Recently, the Food and Drug Administration (FDA) released a Guidance for Industry, entitled “Expedited Programs for Serious Conditions—Drugs and Biologics.” The draft guidance provides a single resource for information on FDA’s policies and procedures for four programs intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious or life threatening condition:
1) fast track designation;
2) breakthrough therapy designation;
3) accelerated approval; and
4) priority review designation.
This guidance also outlines the threshold criteria generally applicable to concluding that a drug is a candidate for these expedited development and review programs.
Comments and suggestions regarding the draft are due Friday August 26, 2013 as published in the Federal Register.
BACKGROUND
The programs described in the guidance are intended to help ensure that therapies for serious conditions are approved and available to patients as soon as it can be concluded that the therapies’ benefits justify their risks. The FDA articulated its initial thinking on expediting the availability of new therapies in 21 CFR part 312, subpart E. In subpart E, the FDA intended to speed the availability of new therapies to patients with serious conditions, especially when there are no satisfactory alternative therapies, while preserving appropriate standards for safety and effectiveness.
The regulations ask for earlier attention to drugs that have promise in treating such conditions. The subpart E regulations specifically recognize that patients and physicians are generally willing to accept greater risk and uncertainty about benefit for the treatment of serious conditions where there is an unmet medical need.
CONCEPTS FOR EXPEDITED PROGRAMS
Criteria for the four expedited programs – fast track designation, breakthrough therapy designation, accelerated approval, and priority review – draw on the same principle of addressing unmet medical need in the treatment of a serious condition.
A. Serious Condition
1. Whether a Condition Is Serious
A serious disease or condition is defined in the expanded access regulation as: “a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient buy 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 severe one.” (21 CFR 312.300(b)(1)).
For the purposes of this guidance, FDA considers the term condition to include a disease or illness. All conditions meeting the definition of life-threatening as set forth at 21 CFR 312.81(A) would also be serious conditions.
2. Whether the Drug Is Intended to Treat a Serious Condition
A drug must be intended to have an effect on a serious aspect of a condition, such as direct effect on a serious manifestation or symptom of a condition, or other intended effects, including
- A diagnostic product intended to improve diagnosis or detection of a serious condition in a way that would lead to improved outcomes
- A product intended to improve or prevent a serious treatment-related side effect (e.g., serious infections in patients receiving immunosuppressive therapy
- A product intended to avoid a serious adverse effect associated with available therapy for a serious condition (e.g., less cardiotoxicity than available cancer therapy)
B. Available Therapy
The FDA considers available therapy (and the terms existing treatment and existing therapy) to mean therapy that:
- Is approved or licensed in the United States for the same indication being considered for the new drug, and
- Is relevant to current U.S. standard of care (SOC) for the indication
Approved or Licensure: Only in rare cases will a treatment that is not approved for the indicated use or is not FDA-regulated be considered available therapy. In those cases, FDA may consider unapproved or unlicensed therapy to constitute available therapy if the safety and effectiveness of the use is supported by compelling evidence, including evidence in published literature.
U.S. Standards of Care: FDA’s available therapy determination generally focuses only on treatment options that reflect the current standard of care for the specific indication for which a product is being developed. In evaluating the current SOC, FDA considered recommendations by authoritative scientific bodies (e.g., National Comprehensive Cancer Network, American Academy of Neurology) based on clinical evidence and other reliable information that reflects current clinical practice. In absence of a well-established and documented SOC, the FDA may consult with special government employees or other experts for advice.
C. Unmet Medical Need
A condition whose treatment or diagnosis is not addressed adequately by available therapy. Includes an immediate need for a defined population or a longer-term need for society.
1. Where There Is No Available Therapy
If no therapy exists for a serious condition, there is an unmet medical need.
2. Where There Is Available Therapy
When available therapy exists for a condition, a new treatment would be considered to address an unmet medical need if the treatment:
- Has effect on serious outcome of the condition that is not known to be influenced by available therapy
- Has an improved effect on a serious outcome(s) of the condition compared to available therapy
- Has a benefit for patients who are unable to tolerate available therapy or whose disease has failed to respond to available therapy, or the treatment can be used effectively with other critical agents that cannot be combined with available therapy
- Provides efficacy similar 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 similar safety and efficacy as available therapy but with another document benefit, such as improve 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
3. Where the Only Available Therapy Was Approved Under the Accelerated Approval Program Based on a Surrogate or Clinical Endpoint and clinical Benefit Has Not Yet Been Verified.
