RyMat Inc. FDA Drug Approval & Applications Series Volume V Breakthrough Therapy Designation

RyMat Inc. FDA Drug Approval & Applications Series

Volume V

Breakthrough Therapy Designation

Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development. Section 902 of the July 9, 2012 Food and Drug Administration Safety and Innovation Act, allows the FDA to grant priority review to drug candidates if preliminary clinical trials indicate that the therapy may offer substantial treatment advantages over existing options for patients with serious or life-threatening diseases.

A breakthrough therapy designation can be assigned to a drug if "it as a drug which is intended alone or in combination with one or more other drugs to treat a serious or life threatening disease or condition" and if the preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development."

A breakthrough therapy designation conveys all of the fast track program features (see below for more details on fast track designation), more intensive FDA guidance on an efficient drug development program, an organizational commitment involving senior managers, and eligibility for rolling review and priority review. Section 902 of FDASIA requires the following actions, as appropriate:

• holding meetings with the sponsor and the review team throughout the development of the drug
• providing timely advice to, and interactive communication with, the sponsor regarding the development of the drug to ensure that the development program to gather the nonclinical and clinical data necessary for approval is as efficient as practicable
• taking steps to ensure that the design of the clinical trials is as efficient as practicable, when scientifically appropriate, such as by minimizing the number of patients exposed to a potentially less efficacious treatment
• assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the cross-discipline members of the review team (i.e., clinical, pharmacology-toxicology, chemistry, manufacturing and control, compliance) for coordinated internal interactions and communications with the sponsor through the review division’s Regulatory Health Project Manager
• involving senior managers and experienced review staff, as appropriate, in a collaborative, cross-disciplinary review

 Critics complain that most of these drugs are not actually “breakthroughs,” because they are based on preliminary evidence, including changes in surrogate markers such as laboratory measurements, that often don't reflect "meaningful clinical benefit." Even when they do, many of these benefits are not eventually confirmed in large clinical trials. And calling a drug a "breakthrough" drug gives the drug a marketing advantage which makes people believe that it is more effective than it actually is.

According to the FDA, in 2013 breakthrough therapy designations were assigned to obinutuzumab (tradename Gazyva) by Hoffmann-La Roche for treatment of chronic lymphocytic leukemia, ibrutinib and sofosbuvir. In 2014 ivacaftor, ofatumumab, ceritinib, idelalisib, ibrutinib (2nd approval), eltrombopag, pembrolizumab, ledipasvir/sofosbuvir, nintedanib, pirfenidone, blinatumomab, Viekira Pak (a combination product of three antiviral drugs, ombitasvir, paritaprevir, ritonavir in combination use with the drug dasabuvir) and nivolumab received the breakthrough therapy designation in 2014.  In 2015, ibrutinib (3rd approval) and palbociclib received FDA breakthrough therapy designation; in 2016, the investigational antidepressant rapastinel.

Qualifying Criteria for Breakthrough Therapy Designation

A. Serious Condition

FDA intends to interpret the term serious as it has done in the past for the purposes of accelerated approval5 and expanded access to investigational drugs for treatment use. A serious disease or condition is defined in the expanded access regulations as follows:

. . . a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and selflimiting morbidity will usually not be sufficient, but the morbidity need not be irreversible if it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.

          B. Existing (or Available) Therapies

FDA generally considers available therapy (and the terms existing treatment and existing therapy) as a therapy that: • Is approved or licensed in the United States for the same indication being considered for the new drug9 and • Is relevant to current U.S. standard of care (SOC) for the indication as appropriate, FDA may consult with special Government employees or other experts when making an available therapy determination.

• A drug would not be considered available therapy if the drug is granted accelerated approval based on a surrogate endpoint or an intermediate clinical endpoint and clinical benefit has not been verified by postapproval studies.

• A drug would be considered available therapy if the drug is granted accelerated approval because of restricted distribution and the study population for the new drug under development is eligible to receive the approved drug under the restricted distribution program. Similarly, a drug would be considered available therapy if the study population for the new drug under development is eligible to receive the approved drug under the ETASU REMS.

