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See article page 426 United States, can yield insights into the feasibility of ongoing evidence development after drug approval, particularly for efficacy data. Trials to confirm efficacy for HIV therapies have generally been reliably completed, most likely because they represent an extension of registration trials and therefore are fully enrolled and ongoing at the time of approval. Accelerated approval in orphan diseases and cancer presents a mixed picture. In cancer, as pointed out by the CBI discussants, further trials in the approved indication are often not feasible or ethically permissible. Therefore, developers and regulators have adopted the strategy of studying other disease stages or indications for confirming efficacy. Drugs for orphan diseases pose similar problems. When trials to confirm efficacy are not completed, regulators are faced with the choice of withdrawing the drug from patients who have a serious or life-threatening disease lacking alternative therapy or acceding to ongoing marketing without clear evidence of efficacy. As a result, the United States accelerated-approval scheme shifts the burden of proof to regulators if the envisioned trials are not finished or fail to confirm benefit when analyzed. More widespread use of accelerated approval would probably require definitively placing this burden on drug developers in exchange for earlier market access. Determining tolerance for uncertainty about drug safety is an even more difficult issue. Establishing safety is the rate-limiting step in development programs for some chronic diseases. FDA has developed a staged approach to safety as wellfor example, the two-step process recommended for establishing the cardiovascular safety of diabetes drugs.2 At the point of approval, data should demonstrate that the upper bound on the confidence limit of the risk ratio for cardiovascular events versus comparators is below 1.8; after approval more randomized data should be collected to show that the upper bound is below 1.3. This staged approach allows developers to reach the market by incorporating cardiovascular safety measures in trials done to demonstrate efficacy, without a huge additional burden, and to further refine the estimate of cardiovascular safety as a postmarket requirement. In other cases, uncertainty about safety or performance in the market

Evidence vs. Access: Can TwentyFirst-Century Drug Regulation Refine the Tradeoffs?
J Woodcock1
As the pharmaceutical industry productivity crisis worsens, there are calls for regulatory changes to support innovation. At the same time, prescribers and payers desire more information about drugs at the time they are released to the market. Will new regulatory schemes be able to accommodate these disparate needs?
Drug development can be defined as the progressive reduction of uncertainty about human responses to a candidate medicine. Considerable uncertainty about these responses often remains at the time of drug approval, despite research programs that can cost hundreds of millions of dollars and span a decade or more. Drug developers and investors are distressed at the magnitude and duration of the investment required to bring a candidate to market; many are concerned that these costs are unsustainable. Conversely, academicians and consumer groups maintain that the evidence about drug safety generated by drug development is inadequate, and medical professionals often call for more information on practical use. Drug regulators are caught between the need for evidence development and the need for accessaccess to markets on the part of drug developers and access to new medicines on the part of patients. Although some advocacy groups are skeptical about the benefits of a robust drug pipeline, most stakeholders feel that a healthy drug development enterprise is essential for translating new biomedical discoveries into patient benefit, and thus they support policies that acknowledge these tradeoffs. In this issue of CPT, Eichler and colleagues report on discussions undertaken by the Center for Biomedical Innovation (CBI), a consortium based at the Massachusetts Institute of Technology, on ways to refine the tradeoffs between evidence development and access by using what they term adaptive licensing.1 Adaptive licensing envisions a more explicit acknowledgment that evidence development is a continuumregulatory approval would come in steps or stages. Market access and use in practice would be restricted in a manner commensurate with the current level of knowledge, and evidence development would continue in parallel with marketing, using evidence from clinical practice as well as randomized trials. Eichler et al. discuss a variety of options for staged approval. Many of these are currently used in the United States (Table 1). The success of an adaptive-licensing approach is predicated on several assumptions: first, that ongoing robust evidence development will reliably occur after approval; second, that restrictions on use in the market are feasible; and finally (the most difficult) that the tradeoffs inherent in such a scheme will be accepted by all the participants in the health-care ecosystem, including providers, drug developers, payers, patients, regulators, and legislators. Current models of staged approval, particularly accelerated approval in the

1Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA. Correspondence: J Woodcock (janet.woodcock@fda.hhs.gov)

