FDA Expedited Programs for Drug Development and Review, Explained

FDA Expedited Programs

It has been my experience that even the most experienced drug development and pharmaceutical consultants will stumble over the definitions of, and differences between FDA’s four expedited programs. Included among them are accelerated approval, priority review, fast track, and breakthrough therapy.[1] This paper is designed as a primer to increase understanding of the expedited programs, and to aid in distinguishing each from the other.

First, here is a useful tip for those times when you cannot remember which is which, but their collective utility must be discussed. Refer to them as “expedited development and review programs” or “expedited programs.” These are the terms that come straight from the guidance. If you wish to memorize them, another useful tip is to think of the accelerated approval as a pathway, and the other three programs as “designations” then review the table that follows.[2] Included in the table are the key distinguishing characteristics, designation particulars, and when the programs were introduced:

Program: Breakthrough Therapy Designation
Distinguishing Characteristic: A drug that is intended to treat a serious condition AND preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies. - Extra FDA resources - Rolling review
When to Request Designation: With an IND or after, ideally, no later than the End-Of-Phase 2 meeting
Year Conceived: 2012
Program: Fast Track Designation
Distinguishing Characteristic: Nonclinical (or clinical) data demonstrate the potential to address an unmet medical need. - Extra FDA resources - Rolling review
When to Request Designation: With an IND or after, ideally, no later than the pre-BLA or pre-NDA meeting.
Year Conceived: 1997
Program: Priority Review Designation
Distinguishing Characteristic: 6 month priority review vs. 10 month standard review
When to Request Designation: With original BLA, NDA, or efficacy supplement.
Year Conceived: 1992
Program: Accelerated Approval
Distinguishing Characteristic: Approval based on a surrogate or intermediate clinical endpoint followed by confirmatory trials.
When to Request Designation: NO DESIGNATION APPROVAL PATHWAY. (Discuss with FDA early in development).
Year Conceived: 1992

It is a common misconception that the orphan drug program is one of the expedited programs. While it is not, it is useful to note that, in similar fashion to priority review, fast track and breakthrough therapy, orphan status requires designation before a drug may be reviewed as such. Orphan drug designation is initiated by submission of the FDA Form 3671, the Common EMEA/FDA Application for Orphan Medicinal Product Designation to the Office of Orphans Product Development (OOPD), the same form that is used for medical device manufacturers seeking Human Device Exemptions (HDEs).[3] Fast Track and Breakthrough designation requests are sent as INDs or amendments and Priority review designation requests are submitted with a BLA, NDA, or efficacy supplement. Another useful tip to aid in understanding is to remember that orphan status relates to medical devices in addition to drugs & biologics,[4] while expedited programs apply only to drugs and biologics.[5]

FDA attempts to respond to breakthrough and fast track designation requests within 60 calendar days of receipt of request, and priority review requests by 60 calendar days after receipt of NDA, BLA or efficacy supplements. If the fast track or breakthrough designation request is found to be incomplete or fails to meet the criterion for designation, FDA will send the sponsor a non-designation letter, to include reasons for the decision. In the case of breakthrough therapy, advice regarding subsequent development, including what would be needed in a new designation request may be provided. FDA provides written notification of the priority review designation by day 60 of the review, or standard review designation by day 74 of the review. One of the major differences lies in the fact that priority review designations are not requested until NDA, BLA or supplement submission. Also, timelines for accelerated approval are “not specified”.[6]

Not surprisingly, in cases where a request for a breakthrough designation was denied, the sponsor often didn’t understand the type of evidence FDA sought. Examples have included basic oversights, such as lack of patient data, thereby foregoing a substantial improvement determination.[7] It is not unreasonable to extrapolate from this example that understanding and attention to detail is critical to requesting consideration from FDA for any of the expedited programs. In reality, a well-planned and strategically executed Pre-IND meeting lies at the heart of any drug development effort.

In no case does designation equal approval. Drug approvals (including accelerated approvals) are issued by FDA after review and are based on “demonstration of substantial evidence of effectiveness in treating or preventing the condition and evidence of safety for that use. Evidence of effectiveness should be obtained from one or more adequate and well-controlled studies in an identified population.”[8] Following is a brief discussion of each of the expedited programs. The discussion begins with accelerated approvals because it is widely believed that complete safety and efficacy data is not needed and that these approvals are based on surrogate or intermediate data only.

