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ICH: BIO Comments on ICH E8(R1) General Considerations for Clinical Studies

September 30, 2019

Re: Docket ID FDA-2019-D-3049: E8(R1) General Considerations for Clinical Studies; International Council for Harmonisation

Dear Sir/Madam:

The Biotechnology Innovation Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on E8(R1) General Considerations for Clinical Studies; International Council for Harmonization.

BIO is the world's largest trade association representing biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial, and environmental biotechnology products.

BIO welcomes this document on internationally accepted principles and practices for the design and conduct of clinical studies of drug and biologic products. The draft guidance provides an overview of the types of clinical studies that may be performed and data sources during the product's life cycle. Although we believe the guidance is well written, we have provided general comments below for FDA’s consideration, as well as detailed comments in the annexed table.

  • The draft guidance uses the traditional framework for the logical progression of drug development in phases (Phase 1-4). BIO recommends that this document resets the framework for how drug development is approached. Scientific methodologies have evolved. There are a multitude of methodologies (e.g., adaptive designs, master protocols, platform trials, observational research, pragmatic research) that can be used to provide evidentiality for drug development. For example, adaptive designs can be used in Phase 1, which is not reflected in the document. BIO recommends that the document lessen the focus on Phase 1-4, which provides appearance of operating in the old paradigm, and instead focus on answering the research questions using appropriate methods at the suitable time.
  • There are a number of terms used which are new to ICH, as such, BIO recommends a glossary be added to clearly define the terms used in the document. For example, the draft guidance introduced new terminology into the ICH efficacy series, “critical to quality factors.” This terminology appears to convey the same intent as the terminology in E6(R2), “critical data and processes.”  It is recommended that consistent language be used throughout the ICH efficacy documents to prevent confusion.  
  • While we agree that we need to raise awareness and encourage seeking patient feedback in trial design, other stakeholders, such as health care professionals and care givers are still important and should be consider earlier in the draft document (i.e., these are not mentioned until line 190).
  • Guidance should be provided how the application of a quality by design approach for clinical study planning and conduct should be documented for regulatory purposes. In particular as the document points to incorporation of patient perspective into the quality by design for clinical studies. As such, further guidance should be provided on how to include patient perspectives for individual studies and overall clinical development to be used for regulatory purposes
  • It is highly appreciated that Quality will become an integral element of clinical trials. Although assessed as a significant step forward the document does not address or incorporate by reference to other documents  (i) some definitions of Quality Measures (e.g., Key Performance Indicators, Key Quality Indicators) addressing performance and Key Quality Elements of a clinical trial and (ii) introduction of strategic audit planning and Quality Management System addressing clinical trial activities of a company.
  • The critical to quality factors need to be explained in conjunction with the quality tolerance limits (QTLs) according to ICH GCP E6 (R2). Otherwise it is confusing to the audience where the differences are. In addition, the draft guidance should provide a linkage to E6 (R2) describing the risk-based approach in more detail. 
  • For consistency with international guidances ‘Clinical Studies’ should be replaced by ‘Clinical Trials’, whenever it is possible considering ICH E3 is still using clinical study.
  • The intended use of Annex 3 is unclear. The table would benefit from explain the use of the critical to quality factors concept, as well as inclusion of other ICH guidelines such as E3, Structure and Content of Clinical Study Reports. 

BIO appreciates this opportunity to submit comments on E8(R1) General Considerations for Clinical Studies; International Council for Harmonization. We provide additional specific, detailed comments to improve the clarity of the Draft Guidance in the following chart. We would be pleased to provide further input or clarification of our comments, as needed.