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Clinical Development: BIO Comments on FDA Draft Guidance Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products

March 27, 2020

March 18, 2020

FDA Docket No: FDA-2019-D-4964: FDA Draft Guidance on Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products

Dear Sir/Madam:

BIO thanks FDA for developing this additional guidance on demonstrating substantial evidence of effectiveness. BIO understands that the new guidance is intended to be complementary to the 1998 guidance entitled Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products[1] by reflecting FDA’s current thinking on trial designs, endpoints, and analysis, and the Agency’s longstanding flexibility when considering the types and amount of evidence for demonstrating effectiveness.

In this letter we provide key areas that we request FDA to consider when finalizing the Guidance as well as redline edits that we hope will help clarify some of FDA’s points.

  1. The Guidance Should be Combined with Existing FDA Guidance on Effectiveness.

BIO believes that the new Draft Guidance provides important information for drug developers, especially given the advances in science and regulatory science since the publication of the 1998 Guidance.[2] However, BIO strongly encourages FDA to consolidate the content of the 1998 Guidance and the new content introduced in the 2019 Draft Guidance into a new, single, revised draft guidance. In several parts of the new Draft Guidance, FDA refers to sections of the 1998 Guidance on the same topic and currently two guidance documents on the topic requires Sponsors, reviewers, and other stakeholders to refer across two documents for the totality of FDA’s thinking on a given issue. Furthermore, FDA will soon be adding to the Agency’s overall guidance on substantial evidence of effectiveness when it publishes the forthcoming Draft Guidance on use of real-world evidence to support safety and effectiveness determinations.[3] At that time, there will be three guidances on this topic when arguably there should be, at most, two (one within the context of clinical studies and one within the context of non-interventional studies). By doing so, industry and FDA staff would have a single document to reference rather than two complementary guidances on the same topic, minimizing confusion and promoting clarity around FDA’s current thinking on the state of the science. Consolidating the 1998 and 2019 guidance would also allow FDA to update the examples in the 1998 guidance with more recent examples. Additionally, over the last 20 years, FDA has increased transparency of the Agency’s review and decision-making process by posting comprehensive action packages on FDA’s website. More recent case examples where a comprehensive action package is available would enhance stakeholder understanding of FDA’s thinking on this issue.

  1. The Guidance Should More Clearly Indicate FDA’s Flexibility Around Data and/or Evidence from a Range of Sources for Demonstrating of Substantial Evidence for Effectiveness.

BIO appreciates FDA’s reference to the use of real-world-data/real-world evidence (RWD/RWE) in the context of demonstrating evidence for effectiveness; however, other significant and robust sources of data also could be leveraged to inform, compliment, or make more substantial the weight of evidence of effectiveness. For example, sponsors often have a range of study data going many decades and spanning multiple populations. These data may or may not have been powered to examine certain outcomes as a primary endpoint but may have incorporated other secondary endpoints or analyses that could inform or help support a determination of effectiveness. Likewise, where data collected in randomized controlled clinical trials were not deemed adequate at that time, or may have fallen short of a historic, prescriptively predetermined endpoint; nonetheless, these data could be useful in confirming or supporting a determination of effectiveness. Data captured in studies conducted outside the U.S., outside of an IND, also could be considered and included in support of an application and may be more rigorous or analogous to traditionally accepted randomized controlled clinical trial data than RWD. BIO strongly believes that all available and appropriate data should be leveraged to inform decisions about effectiveness, and we encourage FDA to indicate that in the final version of the Draft Guidance.

BIO also requests that FDA make it clear in the final version of the Guidance that while RWD/RWE can be used within the context of confirmatory studies, RWD/RWE also has the potential to be leveraged as evidence for effectiveness. Additionally, in many cases real-world evidence may better reflect safety and efficacy in the real-world setting. Especially as regulatory science discussions around RWD/RWE continue to advance and pilot programs help us understand the power of RWD, the guidance should not be overly limiting the uses of RWD/RWE which could limit the Agency’s ability to later conclude that RWE can have a broader role in FDA’s conclusion of substantial evidence of effectiveness. BIO notes that FDA is currently working through considerations on the use of RWE to meet FDA’s evidentiary standard and looks forward to the required draft guidance on the use of RWE to support efficacy and safety determinations.

