ACCELERATING REGULATORY APPROVAL BY DAVID SHOEMAKER Senior Vice President Research FOR DRUGS AND BIOLOGICS IN THE US and Development, Rho What you really need to know about FDA’s Accelerated Approval, Breakthrough Therapy, Fast Track, and Priority Review The Food and Drug Administration (FDA) has created four mechanisms to presumably speed the approval of drugs and biologics that effectively treat serious diseases, especially those that are the first of their kind or those that provide increased benefit over existing treatments. Accelerated Approval (AA), Breakthrough Therapy Designation (BTD), Fast Track Designation (FTD), and Priority Review (PR) – their names imply speed of the highest order, and it’s tempting to assume that acquiring any of these designations will speed your drug’s approval and save you millions of dollars. That’s certainly possible, but just like anything that sounds too good to be true, it’s worth taking the time to understand the requirements and potential benefits of each, so you can make an informed decision about what’s possible or what’s best for your product development program. An overview of the four types of FDA programs is shown in Table 1 (page 2) and is reviewed in the Guidance published in 2014 (Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics). The overlap in benefit and use in development or application review is obvious. However, further analysis is provided below as to how to appropriately use or not use these four programs to maximize speed of approval depending on the product type. rhoworld.com | 1 Table 1. Comparison of Accelerated Approval Mechanisms Program Type Accelerated Breakthrough Fast Track Priority Review (PR) Approval (AA) Therapy Designation (FTD) Designation (BTD) Authority 1992 Rule: 2009 Statute: 1997 Statute: 1996 Agency 21 CFR 314 and 601. FFDCA 506(a) FFDCA 506(b) Procedure: (In 1997, FFDCA CDER MAPP 6020.3; 506(b)) and CBER SOPP 8405 Procedure During early Any time before Any time before Sponsor requests development marketing approval, marketing approval, prior to marketing meetings with Sponsor requests Sponsor requests application agency, Sponsor designation; FDA designation; FDA submission. Clinical requests. grants if criteria are grants if criteria are team leader of met (within 60 days). met FDA review team, (within 60 days). upon receipt of application, makes recommendation. Disease Serious or life- Serious or life- Serious or life- n.a. Criteria threatening disease threatening disease threatening disease or condition. or condition. or condition. Qualifying Criteria Potential to address Preliminary clinical Potential to address Major advance unmet medical need. evidence indicates unmet medical need. in treatment or that the product treatment where no may demonstrate adequate therapy substantial exists. improvement over existing therapies on one or more clinically significant endpoints Benefit During Adjusted trial - Guidance on Frequent FDA n.a. Development requirements efficient product communication development - Senior FDA Official Commitment Benefit During n.a. Rolling review Rolling review Expedited review Review (Submit sections of (Submit sections of (e.g., 4-6 months NDA or BLA as they NDA or BLA as they compared to 10-12 are completed) are completed) months) Post Approval Studies to extend n.a. n.a. n.a. Requirement results from surrogate to clinical outcome. Abbreviations: FFDCA = Federal Food, Drug, and Cosmetic Act. n.a. = not applicable. rhoworld.com | 2 ACCELERATED APPROVAL For many drugs and biologics that treat serious and life- reduce the time required to receive marketing approval for threatening diseases, showing actual improvement for patients, your compound. such as living longer or feeling better, can take a very long It is important to note that AA does not formally change your time. Because of this, FDA created the Accelerated Approval marketing application review time. Instead, it shortens the (AA) regulation, which allows earlier approval of drugs and actual research time prior to approval (see Figure 1. below). biologics based on a surrogate clinical endpoint. For example, instead of two adequate and well-controlled Examples of surrogate endpoints are viral load for HIV studies, if you’re granted AA, you might only have to conduct progression, low-density lipoprotein cholesterol levels for one of these studies prior to FDA approval. Consequently, occurrence of myocardial infarctions, systolic blood pressure this program is far and away the most valuable alternative for occurrence of strokes, and forced expiratory volume in one pathway to the standard development of drugs and biologics. second for respiratory diseases such as asthma, cystic fibrosis, It’s also important to note that if AA is