Under the Prescription Drug User Fee Act (PDUFA) VII Commitment Letter^[1], FDA is creating the Split Real Time Application Review (STAR) pilot program.  

Overview

FDA is establishing a STAR pilot program, which aims to shorten the time from the date of complete submission to the action date, in order to allow earlier patient access to therapies that address an unmet medical need. The STAR pilot program will apply to efficacy supplements across all therapeutic areas and review disciplines that meet specific criteria. Accepted STAR applications will be submitted in a “split” fashion, specifically in two parts with the components submitted approximately two months apart.

FDA will begin to review the data once the agency receives the complete Part 1 Submission. The PDUFA review clock will start once the agency receives the Part 2 Submission, which will include the final clinical study report(s), the Integrated Summary of Safety, and Integrated Summary of Effectiveness. The program applies to both drugs and biologics, collectively referred to as drug(s). STAR is available for certain supplemental new drug applications (sNDAs) and supplemental biologics license applications (sBLAs) that propose new uses of approved therapies to address an unmet medical need. The program is available across all therapeutic areas.

STAR Eligibility Criteria

FDA will consider an application eligible for the STAR pilot program if each of the following criteria are met:

1. Clinical evidence from adequate and well-controlled investigation(s) indicates that the drug may demonstrate substantial improvement on a clinically relevant endpoint(s) over available therapies.
   1. Breakthrough Therapy Designation (BTD) or Regenerative Medicine Advanced Therapy Designation (RMAT) is not required, but above criteria must be met.

   (See clarification 1.a. below for further explanation.)

2. The application is for a drug intended to treat a serious condition with an unmet medical need.
3. No aspect of the submission is likely to require a longer review time (e.g., requirement for new Risk Evaluation and Mitigation Strategies (REMS), etc.)
4. There is no chemistry, manufacturing, or control information that would require a foreign manufacturing site inspection (i.e., domestic site inspections may be allowed if it does not affect the expedited timeframe).

   (See clarification 2. below for further explanation.)

Clarifications

1. Applicants should consider the following when providing clinical data that “may demonstrate substantial improvement”:
   1. The qualifying standard of “substantial improvement” for STAR is the same standard used to qualify for either BTD or RMAT.
   2. While FDA generally anticipates that most non-inferiority trials will not demonstrate substantial improvement, if a non-inferiority trial has built in superiority analysis and the results show substantial improvement over available therapies, then the trial may meet the STAR criteria for substantial improvement.
   3. Efficacy supplements relying on real-world evidence (RWE) to demonstrate substantial improvements on a clinically relevant endpoint(s) over available therapies are not currently included in STAR.
2. The request to enter the STAR pilot must include an attestation statement that clarifies there will be no foreign manufacturing sites associated with the supplement. FDA will verify the attestation statement once the agency receives the Part 1 Submission. If there are any foreign manufacturing sites, the supplement will no longer be eligible for review under STAR.
3. A supplement must qualify for priority review in order to be in the STAR program.
4. Acceptance into STAR does not guarantee an expedited review; however, the agency will make every effort to do so for applications in the program. Under limited circumstances, the review process may be extended, for example, when an applicant submits a Major Amendment during the pending application.
5. Acceptance into STAR does not guarantee an application approval. The application must still meet the applicable standard for approval.

Process Considerations

1. If an applicant believes a proposed efficacy supplement fulfills the conditions outlined in the Eligibility Criteria, the applicant may submit a STAR Entry Request as either: 1) a stand-alone teleconference request, or 2) as part of a Type B pre-sNDA/sBLA meeting request. The STAR Entry Request must provide:
   • Topline results from the adequate and well-controlled trials
   • Proposed labeling
   • An explanation of how the proposed application meets each STAR criterion
   • The subject line of the cover letter should clearly state "STAR Entry Request"
2. For a stand-alone teleconference, the sole focus and discussion will be whether the proposed supplement qualifies for STAR. There will be no meeting minutes, but a letter documenting the decision will be sent after the teleconference.  If the applicant wishes to discuss additional questions (e.g., content and format of the proposed supplement), they must submit the STAR Entry Request combined with a Type B pre-sNDA/sBLA meeting request.
3. STAR Part 1 Submission must include all of the following:
   • All components of the sNDA/sBLA efficacy supplement (e.g., complete datasets, proposed labeling, clinical protocols and amendments, topline efficacy and safety results), except for final clinical study reports for the adequate and well-controlled investigation(s) supporting the proposed claim and the electronic common technical document (eCTD) module 2 clinical summaries.
   • A document providing topline results for each of the adequate and well-controlled investigations, along with the applicant’s overall interpretation of the effectiveness and safety.
   • Clinical protocol and amendments for pivotal trials
   • Statistical analysis plan and statistical programs
   • Tables, figures, and listings
   • Death summaries
4. STAR Part 1 Submission should also include the following:
   • As applicable, the items described in CDER’s bioresearch monitoring (BIMO) inspections draft guidance^[2] should be provided to facilitate development of clinical investigator and sponsor/contract research organization inspection assignments. This information is requested for all major (i.e., pivotal) trials used to support safety and efficacy in the application. Please note that if the items described in CDER’s BIMO draft guidance are provided elsewhere in the submission in the format described, applicants can provide the location or a link to these items.
5. STAR Part 2 Submission* must include all of the following:
   • Clinical study report(s)
   • Integrated summary of safety
   • Integrated summary of effectiveness

   *Part 2 Submission must be received by FDA approximately two months, but no longer than three months, after receipt of Part 1 Submission.

6. The PDUFA clock starts once the agency receives the STAR Part 2 submission, which represents the complete application. FDA will communicate the intent for an expedited action in the filing letter.
7. If an applicant is disqualified from the STAR pilot program due to incomplete submissions, they may still submit a complete application at a later time; however, they would not receive the benefits of the STAR program review.