The FDA recognizes, as a general matter, that it is preferable to have more than one treatment approved under the accelerated approval provisions because of the possibility that clinical benefit may not be verified in the post-approval confirmatory trials.
OVERVIEW OF EXPEDITED PROGRAMS
1. FAST TRACK DESIGNATION
Section 506(b) of the FD&C Act provides for the designation of a drug as a fast track product: “if it is intended, whether alone or in combination with one or more other drugs, for the treatment of a serious or life-threatening disease or condition and it demonstrates the potential to address unmet medical needs for such a disease of condition.”
A. Qualifying Criteria for Fast Track Designation
1. If there is a “Serious Condition”
2. Demonstrating the Potential to Address Unmet Medical Need
This will depend on the stage of drug development in which fast track designation is requested.
B. Features of Fast Track Designation
1. Actions to Expedite Development and Review
There are opportunities for a fast track product. These include: FDA-sponsor meetings, including pre-IND, end of Phase 1, and end of Phase 2 meetings to discuss study design, extent of safety data required to support approval, dose-response concerns, use of biomarkers, and other meetings as appropriate. In addition, a product can be eligible for priority review if supported by clinical data at the time of BLA, NDA, or efficacy supplement submission.
2. Submission of Portions of An Application (Rolling Review)
If the FDA determines after a preliminary evaluation of clinical data that a fast track product may be effective, the Agency shall evaluate for filing, and may consider reviewing portions of a marketing application before the sponsor submits the complete application.
2. BREAKTHROUGH THERAPY DESIGNATION
A. Qualifying Criteria for Breakthrough Therapy Designation
1. If There is a “Serious Condition” or “Existing (or Available) Therapies”
2. Preliminary Clinical Evidence
Breakthrough therapy designation requires preliminary clinical evidence of a treatment effect that would represent substantial improvement over available therapies for the treatment of a serious condition. Assessment of the treatment effect will be based on preliminary clinical evidence. Nonclinical information could support the clinical evidence of drug activity.
3. 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 requires judging the magnitude of the treatment effect. In general, the preliminary clinical evidence should show a clear advantage over available therapy. Where there is an effective available therapy, showing substantial improvement is challenging.
The FDA considers clinically significant endpoint generally to refer to an endpoint that measures an effect on irreversible morbidity or mortality (IMM) or on symptoms that represent serious consequences of the disease. It can also refer to findings that suggest an effect on IMM or serious symptoms, including: an effect on an established surrogate endpoint; an effect on a pharmacodynamic biomarker(s) that does not meet criteria for an acceptable surrogate endpoint, but strongly suggests the potential for a clinically meaningful effect on the underlying disease; a significant improved safety profile compared to available therapy with evidence of similar efficacy.
In a breakthrough therapy designation request, the sponsor should provide justification for why the endpoint, biomarker, or other findings should be considered clinically significant.
B. Features of Breakthrough Therapy Designation
1. All Fast Track Designation Features
Section 902 of FDASIA instructs FDA to take actions appropriate to expedite the development and review of a breakthrough therapy. FDA has determined that it would be appropriate for the features of fast track designation to be available to a drug designated as a breakthrough therapy.
2. Intensive Guidance on an Efficient Drug Development Program, Beginning as Early as Phase 1
FDA notes that a compressed drug development program must generate adequate data to demonstrate that the drug is safe and effective in order to meet the statutory standard for approval.
3. Organizational Commitment Involving Senior Managers
FDA intends to expedite the development and review of a breakthrough therapy by, where appropriate, intensively involving senior managers and experience review staff in a proactive collaborative, cross-disciplinary review.
3. ACCELERATED APPROVAL
The accelerated approval provisions of FDASIA in section 506(c) of the FD&C Act provide that FDA may grant accelerated approval to: “a product for a serious or life-threatening condition … upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or an effect on a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.”
Accelerated approval is usually contingent on a sponsor’s agreement to conduct additional post-approval studies to verify and describe the drug’s clinical benefit.
