Clinical protocols for Phase 3 trials may include efficacy claims that are part of an original New Drug Application (NDA) or Biological Licence Application (BLA) or efficacy supplement to an approved NDA or BLA. The FDA must have some knowledge of the development program before submitting a SPA. Products from outside the U.S. or companies offering new creative formulations sometimes perform Phase 3 early in development in the U.S., meaning the FDA must provide feedback on Phase 3 protocols, while other activities limiting approval rates such as chemistry, manufacturing, and controls (CMC) take place. The FDA announces the availability of an industry guide entitled “Special Protocol Evaluation.” Spa is a process by which sponsors can request a meeting with the FDA to reach agreement on the design and scope of specific studies, clinical trials, or animal studies to determine whether they adequately meet the scientific and regulatory requirements of a study that could support marketing approval. At the end of the SPA review, the FDA will publish a letter containing the review team`s comments, approval or disagreement with the proposed protocol, and responses to relevant questions from the sponsor. Section 119 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) amended Section 505(b) of the Federal Food, Drug and Cosmetic Act (FD&C Act) (21 U.S.C. 355(b)) and requested the FDA to meet with sponsors who, if certain conditions are met, to reach agreement on the design and scope of well-controlled clinical trials to form the primary basis for proof of efficacy in a regulatory filing filed pursuant to Section 505(b) of the FD&C Act or Section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262).
These provisions were subsequently amended in section 7002(d)(1) of the Competition and Innovation in Biologics Prices Act, 2009 to include all clinical trials or studies required for the use of biosimilar bioproducts under section 351(k) of the PhS Act. In 2013, the Pandemic and All Hazards Preparedness Reauthorization Act of 2013 further amended the SPA Regulations to provide for SPA agreements for animal clinical trials and related clinical trials conducted in support of product applications developed pursuant to Subsection I, 21 CFR, and Subsection H of Part 601 of the CFR (the Animal Rule). These marketing applications include New Drug Applications (NDAs), Biologics Licence Applications (BLA), and Efficacy Supplements for Approved NDAs and BLAMs. The FDA has finalized its guidelines for the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research Special Protocol Assessments (SPA). The SPA is a process in which product sponsors can request a meeting with the FDA to reach agreement on the design and size of clinical trials and clinical or animal studies to determine whether they adequately meet scientific and regulatory requirements to support potential marketing approval. While it is useful to describe the types of new information that the FDA may consider important enough to merit the repeal of an SPA, the examples of guidance provided are formulated in such a way that their usefulness is limited as clear and predictive guidelines. In addition, the guide also identifies “an evolving understanding of protocol design; knowledge from ongoing clinical trials; and the accumulation of data on similar product development programs” as additional scientific and medical innovations that could potentially merit a resignation from the spa. Without a more detailed and accurate description of what is considered a major scientific problem, uncertainty surrounding the PSA program will remain. In 2013, the FDA revoked a SPA agreement with Amarin Corporation to extend the existing indication for its drug Vascepa® with severe hypertriglyceridemia to patients with high triglyceride levels. The FDA and Amarin entered into a SPA agreement for Vascepa in 2009. Amarin successfully conducted the clinical trial and met the endpoints agreed in the SPA.
Based on the positive result of their study, Amarin filed an NDA and the FDA accepted the request for standard review. The company then announced that the FDA had approved Vascepa for the treatment of elevated triglycerides in adult patients. However, when reviewing Amarin`s NDA application, the FDA noted that since the protocol for the expanded SPA indication was approved, new scientific evidence had been revealed that raised significant doubts about the validity of the study`s clinical criteria. As a result, the FDA revoked the SPA agreement with Amarin and issued a full response letter informing Amarin that they would need to provide direct evidence of a reduction in cardiovascular events in order to make such a claim. After extensive and repetitive legal offers to repeal the repeal, Amarin and the FDA finally reached a settlement agreement that allowed for a “truthful and non-misleading” promotion of Vascepa`s off-label use. Although a SPA agreement states that the FDA has determined that the study proposed by a sponsor is appropriately designed to support the FDA`s acceptance criteria for its NDA or BLA, an SPA does not guarantee a positive outcome for the product application. Revocation of the PSA agreement may take place if the sponsor does not fully comply with the agreed protocol or if the final results of the study are not favourable. Even if the study is conducted as planned and the agreed assessment criteria are successfully met, the FDA may refuse to submit or approve the application.
In conjunction with the re-approval of the prescription drug program in the FdaMA (Prescription Drug User Fee Act (PDUFA) II)[1] and the Biosimilar User Fee Act of 2012 (BsUFA) enacted under the Food and Drug Administration Safety and Innovation Act, the FDA has approved certain performance targets (PDUFA targets and BsUFA targets, [2] and BsUFA, respectively) for SPA. In accordance with Section 505(b)(5)(B) of the FD&C Act, PDUFA targets and BsUFA targets, the following protocols are appropriate for SPA: (1) Animal Carcinogenicity Protocols; (2) protocols on the stability of medicinal products and medicinal products; (3) animal efficacy protocols for studies intended to provide primary evidence of efficacy required for the authorisation or authorisation of products developed in accordance with the animal rule; (4) the test plans for the tests that will constitute the main basis of a claim of efficacy; and (5) clinical studies necessary to demonstrate biosimilarity and/or interchangeability. Protocols eligible for an SPA application are animal carcinogenicity protocols, drug substance and drug stability protocols, animal efficacy protocols, study protocols to form the primary basis of a efficacy claim, and protocols required for clinical trials to demonstrate the biosimilarity or interchangeability of the proposed biosimilar. Next, it is important to refine the questions in the SPA app so that they create clarity and conciseness. Since there are few ways to interact with the FDA, it is important to formulate high-level questions very carefully. Ideally, protocols will be fully reviewed with robust statistical analysis plans that can be submitted to the FDA with a single question: “Does the agency agree that the protocol design may result in data needed for FDA review to approve the proposed indication?” If the FDA disagrees, it will provide the necessary feedback to resolve existing issues. There is an alternative to SPA meetings that can help streamline the entire development process. If proponents are seeking feedback on the design of a Phase 3 protocol and the proposed analysis, the full minutes can be submitted as an appendix to your EOP2 meeting kit, eliminating the need for an SPA. The issue of the minutes contained in the eOP2 meeting package would be exactly the same as that proposed above for the BSG communication. The final minutes of the EOP2 meeting obtained from the FDA will document their approval of the Phase 3 study design in the same manner as an SPA. The Food and Drug Administration (FDA or Agency) announces the availability of a guide for industry entitled “Evaluation of the Special Protocol”.
This guide provides information on the general procedures and guidelines adopted by the Centre for Drug Evaluation and Research and the Centre for Biologics Evaluation and Research for the Evaluation of Special Protocols (SPAs). These guidelines are intended to improve the quality of PSA applications and accompanying submission documents, as well as the quality of the resulting interactions between sponsors and the FDA. This guide concludes the draft Guide of the same name of 4 May 2016 and replaces the guidelines of the same name of 17 May 2002. For proposed biosimilars, protocols are only eligible for the PSA program if the sponsor has held a meeting with the Agency for the Development of Biosimilar Biologics (BPDs) Type 2 or Type 3. The FDA says, “These detailed discussions are especially important if the development plan includes study elements with which there is little experience in the past.” Spa guidelines recommend submitting an application for an SPA at least 90 days before the start of studies. .