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Table 1 Current feasibility and use of elements of adaptive licensing under the existing US drug regulatory framework
Basis of initial approval On surrogate not fully validated or intermediate clinical end point Restrictions on approval Less rigorous than usual statistical criteria Single-arm study for efficacy Single-arm study plus confirmatory evidence Approval in narrow population with restrictions on use; further studies required postmarket US mechanism Accelerated approval REMS For rare diseasesregulatory flexibility Accelerated or traditional approval Accelerated or traditional approval No satisfactory mechanism to prevent off-label use Feasibility of use Current practice For safety issues Permissiblea When historical control available Survival studies or where strong confirmatory evidence exists for serious disease Would require additional legislative authorities

The current drug regulatory framework has significant flexibility, including the mechanisms listed above the shaded area in the table. These include approval based on an unvalidated surrogate end point, as well as approval with restrictions for drugs with safety problems that could not otherwise be approved absent restriction. There is also flexibility in the requirements for demonstration of efficacy, based on the circumstances. However, a formal early stage approval mechanism does not exist and would require legislative changes. REMS, risk evaluation and mitigation strategy. aSasinowski, F.J. Quantum of effectiveness evidence in FDAs approval of orphan drugs. National Organization for Rare Disorders <http://www.rarediseases.org/docs/policy/ NORDstudyofFDAapprovaloforphandrugs.pdf> (2011).

is handled by imposition of a risk evaluation and mitigation strategy (REMS), which may be removed with additional evidence. Despite these strategies, residual uncertainties about drug safety continue to create considerable controversy. Eichler et al. offer several suggestions for dealing with uncertainty about safety. They suggest, for example, that efficacy trials and large-scale safety trials be de-linked in drug development, with the safety evaluation being carried out in a large, simple trial that would be easier to accrue and conduct. There are no regulatory barriers to this approach, providing that the safety end points are evaluable in such a trial. This can be difficult, as illustrated by the considerable controversy about the RECORD trial evaluating the cardiovascular safety of rosiglitazone against other antidiabetic regimens. Although the RECORD trial was randomized, concerns were raised about its open-label design.3 Large-scale safety evaluations in chronic diseases typically utilize noninferiority designs; in other words, their goal is to establish that the new treatment is not inferior (within a certain margin), with respect to a prespecified safety end point, to alternative therapy or placebo. The safety events of interest are those that already occur with some frequency in the patient population. Under these circumstances, very large randomized trials may be needed to provide adequate statistical power, and double-blind designs may be needed to address concerns about bias. For example, the US Food and Drug Admin-

istration (FDA) has agreed to the design of randomized postmarket trials evaluating the safety (in terms of serious asthma complications) of inhaled long-acting beta agonistcorticosteroid combinations compared with inhaled corticosteroids alone.4 These trials have been criticized both for being too small (to rule out a certain increase in events) and for being too large and complex (to be feasible). Given the above issues, the suggestion by the CBI group that observational data could fill in many of the uncertainties about new drug safety seems unduly optimistic at the present time. Certainly, the growing availability of observational data will enable better understanding of rare, serious adverse events, drug utilization patterns, and overall outcomes of use. For drugs newly approved for uncommon diseases, such data might adequately supplement the information obtained during the development program. However, many safety questions involve numerically small increases in risk during chronic disease therapy, in which even the discriminatory power of randomized controlled trials is severely challenged. Research carried out by the Observational Medical Outcomes Partnership (http://omop.fnih.org) suggests that current methods for analysis of observational data, particularly claims data, are not sufficiently robust to provide definitive conclusions in these circumstances. The FDA is continuing to develop the Sentinel Initiative, which will ultimately cover more than 100 million lives and ena-

ble further analysis and research.5 International collaborations are also ongoing; it is recognized that advances in this area are urgently needed. In addition to assuming postapproval evidence development, implementation of an adaptive licensing framework would rely on the premise that restricting off-label use is feasible. The validity of this presumption may be dependent on national health-care policies: in some cases, national healthcare systems or reimbursement policies may limit permissible use. In the United States, the FDA can impose restrictions on drug distribution with an REMS; such restrictions can include measures that attempt to ensure that use conforms with the labeled indication. These restrictions must be implemented by the drug sponsor and may involve very intensive distribution management techniques, including, at a minimum, central pharmacies, enrollment of prescribers, registration of patients, and verification of diagnoses. At a public meeting held in July 2010, stakeholders told the FDA that REMS are unnecessarily burdensome to the US health-care system and should be standardized and made easier to implement.6 It is unlikely that large-scale implementation of such restrictions, managed by drug sponsors, would be feasible or desirable in the United States. Rather, a new compact or agreement among prescribers, state licensure boards, regulators, payers, pharmacists, and others involved in health care to create and respect a new category of approved drug would probably be nec379

