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Rare Diseases: BIO Comments on FDA Draft Guidance Rare Diseases: Natural History Studies for Drug Development

BIO appreciates the Agency’s work to develop a much-needed guidance on natural history studies for rare disease drug development. The Draft Guidance serves as an important communication tool between the FDA and Sponsors on issues pertaining to natural history studies for rare disease drug development. Such guidance ensures that Sponsors have appropriate information for developing new therapies for rare disease patients, especially given that many rare diseases still do not have an FDA approved treatment. In the following pages of this letter, BIO has included general comments as well as line edits that we believe will make the Draft Guidance more useful for various stakeholders.

May 24, 2019

Re: Docket No. FDA–2017-D-0481: FDA Draft Guidance, Rare Diseases: Natural History Studies for Drug Development

Dear Sir/Madam:

The Biotechnology Innovation Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments regarding the Draft Guidance on Rare Diseases: Natural History Studies for Drug Development.

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’s members develop medical products and technologies to treat patients afflicted with serious diseases, to delay the onset of diseases, and to prevent diseases in the first place.

BIO appreciates the Agency’s work to develop a much-needed guidance on natural history studies for rare disease drug development. The Draft Guidance serves as an important communication tool between the FDA and Sponsors on issues pertaining to natural history studies for rare disease drug development. Such guidance ensures that Sponsors have appropriate information for developing new therapies for rare disease patients, especially given that many rare diseases still do not have an FDA approved treatment. In the following pages of this letter, BIO has included general comments as well as line edits that we believe will make the Draft Guidance more useful for various stakeholders.

Guidance on Natural History Studies is Helpful Information for Stakeholders beyond Drug Developers:

Although this guidance is titled “guidance for industry,” a growing number of advocacy and patient organizations have either initiated or have the potential to initiate or facilitate the development of natural history studies. Thus, the guidance should highlight and recognize that it can apply to a wider range of stakeholders, including patient organizations. To this end, BIO requests that the final Guidance should read “Guidance for Industry and Other Stakeholders.” The guidance should also encourage patient organizations to consider the guidance when developing their natural history studies so that the data is robust and can be considered by the FDA for regulatory decision-making. 

Accept and Encourage use of Appropriate Retrospective Natural History Study Data and Alignment Across FDA Guidance Pertaining to Rare Disease Drug Development:

The recommendations regarding natural history studies included in the recent revision of the Draft Guidance entitled “Rare Diseases: Common Issues in Drug Development” should align with the recommendations made in this Draft Guidance and reduce duplicative language. Overall, with regarding to natural history studies the Draft Guidance on Rare Diseases: Natural History Studies or Drug Development takes a slightly more pragmatic approach than recommended in the guidance on “Rare Diseases: Common Issues in Drug Development”. To this end, As the Agency finalizes both documents, we request that the updated guidance documents are carefully reviewed to ensure that the recommendations regarding natural history studies align and take a more forward-leaning approach as outlined in the natural history guidance.

In the interest of meeting unmet medical need and getting drugs to patients efficiently, the guidance should generally acknowledge that limitations may exist in rare disease natural history data, but that the limitations should not hinder drug development. FDA’s stance to recommend prospective natural history studies may discourage efforts to collect natural history data to support multiple drug development programs. BIO requests that FDA adopt a more pragmatic approach to recommending use of prospective versus retrospective natural history studies and data, based on totality of evidence available, as well as the quality, appropriateness, and applicability of the available natural history data. Additionally, gaps in retrospective data may often be addressed by other means, such as using real-world data/evidence (RWD/RWE) or other data, instead of conducting a duplicative complete prospective natural history study. To this end, BIO suggests that FDA build on and provide further detail on their recommendation in guidance that “Real-world data (i.e., data relating to patient health status and /or the delivery of health care that is routinely collected from a variety of sources) may be useful to collect data for natural studies.” It would be helpful if FDA could expand on their recommendation in the guidance to address RWD collection and analysis with respect to natural history studies, in line with their proposed RWE framework. BIO also requests that the FDA encourage the use of existing (e.g. retrospective) natural history data, when such data is available and appropriate, to enhance efficiency of drug development and to avoid unnecessary duplication of studies. It is acknowledged that FDA encourages the use of combination of data sets from natural history studies and from randomized controlled studies, FDA might provide further guidance on regulatory expectations for this hybrid approach.

Leveraging Existing Natural History Data When a New Treatment is Approved:

Increasing interest in developing rare disease treatments presents industry with a unique challenge. In instances, wherein, a treatment is approved (product A) for a rare disease where no treatment existed before, there may still be a case for other drug developers to leverage existing, non-proprietary, natural history data that was collected prior to the approval of product A to aid development of other products still in the pipeline (products B, C, D, etc.). Such circumstances may include:

  1. When the newly approved treatment (product A) is symptom-alleviating and not disease-modifying. In these cases, existing natural history data can still be leveraged to aid in development of drugs in the pipeline (products B, C, D, etc.).
  2. When the new treatment (product A) introduced is "disease-modifying" and/or has limited uptake or is not considered the standard of care. Sponsors of products in the pipeline (products B, C, D, Etc.) should be able to leverage existing natural history data to supplement an ongoing or new study.

Provide more flexibility and clarify considerations for the Statistical Analysis Plan (SAP):

The level of rigor recommended in the first paragraph of section on the “Statistical Analysis Plan” is desirable by all stakeholders, including FDA and industry alike. However, in some cases, achieving such rigor may be difficult. BIO recommends that changes to a SAP should be documented with rationale, but should not necessarily require a protocol amendment [428-429]. BIO also acknowledges that some principles outlined in this section are pertinent to using the natural history data as a comparator in a treatment trial and should be considered when planning such analyses. Accordingly, BIO suggests that FDA consider distinguishing recommendations for analyses of natural history data on their own, independent of any drug effectiveness studies, from analyses of natural history data when used for comparative analyses. Additionally, topics such as language and cultural differences (and their impact on assessment instruments), intra- and inter-rater reliability, and biomarkers should perhaps be primarily addressed in a separate section about trial endpoints, instead of within the section on SAP. In addition, the analytical plan is mentioned several times throughout the Draft Guidance. For clarity, BIO suggests that the guidance note in these sections that, generally, protocols contain only a summary of planned statistical methods, with the details being relegated to the study’s SAP.

BIO appreciates this opportunity to submit comments regarding FDA Draft Guidance, Rare Diseases: Natural History Studies for Drug Development.  We would be pleased to provide further input or clarification of our comments, as needed.