Did it Go Far Enough? FDA Issues Draft Guidance on Rare Disease Drug Development

Posted Saturday August 15, 2015 by Melissa

FDA-Guidance

Yesterday, the FDA issued draft guidance on common issues related to rare disease drug development. It is another importance event in the shift of thinking about how drugs are developed for rare and devastating diseases. You can find the complete document here and the docket on the Federal Register will be here (as of 8/17/15). We will also post a link to where you can submit comments on Regulations.gov when it is posted. [pullquote]It’s altogether too easy for sponsors to gloss over the references to patient perspective and decide that actually asking for patient input on those issues is unnecessary, too biased, or insufficiently scientific.[/pullquote]

But I pose the question: Does it go far enough? It is a compendium, in many ways, of the issues in drug development generally and how they might apply in rare disease, but there remains a lot of wiggle room that will leave rare advocates wanting more, such as the discount of historical controls and reiteration of the import of control groups. And while there are allusions to patient inclusion in the process (“An understanding of which aspects of the disease are meaningful to the patient and might also be affected by the drug’s activity.”), it’s altogether too easy for sponsors to gloss over the references to patient perspective and decide that actually asking for patient input on those issues is unnecessary, too biased, or insufficiently scientific.

Given the large influx of companies into the rare disease space in recent years, both small biotechs and big pharma, this may serve as guidance for the newly initiated. But for the seasoned, it seems unlikely to give them enough assurance to significantly alter their current course of drug development. Rather, let’s hope there are some golden nuggets that still cause them to think and take new steps toward better programs, such as the discussion about endpoints and assessments.

Some salient points from the guidance:

  • While not requiring that natural history studies be done, “FDA advises sponsors to evaluate the depth and quality of existing natural history knowledge early in drug development,” specifically prospective longitudinal studies.
  • While not requiring sponsors to fully understand the biochemical basis of a disease, “sponsors should seek to understand the pathophysiology of a disease as fully as possible at the outset of drug development” as it may be helpful in selecting endpoints, measuring treatment effect, selection of test timing, drug administration scheduling, identification of biomarkers, as well as possible identification of other therapeutic targets.
  • “FDA may apply additional flexibility in evaluating development programs for drugs to treat serious and life-threatening disorders.”
  • And a specific recommendations we’ve discussed with FDA representatives was mentioned: “An assessment tool training program for investigators may improve both intra-rater and inter-rater (i.e., across study sites) consistency.”
  • “Including several endpoints with different characteristics may improve the overall interpretability of the study results. For example, a phase 3 clinical trial with a clinically meaningful but subjective primary efficacy endpoint (i.e., one that may be prone to bias) may benefit from having secondary endpoints that are resistant to bias (such as laboratory measurements).”
  • “When conducting a benefit-risk assessment for a drug for a serious or life-threatening illness, FDA also recognizes that greater risks may be accepted for a treatment that is an advantage over available therapy. This reflects FDA’s commitment to expediting the availability of drugs for serious diseases as soon as it can be concluded that the benefits of the drugs exceed their risks, while preserving appropriate standards for safety and effectiveness, especially when these patients have unmet needs, as is often the case with patients with rare diseases.”
  • “FDA recommends that sponsors consider the potential development of the manufacturing process in the entire drug development program early, including which nonclinical and clinical studies are intended to be conducted with each change in the manufacturing process, and whether bridging studies will be needed.”

I encourage you to submit comments to the draft guidance, offering suggestions for additions, clarifications, or improvements [link to be posted 8/17/15]. We have submitted numerous and extensive comments on issues related to rare disease drug development. If you’re not sure what might be appropriate thoughts or suggestions for such comments, feel free to read our past docket submissions below. We will also be posting our comments to this draft guidance once submitted.

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