          C. Preliminary Clinical Evidence

Unlike the information that could support fast track designation, which could include theoretical rationale, mechanistic rationale (based on nonclinical data), or evidence of nonclinical activity, breakthrough therapy designation requires preliminary clinical evidence of a treatment effect that may represent substantial improvement over available therapies for the treatment of a serious condition. For purposes of breakthrough therapy designation, preliminary clinical evidence means evidence that is sufficient to indicate that the drug may demonstrate substantial improvement in effectiveness or safety over available therapies, but in most cases is not sufficient to establish safety and effectiveness for purposes of approval. FDA expects that such evidence generally would be derived from phase 1 or 2 trials. Nonclinical information could support the clinical evidence of drug activity. In all cases, preliminary clinical evidence demonstrating that the drug may represent a substantial improvement over available therapy should involve a sufficient number of patients to be considered credible. However, FDA recognizes that the data cannot be expected to be definitive at the time of designation.

Ideally, preliminary clinical evidence indicating a substantial improvement over available therapies would be derived from a study that compares the investigational drug to an available therapy (or placebo, if there is no available therapy) in clinical testing or from a study that compares the new treatment plus SOC to the SOC alone. FDA encourages sponsors to obtain some preliminary comparative data of this type early in development. Other types of clinical data that also could be persuasive include single-arm studies comparing the new treatment with well-documented historical experience. Generally, FDA expects that such historically controlled data would be persuasive only if there is a large difference between the new treatment and historical experience. For example, where lung function decline is a major manifestation of a disease, single-arm study data showing that a new drug significantly increases lung function could be persuasive if there is no available therapy that increases lung function. Data demonstrating that a cancer drug substantially increases overall response rate compared with historical controls (e.g., historical response rate with available therapy), with consideration of duration of the response, also could be persuasive. Sponsors contemplating the use of historical controls should consult FDA’s ICH guidance for industry E10 Choice of Control Group and Related Issues in Clinical Trials for more-detailed discussions.

D.  May Demonstrate Substantial Improvement on Clinically Significant Endpoint(s)

To support a breakthrough therapy designation, the preliminary clinical evidence must show that the drug may demonstrate substantial improvement over available therapy on one or more clinically significant endpoints.

Substantial Improvement: The determination of 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.

Features of Breakthrough Therapy Designation

1. Intensive Guidance on an Efficient Drug Development Program, Beginning as Early as Phase 1

As discussed previously, breakthrough therapy designation will usually mean that the effect of the drug will be large compared with available therapies. In such cases, the development program for the breakthrough therapy could be considerably shorter than for other drugs intended to treat the disease being studied. However, FDA notes that a compressed drug development program still must generate adequate data to demonstrate that the drug is safe and effective to meet the statutory standard for approval.  Omitting components of the drug development program that are necessary for such a determination can significantly delay, or even preclude, marketing approval.

Sponsors can design efficient clinical trials in a number of ways. FDA will seek to ensure that a sponsor of a product designated as a breakthrough therapy receives timely advice and interactive communications to help the sponsor design and conduct a drug development program as efficiently as possible.  During these interactions, the Agency may suggest, or a sponsor may propose, alternative clinical trial designs (e.g., adaptive designs, an enrichment strategy, crossover or N-of-1 design, use of historical controls) or use of an interim analysis by a data monitoring committee.  These trial designs may result in smaller trials or more efficient trials that require less time to complete and may help minimize the number of patients exposed to a potentially less efficacious treatment (i.e., the control group treated with available therapy). Such approaches may be especially useful in studies in rare diseases. For example, single-arm trials may be an important option in rare diseases with well-understood pathophysiology and a well-defined disease course.

FDA anticipates that the review team and the sponsor will meet and interact throughout drug development to address these and other important issues at different phases of development. In addition, a sponsor should be prepared for a more rapid pace for other aspects of the drug development (e.g., manufacturing development of a necessary companion diagnostic.

2. Organizational Commitment Involving Senior Managers

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.

3. Submission of Portions of an Application (Rolling Review)

FDA has determined that it is appropriate for a drug designated as a breakthrough therapy to be able to obtain rolling review. Therefore, if FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a breakthrough therapy product may be effective, the Agency may consider reviewing portions of a marketing application before the sponsor submits the complete application.

For drug manufacturers, it is about the intensity and frequency of their interactions with FDA. Once the designation is granted, the FDA takes an “all hands-on-deck” approach to providing the manufacturer with ongoing guidance and feedback throughout the clinical development process. Products that receive BTD are also able to submit portions of their marketing application on a rolling basis (rather than all at once at the end of clinical trials) and BTD can also be used in combination with other expedited programs in order to further reduce the product’s time to market.

For patients, the potential benefits are straightforward: earlier access to therapies that may significantly improve or extend their lives.