Accelerated Approval

As noted above, there is no designation process for Accelerated Approvals. Unlike the other three expedited programs, the accelerated approval is a pathway. The purpose of the accelerated approval pathway is the review of drug candidates addressing serious conditions that might offer meaningful advantages over available therapies, while allowing for the use of surrogate or intermediate endpoints in the pivotal clinical trial(s). Surrogate endpoints stand-in for clinical endpoints to show how well the therapy might treat a condition by measuring change(s) in disease state. As such, surrogate endpoints are likely to predict clinical benefits.[9] Similarly, intermediate endpoints are those that can be measured earlier than direct effects on irreversible morbidity or mortality (IMM) and are considered reasonably likely to predict the drug’s effect on IMM or some other clinical benefit.[10]

While such endpoints may get drugs to the market more quickly, they must still meet the same standards for safety and efficacy as their traditionally approved counterparts (substantial evidence based on adequate and well-controlled clinical investigations). The difference is that drugs granted accelerated approval must promptly conduct post-marketing confirmatory trials to verify the clinical benefit (as early as underway at the time the marketing application is submitted).[11]

Sponsors considering accelerated approval should discuss their drug development program with the reviewing division at the earliest stages of development. Among other concerns, accelerated approval will necessarily dictate a more rapid pace for other aspects of the development program such as CMC or development of necessary companion diagnostics.[12]

Priority Review Designation

A new drug or biologic application for a product intended to treat a serious condition that promises to provide a significant improvement in safety or effectiveness upon approval will receive a priority review designation. Priority designation is “intended to direct overall attention and resources to the evaluation of such applications”[13] and reduces the standard review time of ten months down to six months.[14]

Priority review is less complicated than accelerated approval. The request for priority review designation is not made until submission of the NDA/BLA (or efficacy supplement), after clinical trials are complete. Hence, significant improvement in safety and/or effectiveness will have already been shown.[15]

The most obvious form of significant improvement is superior effect or a reduction in adverse events. However, other examples of significant improvement include enhancement of patient compliance coupled with improved outcomes or evidence of safety and effectiveness in a previously unserved subpopulation. While clinical trials comparing an investigational drug to a marketed product are clearly a gold standard, a priority review designation may allow for other scientifically valid information. For example, studies of patients unable to tolerate, or who have not responded to, current therapies may be acceptable. Although randomized trials are the preferred standard, other types of investigation such as historical controls may also be employed.[16]

As with accelerated approvals, priority review may necessitate a more rapid manufacturing development program to keep pace of the accelerated clinical program. Early communication between quality/CMC representatives and FDA is critical to ensure that marketing approval coincides with product availability.[17]

From Accelerated Approval and Priority Review to Fast Track and Breakthrough

Recognizing the difference between accelerated approval and priority review is easy. Accelerated approval is based on surrogate or intermediate endpoints followed by confirmatory study(ies) and a priority review is six months rather than ten. The difference between fast track and breakthrough is not quite as straightforward. After all, each are intended, whether alone or in combination with one or more other drugs, for the treatment of a serious or life-threatening disease or condition. Both are subject to rolling review and command increased attention and resources from FDA.

Looking at their differences per the FD&C Act can cause your head to spin: fast track “demonstrates the potential to address unmet medical needs for such a disease or condition”[18] and breakthrough demonstrates preliminary clinical evidence indicating “that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.”[19] The similarities and differences between these two expedited programs alone would be a justifiable topic for a follow-up paper. However, the easy way to tell the difference is to equate fast track designation with animal data and breakthrough therapy designation with clinical data.

As noted in the table above, breakthrough applies to a drug with preliminary clinical evidence indicating it may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies, while fast track accommodates “Nonclinical (or clinical) data that demonstrate the potential to address unmet medical need.

Fast Track Designation

Also as noted above, fast track was “designed for drug candidates intended to treat a serious condition and that demonstrated in non-clinical studies the potential to address an unmet medical need.” Clinical evidence may be used, but is not required, and the designation may be obtained very early in the drug development process. “This requirement distinguishes Fast Track from the other expedited programs, which require evidence in human patients.”[20]

The actions associated with an accelerated approval (approval via surrogate/intermediate endpoints followed by confirmatory study) and priority review (6 month vs. standard 10 month review) are straightforward and contrast clearly with one another. In comparison, fast track and breakthrough do not. While both fast track and breakthrough are afforded the opportunity for rolling reviews and increased resource allocation by FDA, the increased resource allocations differ. Breakthrough designation resources are described in the section below. In the case of fast track designation:

There are opportunities for frequent interactions with the review team for a fast track product. These include meetings with FDA, including pre-IND meetings, end-of-phase 1 meetings, and end-of-phase 2 meetings to discuss study design, extent of safety data required to support approval, dose-response concerns, and use of biomarkers. Other meetings may be scheduled as appropriate (e.g., to discuss accelerated approval, the structure and content of an NDA, and other critical issues).[21]

Breakthrough Designation

As with the other programs, breakthrough designation is aimed at treatments of serious illness. Like fast track, breakthrough applications may be reviewed on a rolling basis. However, unlike the fast track designation, which may include theoretical and mechanism-of-action rationale based on nonclinical data, or evidence of actual nonclinical activity,[22] breakthrough therapy demonstrates preliminary clinical of substantial improvement over available therapies.[23] Preliminary clinical evidence is generally that which is sufficient to show substantial improvement in effectiveness or safety over available therapies, but not strong enough to establish safety and effectiveness for the purpose of approval.

