Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review
Expediting Availability of New Drugs for Patients with Serious Conditions
Speeding the development and availability of drugs that treat serious diseases are in everyone's interest, especially when the drugs are the first available treatment or have advantages over existing treatments. The Food and Drug Administration (FDA) has developed four distinct and successful approaches to making such drugs available as rapidly as possible: Priority Review, Accelerated Approval, Fast Track Designation, and breakthrough therapy designation. Because each of these approaches implies speed, there can be confusion about the specific meaning of each and the distinctions among them.
The following summary describes each element, how they differ, and how they complement each other.
Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need. The purpose is to get important new drugs to the patient earlier. Fast Track addresses a broad range of serious conditions.
Determining whether a condition is serious is a matter of judgment, but generally is based on whether the drug will have an impact on such factors as survival, day-to-day functioning, or the likelihood that the condition, if left untreated, will progress from a less severe condition to a more serious one. AIDS, Alzheimer’s, heart failure and cancer are obvious examples of serious conditions. However, diseases such as epilepsy, depression and diabetes are also considered to be serious conditions.
An unmet medical need is a condition whose treatment or diagnosis is not addressed adequately by available therapy.
If there is no available therapy there is clearly an unmet medical need. If there are available therapies, a new treatment generally would be considered to address an umet medical need if the treatment:
- Has an effect on a serious outcome of the condition that is not known to be influenced by available therapy (e.g., progressive disability or disease progression when the available therapy has shown an effect on symptoms, but has not shown an effect on progressive disability or disease progression)
- Has an improved effect on a serious outcome(s) of the condition compared with available therapy (e.g., superiority of the new drug to available therapy when either used alone or in combination with available therapy (i.e., as demonstrated in an add-on study))
- Has an effect on a serious outcome of the condition in patients who are unable to tolerate or failed to respond to available therapy
- Can be used effectively with other critical agents that cannot be combined with available therapy
- Provides efficacy comparable to those of available therapy, while (1) avoiding serious toxicity that occurs with available therapy, (2) avoiding less serious toxicity that is common and causes discontinuation of treatment of a serious condition, or (3) reducing the potential for harmful drug interactions
- Provides safety and efficacy comparable to those of available therapy but has a documented benefit, such as improved compliance, that is expected to lead to an improvement in serious outcomes
- Addresses an emerging or anticipated public health need, such as a drug shortage
A drug that receives Fast Track designation is eligible for some or all of the following:
- More frequent meetings with FDA to discuss the drug’s development plan and ensure collection of appropriate data needed to support drug approval
- More frequent written correspondence from FDA about such things as the design of the proposed clinical trials and use of biomarkers
- Eligibility for Accelerated Approval and Priority Review, if relevant criteria are met
- Rolling Review, which means that a drug company can submit completed sections of its Biological License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the application is completed before the entire application can be reviewed. BLA or NDA review usually does not begin until the drug company has submitted the entire application to the FDA
Fast Track designation must be requested by the drug company. The request can be initiated at any time during the drug development process. FDA will review the request and make a decision within sixty days based on whether the drug fills an unmet medical need in a serious condition.
Once a drug receives Fast Track designation, early and frequent communication between the FDA and a drug company is encouraged throughout the entire drug development and review process. The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients.
Breakthrough Therapy designation is a process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).
To determine whether the improvement over available therapy is substantial is a matter of judgment and depends on both the magnitude of the drug's effect on a clinically significant endpoint (which could include duration of the effect) and the importance of the observed effect to the treatment of the serious condition or serious aspect of the condition. In general, the preliminary clinical evidence should show a clear advantage over available therapy.
For purposes of Breakthrough Therapy designation, clinically significant endpoint generally refers to an endpoint that measures an effect on irreversible morbidity or mortality (IMM) or on symptoms that represent serious consequences of the disease. A clinically significant endpoint can also refer to findings that suggest an effect on IMM or serious symptoms, including:
- An effect on an established surrogate endpoint that typically would be used to support traditional approval
- An effect on a surrogate endpoint or intermediate clinical endpoint considered reasonably likely to predict a clinical benefit (i.e., the accelerated approval standard)
- A significantly improved safety profile compared with available therapy (e.g., less dose-limiting toxicity for an oncology agent), with evidence of similar efficacy
A drug that receives Breakthrough Therapy designation is eligible for the following:
- All Fast Track designation features
- Intensive guidance on an efficient drug development program, beginning as early as Phase 1
- Organizational commitment involving senior managers
- Eligibility for rolling review and priority review
Breakthrough Therapy designation is requested by the drug company. If a sponsor has not requested breakthrough therapy designation, FDA may suggest that the sponsor consider submitting a request if: (1) after reviewing submitted data and information (including preliminary clinical evidence), the Agency thinks the drug development program may meet the criteria for Breakthrough Therapy designation and (2) the remaining drug development program can benefit from the designation.