granted, FDA requires a or chronic obstructive pulmonary disease. Using surrogate post-marketing commitment to demonstrate actual improved endpoints instead of clinical outcome data can significantly clinical outcomes in a controlled clinical study. Figure 1. Comparison of Standard and Accelerated Approval Development Standard Development APPROVAL Clinical Marketing Application Start Submission Pre-clinical NDA Phase 1 Phase 2 Phase 3 Research Review Labeling Meeting SPA Pre-IND EOP2 Pre- Meeting(s) Meeting NDA/BLA Meeting Accelerated Approval Development Clinical Marketing Application Start Submission Pre-clinical NDA Many Phase 1 1 x Phase 2/3 $ Millions Research Review SAVED SPA Pre-IND EOP2 Pre- Labeling Meeting(s) Meeting NDA/BLA Meeting Meeting rhoworld.com | 3 Eligibility for Accelerated Approval FDA can withdraw marketing approval if any of the following apply: 1. Applicable to drugs (21 CFR 314 Subpart H) or biologics (21 • Post-marketing studies fail to show a clinical benefit CFR 601 Subpart E) • Product sponsor fails to conduct post-marketing studies 2. Only serious and life-threatening diseases and conditions • Use after approval indicates that restrictions are 3. Meaningful therapeutic benefit over existing treatments inadequate • Product sponsor doesn’t adhere to restrictions required by FDA Logistics, Restrictions, and Withdrawal of Accelerated Approval • Promotional materials are false or misleading There’s no formal submission process to apply for Accelerated Approval. If you’re interested in Accelerated Approval, discuss with your reviewing division at FDA early in your development Post-Marketing Commitment Requirements process (Pre-IND Meeting). FDA requires a post-marketing commitment for Accelerated Accelerated Approval can be granted with restrictions, such as: Approval of NDAs (21 CFR 314 Subpart H) or BLAs (21 CFR 601 • FDA determination that treatment can only be used Subpart E). In the post-marketing phase, sponsors are required to design and conduct adequate and well-controlled confirmatory safely if prescribed by specially trained physicians trials that are intended to validate the results obtained with the • Distribution may be conditioned on performance of surrogate clinical endpoint, i.e., demonstration of true clinical specified medical procedures benefit. These confirmatory trials may be ongoing at the time • FDA may require a risk evaluation and mitigation of approval. In order to ensure compliance, FDA has created a strategy (REMS) Post-marketing Study Commitments website: g BREAKTHROUGH THERAPY DESIGNATION The advent of Breakthrough Therapy Designation (BTD) was seen indication that the program is potentially maturing. However by many as a replacement for Fast Track Designation and indeed the overall approval rating for BTD applications overall still this has seemed to be the case. There are considerable advantages hovers at approximately 35% indicating that industry still needs to obtaining the Breakthrough Therapy Designation rather than counselling from FDA on what constitutes a viable application. the Fast Track Designation most notably the commitment from senior management at FDA to champion these products through Once granted the BTD affords the company opportunities the approval process. There is the requirement for preliminary increased support from FDA leveraging the agency’s experience data to demonstrate safety and efficacy which although a higher with novel study designs to attempt to accelerate the development bar than that to obtain Fast Track Designation makes practical timeline. A cross-disciplinary project lead is assigned by FDA sense so as not to waste FDA resources reviewing hypothetical to the review team who facilitates frequent interactions with advantageous products. the necessary resources at FDA. Unlike portions of marketing applications submitted for Fast Track Designated products via The program has been in existence since enactment of the Food and Drug Administration Innovation Act of 2012 and is perhaps rolling submissions that often languish at the FDA until the complete showing signs of maturation. The number of BTDs granted in marketing application is submitted due to lack of FDA resources, 2015 (21) and 2016 (20) were constant with approximately 80 the rolling submissions for products obtaining BTD are actually designated products currently in development or under marketing reviewed upon receipt by the agency accelerating review times application review. This number of 80 actively designated products significantly. This is a direct reflection of the increased awareness remained constant for the fourth quarter of 2016, another of the agency of the importance of products obtaining the BTD. rhoworld.com | 4 FAST TRACK DESIGNATION FDA’s