By Dr. Jack Snyder, RAC (US, EU, CA, GS), Asst. Managing Director and Clinical Research Physician at Cato Research
“Early access pathways” for biomedical product marketing approval have attracted substantial attention recently, as Sarepta Therapeutics’ drug Exondys (eteplirsen) gained accelerated approval based on clinical data from just 12 patients. In the United States, four “expedited” or “conditional” pathways for novel products for serious diseases or unmet medical need are available: Fast Track designation (FT), Breakthrough Therapy designation (BTD), Priority Review designation (PR), and Accelerated Approval pathway (AA). Characteristics and distinguishing elements of these pathways have been well described by FDA in a 2014 Guidance for Industry: Expedited Programs for Serious Conditions — Drugs and Biologics. Proposed benefits include increased levels of communication and commitment between FDA and product sponsors, greater roles for surrogate endpoints, transfer of burden of evidence generation from pre- to post-authorization phases, and shortened review timelines. None of these programs are exclusive, any combination is permissible, and any designation may be rescinded if products do not continue to meet defined criteria upon periodic reassessment.
Some voices now are clamoring for FDA to adopt the approach of the European Medicines Agency (EMA), which instituted Conditional Marketing Authorization (CMA) procedures in 2006 for products where (a) benefit/risk balance is positive; (b) it is likely that comprehensive clinical data will be provided; (c) unmet medical needs will be fulfilled; and
(d) benefit to public health of immediate availability outweighs risks that additional data are still required. These EMA-CMA approvals require annual renewal and can be converted to full marketing authorizations upon review of definitive data generated during the conditional approval period.
Do any of these initiatives significantly alter timelines in biomedical product development? A group of European investigators recently assessed the influence of “Facilitated Regulatory Pathways” (FRP) on review times for 125 new active substances approved by FDA between January 2013 and December 2015. Metrics for this study included the following:
|NAS approved using FRP||74 (no use of BTD alone, FT + BTD, or AA ± BTD)|
|Median development times (IND to NDA submission|
|Any FRP||2377 days|
|No FRP||2148 days|
|BTD + PR + AA||1458 days|
|FT alone||2620 days|
|PR alone||3515 days|
|Median Approval Times|
|Any FRP||243 days|
|No FRP||365 days|
|FT + BTD + PR + AA [a]||145 days|
|BTD + AA + PR||166 days|
|FT + BTD + PR||242 days|
|FT + PR||292 days|
|PR alone||242 days|
|Median Developmental + Approval Times (IND to Approval)|
|Any FRP||2620 days|
|No FRP||2513 days|
|BTD + AA + PR||1624 days|
|BTD + FT + PR||1720 days|
|FT + PR||2308 days|
|FT + BTD + AA + PR||2434 days|
|FT alone||2981 days|
|PR alone||3757 days|
AA = Accelerated Approval; BTD = Breakthrough Therapy Designation; FRP = facilitated regulatory pathways; FT = Fast Track Designation; PR = Priority Review; NAS = new active substances
[a] Four NAS qualified for all four FRPs: ibrutinib, idelalisib, nivolumab, osimertinib mesylate, daratumumab
The authors concluded that combinations of FRPs can shorten review times beyond those provided by PR alone. The data do not appear, however, to support a general conclusion that various combinations of FRPs reliably shorten the time elapsing between IND submission and marketing approval, or between product conception and marketing approval.
Although FRPs aim to accelerate patient access to medicines, some analyses have in fact shown that development times from first-in-human testing to marketing authorization using FRPs are comparable to development times associated with full (no FRP) marketing authorization, yet are based on less comprehensive data. Consequently, commentators have raised the possibility that instead of using the FRPs prospectively, sponsors are using them as a backup to full authorization when data packages may not be strong enough to support a full market authorization through conventional pathways. In any case, more data are needed to determine whether or not implementation of FRPs makes a meaningful difference in terms of conservation of time and/or resources in the biomedical product development plus approval process.
Meanwhile, as of June 2017, the same drug can be eligible for FRPs simultaneously in the U.S., Canada, Europe and Australia. Since most countries in South America, Africa and Asia grant preferential review to drugs approved by regulators in the U.S., Canada, Europe and Australia, expedited approval in these regions potential translates into world-wide approval of a given drug. With multinational adoption of most expedited approval pathways, it may be tempting for sponsors to simultaneously apply for designations in all regions. However, if any one regulatory agency disagrees with the designation request, it is likely that other regulators will follow suit as well. So, the best strategy is to get successful designation in one region and then try to use that in others.
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