Ideally, a Breakthrough Therapy designation request should be received by FDA no later than the end-of-phase-2 meetings if any of the features of the designation are to be obtained. Because the primary intent of Breakthrough Therapy designation is to develop evidence needed to support approval as efficiently as possible, FDA does not anticipate that Breakthrough Therapy designation requests will be made after the submission of an original BLA or NDA or a supplement. FDA will respond to Breakthrough Therapy designation requests within sixty days of receipt of the request.
When studying a new drug, it can sometimes take many years to learn whether a drug actually provides a real effect on how a patient survives, feels, or functions. A positive therapeutic effect that is clinically meaningful in the context of a given disease is known as “clinical benefit”. Mindful of the fact that it may take an extended period of time to measure a drug’s intended clinical benefit, in 1992 FDA instituted the Accelerated Approval regulations. These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint. Using a surrogate endpoint enabled the FDA to approve these drugs faster.
In 2012, Congress passed the Food and Drug Administration Safety Innovations Act (FDASIA). Section 901 of FDASIA amends the Federal Food, Drug, and Cosmetic Act (FD&C Act) to allow the FDA to base accelerated approval for drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate or an intermediate clinical endpoint.
A surrogate endpoint used for accelerated approval is a marker - a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. Likewise, an intermediate clinical endpoint is a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality (IMM).
The FDA bases its decision on whether to accept the proposed surrogate or intermediate clinical endpoint on the scientific support for that endpoint. Studies that demonstrate a drug’s effect on a surrogate or intermediate clinical endpoint must be “adequate and well controlled” as required by the FD&C Act.
Using surrogate or intermediate clinical endpoints can save valuable time in the drug approval process. For example, instead of having to wait to learn if a drug actually extends survival for cancer patients, the FDA may approve a drug based on evidence that the drug shrinks tumors, because tumor shrinkage is considered reasonably likely to predict a real clinical benefit. In this example, an approval based upon tumor shrinkage can occur far sooner than waiting to learn whether patients actually lived longer. The drug company will still need to conduct studies to confirm that tumor shrinkage actually predicts that patients will live longer. These studies are known as phase 4 confirmatory trials.
Where confirmatory trials verify clinical benefit, FDA will generally terminate the requirement. Approval of a drug may be withdrawn or the labeled indication of the drug changed if trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug (e.g., show a significantly smaller magnitude or duration of benefit than was anticipated based on the observed effect on the surrogate).
As part of its commitments in PDUFA V, FDA has established a review model, the Program. The Program applies to all new molecular entity NDAs and original BLAs, including applications that are resubmitted following a Refuse-to-File action, received from October 1, 2012, through September 30, 2017. For applications filed by FDA under the Program, the PDUFA review clock will begin at the conclusion of the 60 calendar day filing review period that begins on the date of FDA receipt of the original submission.
A Priority Review designation will direct overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.
Significant improvement may be demonstrated by the following examples:
- evidence of increased effectiveness in treatment, prevention, or diagnosis of condition;
- elimination or substantial reduction of a treatment-limiting adverse reaction;
- documented enhancement of patient compliance that is expected to lead to an improvement in serious outcomes; or
- evidence of safety and effectiveness in a new subpopulation.
FDA decides on the review designation for every application. However, an applicant may expressly request priority review as described in the Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics. It does not affect the length of the clinical trial period. FDA informs the applicant of a Priority Review designation within 60 days of the receipt of the original BLA, NDA, or efficacy supplement. Designation of a drug as “Priority” does not alter the scientific/medical standard for approval or the quality of evidence necessary.
Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review are approaches that are intended to make therapeutically important drugs available at an earlier time. They do not compromise the standards for the safety and effectiveness of the drugs that become available through this process.
Fast Track, Accelerated Approval, and Priority Review have evolved over time. Breakthrough Therapy is a new program at FDA that will complement these existing programs and facilitate and expedite drug development and review for serious conditions. FDA has been vigilant in assuring that reducing the time necessary for drug development has not compromised the safety and effectiveness of drugs for patients with serious conditions.