it will do you no harm” and “if it does not work, we shall return the money, no questions asked”. Dr. von Eschenbach has this back to front…

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