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essary. Given that many such restrictions are now imposed by formulary management and tiered-reimbursement schemes, integration of the staged-approval concept into existing prescribing patterns would not be difficult. However, acceptance by professional groups with a long tradition of extensive off-label use (e.g., oncologists) might be problematic, so use of a staged mechanism in these areas might be challenged. Finally, implementation of true staged approval, beyond the current measures described in Table 1 (i.e., that would require legislation in the United States), would require the disparate stakeholders in health care to find common ground around acceptance of risks, particularly the tolerance for greater uncertainty about benefits and harms. Development of benefitrisk frameworks that incorporate the risks of residual uncertainties and support communication about tradeoffs will be critical to defining areas of consensus. Would implementation of adaptive licensing, as the CBI article asserts, address many of the root causes of the overall high costs of drug development? A large proportion of these costs are attributable to the high failure rate in clinical development (~90%). Lowering barriers to market access would probably increase investment and allow continued development of some candidate drugs that would otherwise be abandoned. However, adaptive licensing would not address the scientific uncertainties that lead to most clinical development failures. For example, a recent study of drugs failing in phase III found that 66% were terminated for lack of efficacy (half against placebo!)a failure of prediction that regulatory changes cannot address.7 It is likely that new drug regulatory paradigms will evolve during the next few decades. Such innovations will need to be practical and feasible and address the needs of many stakeholders. If premarket evidence generation is limited, then marketing might also be limited; however, postmarket evidence generation would need to be robust and reliable. If the initial approval is restricted to a very narrow population, then consideration must be given to rewarding (or at least not penalizing) developers who ultimately demonstrate significant benefits in a wider populationfor example, through patent
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extensions or exclusivity. Because complex adaptive-licensing schemes would probably be highly labor-intensive for regulators, provision for adequate resources would have to be included. Most importantly, the wider medical community would need to embrace the explicit tradeoffs between evidence generation and access.
CONFLICT OF INTEREST The author declared no conflict of interest.
2012 ASCPT

1. Eichler, H.-G. et al. Adaptive licensing: taking the next step in the evolution of drug approval. Clin. Pharmacol. Ther. 91, 426437 (2012). 2. US Food and Drug Administration. Center for Drug Evaluation and Research. Guidance for Industry: diabetes mellitusevaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes <http://www.pharmacy. arizona.edu/sites/default/files/Guidance_for_ Industry.pdf> (December 2008).

3. US Food and Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee. Drug Safety and Risk Management Advisory Committee. Advisory Committee Briefing document. Cardiovascular safety of rosiglitazone. Meeting on 1314 July 2010 <http://www.fda.gov/downloads/ advisorycommittees/committeesmeeting materials/drugs/endocrinologicandmetabolic drugsadvisorycommittee/ucm218492.pdf> (2010). 4. Chowdhury, B.A., Seymour, S.M. & Levenson, M.S. Assessing the safety of adding LABAs to inhaled corticosteroids for treating asthma. N. Engl. J. Med. 364, 24732475 (2011). 5. US Food and Drug Administration. FDAs Sentinel Initiative. Transforming how we monitor the safety of FDA-regulated products <http:// www.fda.gov/safety/FDAsSentinelInitiative/ ucm2007250.htm> (May 2008). 6. US Food and Drug Administration. Risk evaluation and mitigation strategy (REMS) public meeting, 2728 July 2010 <http://www.fda.gov/drugs/ newsevents/ucm210201.htm> (2010). 7. Arrowsmith, J. Trial watch: phase III and submission failures: 20072010. Nat. Rev. Drug Discov. 10, 87 (2011).

The Critical Path Initiative: Leveraging Collaborations to Enhance Regulatory Science

RA Barratt1, SL Bowens1, SK McCune1, JN Johannessen1 and SY Buckman1
Since 2004, the Critical Path Initiative has prompted industry, academia, and government agencies to work together to share the information, technology, and expertise critical to modernize and transform our approach to drug development and review. Various collaborations have been sharing data in a precompetitive space, establishing data standards, and facilitating collective tool development. As a result, the organization is making progress toward developing knowledge and tools that can reduce uncertainty in medical product development.
The Critical Path Initiative, introduced in 2004 with the release of the report Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products,1 challenged the
The first two authors contributed equally to this work.
1Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA. Correspondence: SY Buckman (shaavhree.buckman@fda.hhs.gov)

scientific community to work together to diminish the gap between scientific discoveries and their translation into innovative medical therapies. It called for a collaborative cross-sector effort to incor-

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