BIO Comments on FDA Draft Guidance Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease

Re: Docket ID: FDA-2017-D-6617: Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease

Dear Sir/Madam:

The Biotechnology Innovation Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments to the Draft Guidance titled “Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease.”

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 FDA’s efforts to provide clear guidance on the regulatory and scientific framework for product developers of targeted treatments and applauds the Agency for issuing guidance in a more concise and streamlined manner. This Draft Guidance is easy to read and succinctly outlines FDA’s recommendations for targeted therapy development, including the types/levels of evidence to support a grouping strategy for clinical trial eligibility and benefit-risk evaluation approaches within a disease that exhibits differences in molecular subset.

BIO encourages the FDA to continue to gather stakeholder input on the topic of development of targeted therapies to ensure that FDA guidance keeps pace with scientific advances. BIO has made the following observations worthy of attention with respect to the Draft Guidance:

  • BIO suggest the Draft Guidance provide further thinking on the Agency’s receptivity to innovative approaches for the development of targeted therapies.
  • The Draft Guidance is written with a focus on grouping multiple molecular alterations in a [single] clinically defined disease. BIO recommends the Draft Guidance also reflect the scenario where one or more molecular alterations occur across multiple “diseases” (e.g., a single genetic mutation which occurs in tumors of different tissue types).
  • BIO appreciates the Agency’s directive to ideally design clinical trial assays to detect all possible molecular alterations that comprise the group expected to respond to a targeted therapy. However, the scope is very broad. BIO proposes that the Agency provide examples that help clarify what defines a group. For example, can the group be defined by a specific gene, or by a group of related genes (such as an immune panel)? Further, detecting all molecular alterations of clinical significance in a particular indication can be difficult in the absence of whole genome or whole exome sequencing which may not always be practical. Even if such techniques are pursued, clinically validating a molecular alteration can be challenging (i.e., clearly establishing that a specific molecular alteration is of clinical significance in that particular disease). For example, in oncology, distinguishing between passenger and driver mutations or in cases of exceptional responders who can respond to treatments because of unknown or yet to be validated secondary mutations. Therefore, BIO requests that the Agency acknowledges these practical challenges and develop a regulatory pathway that allows a flexible path to approval of a targeted therapy for all patients who may benefit. We note that this pathway would be distinct from post-market requirements to confirm findings of the initial clinical study or to gather additional information regarding risks and benefits of the drug.
  • BIO suggest that the Agency provide clarity on how these outlined principles could be interpreted in a "complementary diagnostic" situation, for example an all-comer population where patients with a range of mutations in a defined gene may respond to the targeted therapy.

BIO appreciates this opportunity to submit comments and have provided additional 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.