What’s missing from the FDA’s draft guidance on natural history studies in rare disease

The regulator got a lot of things right, but this is how its thinking could be improved.

When the US FDA issues draft guidance on a subject of strategic importance to the pharmaceutical industry, two things tend to happen. Pharma companies pore over the details to understand how the regulator’s latest thinking will impact on their established ways of working. And the more proactive among them respond with recommendations of their own, hoping that the FDA will incorporate them into the guidance when it is finalized.

Feedback on the FDA’s draft guidance to industry titled “Rare Diseases: Natural History Studies for Drug Development” was a prime example of this. As rare disease has become a growing priority for pharma, a healthy response to the draft guidance was to be expected. Raremark’s review of the responses published to date has revealed the key areas in which the regulator’s position could be refined to better support companies developing and marketing drugs to treat rare disease.

The first would be a clear articulation of the utility of real-world data (RWD) and real-world evidence (RWE) as inputs to natural history studies. RWD appears just once in the draft guidance, in a footnote. This reductive stance has left companies wondering about possible disconnects between different parts of the agency. Just three months before issuing the draft guidance, the FDA published a detailed framework for its Real-World Evidence (RWE) Program. Companies want the final guidance on natural history studies to draw on some of the content of the RWE framework. PhRMA, the pharma industry association, stated: “… additional context and examples of characteristics of RWD/RWE and related analyses that would be acceptable to FDA would be helpful to sponsors”.

Raremark’s response took the RWD argument a step further. We noted that the draft guidance fails to acknowledge the possibility of patients providing their own data for natural history studies, without the oversight of a healthcare professional (HCP); for example, through a mobile app. We argued that people living with rare disease can be trusted to answer questions, accurately and truthfully, in the category of information we call patient-reported experience data. Such data might include: patients’ opinions of treatments; patients’ main day-to-day challenges living with their condition; and the strategies they employ to cope with it. Patient-reported experience data represent a goldmine of potential insight for drug developers, in addition to the RWD traditionally captured by HCPs in electronic medical records.

Another worry for pharma centers on the FDA’s clear preference for prospective natural history studies over those with a retrospective design. Companies are concerned that the regulator is too fixated on the limitations and biases of retrospective studies (based on data that has already been collected), while not being cognizant enough of the challenges of conducting prospective ones. Pragmatic use of limited resources is likely top of mind for companies. Large pharma sponsors may have deep enough pockets to pursue the prospective study approach most of the time. But the majority of biopharmaceutical companies active in rare disease are neither large nor deep-pocketed.

BIO, the other major US-based industry association, frets that the “FDA’s stance to recommend prospective natural history studies may discourage efforts to collect natural history data to support multiple drug development programs”. If the agency can be convinced to reflect on this problem, hybrid study designs might become the accepted norm. Novartis argued that “the final guidance should clarify that there might be prospective studies that combine retrospective data collection”. BioMarin wants the final guidance to include “recommendations regarding the utility of retrospective natural history data as a bridge where prospective natural history data is limited”.

An additional area in which companies want the FDA to be more flexible is in asking sponsors to detail up front how they plan to analyze study data. The draft guidance states: “For natural history studies to be most informative, the Agency recommends that natural history studies have a prospectively defined statistical analysis plan (SAP)”. Specifically, the FDA wants SAPs to “delineate the analysis population, definition of endpoints, descriptive objectives, testable hypotheses and statistical methods to be employed in analysis of the data including the timing of the data analyses conducted in the study”.

Companies believe they shouldn’t be expected to tick all those boxes in every scenario, since different natural history studies serve different purposes. A detailed SAP is appropriate in cases where a natural history study is intended to provide an external control to a clinical trial. But in scenarios where a natural history study is being conducted to increase understanding of a poorly-understood disease, flexible study designs should allow statistical methods to be defined, or refined, after some data has been collected.

Genentech’s observation that subtypes of disease are often identified after studies are well under way underlines why flexibility is important. TriNetX, a health research network powered by RWD, stated: “natural history studies are usually descriptive and hypothesis generating. Furthermore, the small sample sizes in orphan diseases would in most cases not be sufficient for confirmatory statistics”. Natural history data generated without a full SAP being detailed in advance is more valuable than no data at all.

Raremark’s final observation focuses on the types of organization that have submitted responses to the draft guidance. Most of the 15 responses published to date came from biopharmaceutical companies. No CROs appear in the list of respondents. That’s notable, given the level of noise the largest CRO players are all making about their capabilities in rare disease and in RWD/RWE. Perhaps that’s because they have read the draft guidance and accepted everything the FDA has to say. Or perhaps they think shaping the regulator’s thinking on such a strategic theme is more of a job for their biopharmaceutical sponsors.<o:p></o:p>

By Pete Chan, Head of Research & Analysis

Published on September 12, 2019

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