As with fast track, breakthrough designation earns additional FDA attention, resources and action:

FDA intends to expedite the development and review of a breakthrough therapy by intensively involving senior managers and experienced review and regulatory health project management staff in a proactive, collaborative, cross-disciplinary review. Where appropriate, FDA also intends to assign a cross-disciplinary project lead for the review team to facilitate an efficient review of the drug development program. The cross-disciplinary project lead will serve as a scientific liaison between members of the review team (e.g., medical; clinical pharmacology; pharmacology-toxicology; chemistry, manufacturing, and controls (CMC); compliance; biostatistics), facilitating coordinated internal interactions and communications with a sponsor through the review division’s regulatory health project manager.” – “In addition, such a product could be eligible for priority review if supported by clinical data at the time of BLA, NDA, or efficacy supplement submission.[24]

There are multiple approaches that a sponsor may utilize to show substantial improvement. For example, a head-to-head comparison of the new drug to the current standard of care in an early stage trial may offer enough evidence of a meaningful basis for the breakthrough designation. Early patient data without a direct comparison in a clinical trial study that provides better understanding of disease progression may also suffice. For instance, if a certain cancer type has an 80 percent progression rate in a one-year period, yet a drug in early trials shows a 10 percent progression during the same timeframe, a head-to-head trial to prove substantial improvement may not be needed.[25]

Rolling Reviews

Both breakthrough therapy and fast track designees may be reviewed on a rolling basis. This facilitates review of the data as it is received, rather than a complete review only beginning upon receipt of complete NDA/BLA submissions.[26] Sponsors are encouraged to obtain preliminary agreement with FDA at a pre-NDA/BLA meeting or earlier (e.g., breakthrough therapies at End-Of-Phase 2 meeting) as to data to be used in support effectiveness, timing for submission of each portion of the NDA/BLA, and those portions of the applications to be submitted separately.[27]

Conclusion

It is important to note that two common threads of expedited programs are their applicability to serious disease only and the need for early consultation with FDA. Expedited programs frequently overlap and it is not unheard of for drug development programs to make simultaneous use of three or four of them. For example, a breakthrough therapy drug can receive a priority review and an accelerated approval as part of its path to patients.[28] Clearly, a proven regulatory strategist is critical to such development programs.

Expedited programs have now been used by CDER for over two decades. Drug development and review processes have been streamlined in a way that allows for therapies showing early promise to reach patients faster. Not surprisingly, their use has increased dramatically. In fact, over half of CDER’s 2015 novel drug approvals received expedited review of one type or another.[29] If you are unsure as to the applicability of the various expedited programs to your drug development effort, or when and how to proceed, please call PDG™.

Charles Jaap is Vice-President of Operations and Business Development for PDG™, a global pharmaceutical and medical device consultant with extensive experience in the strategic development of drug products and medical devices. Please feel free to contact us for more information. The opinions and statements in this paper are solely those of Charles Jaap and do not necessarily reflect those of PDG™.

Sources:
[1] Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics – May 2014
[2] Ibid.@1
[3] www.fda.gov “Forms” as accessed on June 6, 2016
[4] www.fda.gov: FDA at Rare Disease Day/ February 28, 2011 as accessed on June 6, 2016
[5] Ibid.@1
[6] Ibid.@1
[7] CDER Conversations; FDA’s Breakthrough Therapy Designation and Expedited Review Programs: Part I; What types of exciting evidence or signals in early drug development might result in a breakthrough designation? Richard Moscicki, M.D., Deputy Director for Science Operations
[8] Guidance for Industry – Rare Diseases: Common Issues in Drug Development– August 2015
[9] CDER Conversations; FDA’s Breakthrough Therapy Designation and Expedited Review Programs: Part II; So what’s a surrogate endpoint? Richard Moscicki, M.D., Deputy Director for Science Operations
[10] Ibid.@1
[11] Ibid.@1
[12] Ibid.@1
[13] Ibid.@1
[14] CDER Conversations; FDA’s Breakthrough Therapy Designation and Expedited Review Programs: Part II; What about the Priority Review and Fast Track designations? Richard Moscicki, M.D., Deputy Director for Science Operations
[15] Ibid.@14
[16] Ibid.@1
[17] Ibid.@1
[18] Section 506(b) of the FD&C Act
[19] Section 506(a) of the FD&C Act
[20] CDER Conversations; FDA’s Breakthrough Therapy Designation and Expedited Review Programs: Part II; Let’s recap. What are the primary similarities and differences in these expedited programs? Richard Moscicki, M.D., Deputy Director for Science Operations
[21] Ibid.@1
[22] Ibid.@1
[23] CDER Conversations; FDA’s Breakthrough Therapy Designation and Expedited Review Programs: Part I; So what does FDA mean when it uses the term “breakthrough?” Richard Moscicki, M.D., Deputy Director for Science Operations
[24] Ibid.@1
[25] Ibid.@7
[26] Ibid.@20
[27] Ibid.@1
[28] Ibid.@26
[29] Preface to PART I – FDA’s Breakthrough Therapy Designation(www.fda.gov/Drugs/NewsEvents/ucm496424.htm)
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