Financial Incentives to Encourage Development of Therapies That Address Unmet Medical Needs for Nervous System Disorders Workshop Summary (2015) / Chapter Skim
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3 Strengthening the Regulatory Pathway
3 Strengthening the Regulatory Pathway
Pages 31-50
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From page 31... ...
. • The 21st Century Cures Act, which aims to accelerate the discov ery, development, and delivery of new therapies, is currently being discussed in Congress and contains elements that might incentivize companies to pursue CNS drugs that meet serious unmet medical needs (Sperling and others)
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From page 32... ...
Although the regulatory pathway is designed to ensure that only drugs that are safe and efficacious enter the market, several participants noted that the current system has several critical challenges, such as the length of time to approval and to market, and the lack of clarity about regulatory decisions. Workshop participants explored current pathways intended to speed drugs to market in areas of unmet need for serious medical conditions, and examined the promises and pitfalls of adaptive clinical trials and conditional approval pathways for CNS drugs.
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From page 33... ...
Existing Accelerated Pathways FDA has several mechanisms that have been designed to encourage and accelerate development and review of drugs that address unmet medical needs in the treatment of serious or life-threatening conditions: priority review designation, accelerated approval, breakthrough therapy designation, and fast-track designation (see Box 3-1)
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From page 34... ...
To be designated a priority review, the application should con tain data suggesting that the agent provides significant improvement in safety or effectiveness compared to existing therapies, not just deliver the same effect, even if the agent itself is new. • Accelerated approval: FDA gives approval based on a surrogate endpoint or intermediate clinical endpoint that is reasonably likely to predict clinical benefit.
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From page 35... ...
Finally, for accelerated approval, FDA would have to see the effect of the drug on a surrogate or on an intermediate clinical endpoint. For example, FDA has issued draft guidance for developing drugs for the treatment of early-stage AD that says it would use accelerated approval for a drug that improves neurocognitive testing in pre-symptomatic patients (FDA, 2013)
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From page 36... ...
As discussed in Chapter 1, FDA approval times for CNS disorder drugs exceed those in other disease sectors. Approval rates fall only slightly short of those for other medical areas, but this minor difference combined with the other difficulties associated with drug development in the neurological realm makes the area relatively unappealing, said Dennis Choi.
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From page 37... ...
The ability to get accelerated approval on findings that are biologically plausible should trump statistical purity in such disease settings, said Jonas. Woodcock said FDA does accept compelling series in which no one expected people to rise from their bed and walk, yet they did.
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From page 38... ...
The 21st Century Cures Act proposes to permit adaptive trial design and associated analytic methods, a strategy that might better fit some CNS trials, according to a few participants. Adaptive clinical trials allow changes in study design in response to analysis of data at pre-specified points, noted George Vrandenburg.
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From page 39... ...
Detecting subtle increases in dangerous side effects requires large study populations. In addition, Woodcock stated that at this time FDA does not have statutory approval to issue conditional approvals for human drugs.
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. In this system, highly selected drugs would be marketed in a limited fashion, based on biomarker or intermediate clinical data; a full period of market protection would become available after the drug sponsor obtains conventional data and clears the usual regulatory hurdles.
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From page 41... ...
Early-phase studies provide crucial information about how best to use the drug -- the clinical window for intervention, appropriate indications and dosage, and under what conditions toxicities appear. To shorten the time period of pre-market testing, it is likely that clinical trials would accept a more idealized and narrow population for study; as a result, some of this information would not be forthcoming before approval.
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From page 42... ...
Coetzee underscored the idea that workshop participants held widely disparate views on whether and how to improve the regulatory process. He noted a "mixed kind of view" about whether such changes are needed and highlighted the strong "differences of perspective." CLARITY OF REGULATORY PROCESSES AND DECISIONS Woodcock emphasized the importance of predictability, as previously discussed, and described the agency's efforts to communicate and work with relevant constituencies on the use of the various existing regulatory pathways.
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From page 43... ...
In the MODDERN Cures Act, "unmet medical need" is determined and designated not at the time a drug is approved, but at the time a drug sponsor files a clinical plan, said Engelberg. This can be problematic because companies tend to be overly optimistic; they often think that agents that are the second or third in a class will meet some unmet medical need.
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From page 44... ...
BOX 3-2 Opportunities for Improving Pathways to Market: A Global Perspective on Dementia Improving regulatory processes to help bring innovative therapies that treat unmet medical needs for nervous system disorders to patients faster requires a global effort, according to several workshop participants. Using dementia as a starting point, Raj Long, senior regulatory officer for integrated development in global health at The Bill & Melinda Gates Foundation, described the efforts from the G8 Summit on Dementia held in December 2013a which brought together health and science ministers from all G8 countries to discuss finding a cure for dementia.
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From page 45... ...
Each country was also charged with hosting a follow-on global dementia legacy event to con tinue to discuss how to foster the development of effective therapies for dementia. As a follow-on activity, the first Global Dementia Regulators work shop was held in November 2014 to discuss dementia research gaps, de velopment challenges, and regulatory science.
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Rhonda Robinson Beale, senior vice president and chief medical officer at Blue Cross of Idaho, discussed how health plans decide what drugs to cover. The amount of money that goes into specialty drugs recently has increased dramatically.
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From page 47... ...
Insurance companies seek guidance from FDA about which patient populations benefit from new treatments, but such an approach does not take into account information gathered by practicing physicians, who commonly use drugs off label as they attempt to improve outcomes for their patients. In addition, Robinson Beale noted that clinical trials do not always compare the test treatment with a standard one, so when a new drug comes to market, insurance companies do not know how it compares with available treatments.
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From page 48... ...
OPPORTUNITIES TO INCENTIVIZE R&D BY STRENGTHENING REGULATORY PATHWAYS • Amid the broader discussion, several participants also made a specific proposal to develop a regulatory pathway that aggres sively hastens conditional approval of drugs that help patients with serious CNS diseases for which no therapies exist. Such a pathway would empower FDA to extend the existing accelerated approval pathway to CNS drugs that demonstrate substantial im provements early during clinical development based on bi omarker or intermediate clinical data, with the understanding that such surrogates are not as available or strong as they are for other medical arenas in which this type of pathway has previous ly been deployed (HIV/AIDS and cancer)
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From page 49... ...
This mechanism is intended to increase market protection for therapies that address medical problems that currently have no effective treatments, and its initial use would be targeted toward a few drugs that show unusual promise in terms of effect on a serious unmet medical need, underlying scientific support, and availability of an appropriate surrogate marker. Woodcock raised several challenges about this proposed mechanism, stating that there are a number of legal and ethical considerations, including determining which patients should have access to the drug, restricting the distribution of the drug to the limited population, and facing the implications if the drug has to be rescinded (Choi, Engelberg, Maderis, O'Donovan,3 Reddy, Rogawski, and others)
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