A. Qualifying Criteria for Breakthrough Therapy Designation
1. If There is a Serious Condition
2. Meaningful Advantage Over Available Therapy
The accelerated approval regulations state that accelerated approval is available only for drugs that provide a meaningful therapeutic benefit over existing treatments. The accelerated approval provision of section 901 of FDASIA requires the FDA to “tak[e] into account … the availability or lack of alternative treatments.”
B. Accelerated Approval Endpoints
There are two types of endpoints that can be used as a basis for accelerated approval: (1) a surrogate endpoint that is considered reasonably likely to predict clinical benefit; and (2) a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit.
1. Surrogate Endpoints
For the purposes of accelerated approval, a surrogate endpoint is a marker, such as 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.
2. Intermediate Clinical Endpoints
An intermediate clinical endpoint is a measurement of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on IMM.
C. Evidentiary Criteria for Accelerated Approval
Drugs granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval. For effectiveness, the standard is substantial evidence based on adequate and well-controlled clinical investigations. For safety, the standard is having sufficient information to determine whether the drug is safe for use under conditions prescribed, recommended, or suggested in the proposed labeling. Under accelerated approval, FDA can rely on a particular kind of evidence, such as a drug’s effect on a surrogate endpoint, as a basis for approval. An application for accelerated approval should also include evidence that a surrogate or intermediate clinical endpoint is reasonably likely to predict the intended clinical benefit of a drug.
1. Whether an Endpoint is “Reasonably Likely to Predict” Clinical Benefit
This is a function of the biological plausibility of the relationship between the disease, endpoint, and the desired effect, and the empirical evidence to support that relationship.
D. Conditions of Accelerated Approval
1. Promotional Materials
An applicant must submit to the Agency for consideration during the preapproval review period, copies of all promotional materials, including promotional labeling as well as advertisements, intended for dissemination or publication within 120 days following marketing approval. After 120 days following marketing approval, unless otherwise informed by the Agency, the applicant must submit promotional materials at least 30 days prior to the intended time of initial dissemination of the labeling or initial publication of the advertisement.
2. Confirmatory trials
For drugs granted accelerated approval, postmarketing confirmatory trials are generally required to verify and describe the anticipated clinical benefit or effect on IMM. These trials must be completed with due diligence. Where confirmatory trials verify clinical benefit, FDA will generally terminate the requirement.
3. Withdrawal of Accelerated Approval
The FDA may withdraw approval of a drug or indication approved under the accelerated pathway, if, for example, trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug. If the FDA determines there are grounds for withdrawal, the agency may ask the applicant to voluntarily request withdrawal of approval under 21 CFR 314.150(d) or notify the applicant of FDA’s proposal to withdraw approval in a notice of opportunity for hearing (NOOH) which will generally state the proposed grounds for withdrawal of approval. Upon receipt of an NOOH, an applicant has 15 days to file a written request for a hearing. If an applicant does not request a hearing within 15 days, this is waived. An applicant may also voluntarily request the Agency to withdraw approval of an application approved under accelerated approval.
4. PRIORITY REVIEW DESIGNATION
An application for a drug will receive priority review designation if it is for a drug that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness. In addition, there are specific statutory provisions that provide for priority review for various types of applications. A priority designation is intended to direct overall attention and resources to the evaluation of such applications.
A. Qualifying Criteria for Priority Review Designation
1. Serious Condition
2. Demonstrating the Potential To Be a Significant Improvement in Safety or Effectiveness
On a case-by-case basis, the FDA determines whether the proposed drug would be a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious condition.
B. Features of Priority Review Designation
A priority review designation mean FDA’s goal is to take action on the marketing application within 6 months, compared to 10 months under standard review.
5. GENERAL CONSIDERATIONS
The FDA will strive to provide a timely response to a sponsor’s inquiry regarding an expedited development program.
A. Manufacturing and Product Quality Considerations
The sponsor of a product that receives an expedited drug development designation will probably need to pursue a more rapid manufacturing development program to accommodate the accelerated pace of the clinical program.
B. Nonclinical Considerations
To ensure timely submission and review of nonclinical data, sponsors should initiate early communication with the FDA for their nonclinical study programs.
C. Clinical Inspection Considerations
Sponsors should anticipate the Agency’s need to inspect clinical trials, including, if applicable, the analytical component of bioavailability or bioequivalence studies. Inspections should be scheduled early in the application review process so results are available to inform the review division and allow time for the sponsor to address significant inspection findings.