  1. The Guidance Should Include Reference to the Use of Patient Experience Data in the Context of Demonstrating Substantial Evidence for Effectiveness.

Over the last several years through PDUFA V, PDUFA VI, and 21st Century Cures, the Agency has shown a strong commitment to supporting patient input, and the requirement in law that it explain its accounting for patient experience data in the context of the benefit-risk framework and statement of patient experience. BIO notes that the draft guidance describes the subjective nature of patient- and clinician-reported outcomes (PRO/ClinRO). BIO encourages FDA to provide additional context regarding PROs and ClinROs to describe their potential value and contribution to FDA’s overall conclusion on substantial evidence of effectiveness. While these tools involve some element of subjectivity, they are recognized as an appropriate method by which to gather relevant data regarding patients’ experiences with diseases and treatments, including how patients feel and function. When these data are captured by reliable and well-defined tools and analyzed and interpreted according to pre-specified and scientifically sound methods, patient reported outcomes (PROs) and other assessments from clinicians and caregivers can provide a reliable evaluation of a treatment’s clinical benefit. BIO believes these endpoints can serve as a rich source of data regarding the patient experience that provides information that is distinct from and complementary to what can be obtained with more traditional objective endpoints.  Therefore, BIO recommends that FDA provide more detail to describe how patient experience data, specifically COAs are considered in the totality of evidence assessment. For example, it would be helpful for FDA to address under what circumstances COA data would be influential in FDA’s conclusion of substantial evidence of effectiveness. BIO requests that FDA confirm in the final version of the Guidance that COAs can contribute to the demonstration of substantial evidence of effectiveness, under appropriate circumstances. Additionally, BIO recommends that the Draft Guidance reference other types of patient input in the context of drug development, review, or subsequent approval. While we understand that this Draft Guidance is addressing data used to inform determinations of “substantial evidence,” a lack of reference to other types of patient experience data may cause stakeholders to conclude that FDA does not view those data types as important for drug review. BIO requests that FDA confirm in the final version of the Guidance that patient experience data (e.g., COAs, patient preference information, and other data on a patients’ lived experience) is always considered relevant for the development of outcomes measures and review, including benefit-risk assessments and/or determinations of substantial evidence for effectiveness.

  1. The Guidance Could Benefit from Examples that are Relevant to the Center for Biologics Evaluation and Research (CBER)-Regulated Products.

While BIO appreciates the examples that FDA has included throughout the Draft Guidance, it does appear that the majority of the examples are Center for Drug Evaluation and Research (CDER)-regulated examples. Given that the Draft Guidance is applicable to both CDER and CBER-regulated products, BIO requests that FDA consider incorporating more examples to better illustrate how the Draft Guidance applies to CBER-regulated products.

  1. The Guidance Should Reflect Flexibility with Respect to the Full Range of Therapies and Patients.

Generally, the guidance reflects FDA‘s willingness to be more flexible in certain contexts, especially for rare and life threatening or severely debilitating conditions which is appreciated. However, we request that FDA incorporate discussions of rare diseases through the Draft Guidance, rather than just in the section focused on determination of substantial evidence of effectiveness for rare diseases.

BIO also requests that FDA acknowledge flexibility with respect to the full range of therapies and patients. Patients suffering from chronic, potentially more common illnesses, for instance, also should benefit from newer/ better therapies, or more informed treatment regimens, based on new uses of available data. To this end, BIO requests that FDA elaborate on how flexibility may be applied to a wide rage of diseases and therapies.

Finally, BIO also believes that the Guidance would be strengthened if there was an additional section that addressed flexibility pertaining to modalities of certain therapies (e.g. gene therapy products). In particular it would be helpful if FDA referenced, as relevant, the final guidance documents pertaining to gene therapies that were released earlier in 2020[4] and provided additional detail regarding clinical trials designs, including use of external controls and adaptive trials or master protocols.

Download Full Comments Below
BIO Comments on FDA DG Substantial Evidence
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