FDA Hearing on Rare Disease Drug Evaluation--Comment Period

The Food and Drug Administration is holding a public hearing on June 29th called "Considerations regarding FDA review and regulation for Articles for the treatment of rare disease."  I've attached the file announcing the hearing (see the highlighted Notice near bottom right and on to the next page).


But, they basically want to know if

1.  The methods used to regulate all drugs are working for the regulation of rare disease drugs (and if not, what isn't working and they want suggestions)

2.-3.  Two questions about devices for rare disease that I think we are less interested in; and

4  If the communication avenues they've established with the public about regulatory review in rare disease is adequate.


You can attend this meeting in person or you can submit a public comment. You can submit comments electronically at www.regulations.gov.  You should mention to which "Docket" you are referring--in this case No. FDA-2010-N-0218 and to which question of the four above you are responding. 


PPMD is planning to post comments but you are all welcome to submit comments on your own.  I can post the PPMD comments here as well--still drafting those.  The deadline for submitting comments is May 31st.  I think it would be great for the FDA to hear from this community!



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Thanks for sending this. Can we see a draft of the PPMD comments in advance? It's probably helpful if everyone echoes them in our own words, much as we do at the Advocacy to Congress.


I've been worrying about the FDA's pace and process ever since Alex was diagnosed. Now's our chance to be heard.
I will try to post PPMD's draft by the end of the day--I'm working on another one for a meeting about the NIH-FDA collaboration on regulatory science that's actually due today so I need to get that one done first. The FDA comments for the meeting I referenced above are due May 31st.

Just an update--this comment period is still open (you can can actually submit comments until August 31st). Here is the comment PPMD submitted:

Docket No. FDA-2010-N-0218
June 2, 2010
Comment from Sharon Hesterlee, Ph.D., Senior Director of Research and Advocacy for Parent Project Muscular Dystrophy

1. Orphan Drug marketing applications are reviewed under the same review process and statutory standards regarding demonstration of safety, effectiveness and product quality as drugs for patients with non orphan diseases or conditions. FDA is sensitive to the unique needs of patients with rare diseases as it makes approval decisions regarding the overall risk-benefit for the particular patient population for which they are being considered. Please comment on whether this practice has adequately addressed the needs of patients with rare diseases. If improvements are suggested, please provide specific examples/suggestions for any recommended changes.

Parent Project Muscular Dystrophy (PPMD) is a 501c3 devoted to developing therapies for Duchenne muscular dystrophy (DMD), a fatal, X-linked muscle wasting disease, and the slightly less severe form known as Becker muscular dystrophy (BMD). Approximately 15,000 boys and young men in the US have DMD and about a third of these are due to new spontaneous mutations. Due to the hard work of the amazingly dedicated families affected by this disease, PPMD and other organizations, and our academic and corporate partners, we now have multiple drugs in early stage clinical testing. Although the FDA review process has clearly succeeded in the vast majority of cases in protecting the safety of Americans who take prescription drugs, some changes would benefit those with DMD/BMD and the rare disease populations in the US, which collectively include close to 15 million people.

Our comments on the review process come in three categories: patient recruitment, personalized medicine and risk/benefit analysis.

Patient Recruitment

First, the “typical” drug approval path usually includes one or more phase I studies, two phase II studies and at least two phase III pivotal studies. Drugs that are marketed in other countries must go through parallel clinical studies for approval in those countries. Because DMD is rare and fatal on average by the mid-twenties, both the numbers of trial participants required for this review process and the time-line are problematic.

1. Because of the small numbers of patients, creative trial designs that use fewer patients should be more accepted in rare disease. For example, the use of tightly controlled, current natural history data instead of a placebo arm could be considered. A phase II study that demonstrates compelling benefit should be considered a registration study.

2. The small number of participants available for studies is further reduced by the need to use patients with “optimal outcomes”—usually those in earlier stages of the disease. We need to think creatively about developing acceptable outcomes for more severely affected patients and including that group in the approval process. For example, although it may difficult to show clinically meaningful results in this group, it could be demonstrated in the more severely affected patients that the drug is hitting target. More severely affected patients should be included at every stage of the approval process.

3. Because patient populations are smaller, it can be difficult to validate clinically meaningful endpoints, biomarkers and surrogate markers. In rare disease the endpoints are often as experimental as the drug. Some flexibility on the part of the FDA to accept compelling data from secondary endpoints would be useful

4. In order to make the economics work, companies must seek approval of drugs for orphan diseases in multiple countries simultaneously to maximize the market size for the drug—this means that all the approval studies must take place duplicate in the US, Europe, Japan and other global markets to meet the regulatory requirements for each area. The lack of harmonization among regulatory bodies in different areas of the world places a particular burden on rare disease by using a larger than needed proportion of patients from a very limited global pool to conduct each study. The cost for developing drugs for these small markets is also higher due to the need to conduct studies in duplicate and triplicate for approval in different markets. Although we understand that some efforts at harmonization, particularly between the FDA and the EMEA have been advanced, until we no longer have the need to use two to three times more patients for these studies than necessary we cannot do effective drug development in these populations.

Personalized Medicine

Any disease has the potential to be rare with the advance of personalized medicine, and the rare diseases get even rarer. As new technologies allow us to target not just disease-causing genes, but individual mutations within those genes, we find that our small markets have been parsed into smaller and smaller groups—becoming “ultra-rare” through personalized therapeutic approaches. An example of this situation can be seen with antisense oligos (AONS) in DMD. AONS can be used to bring an out-of-frame deletion back into frame by inducing “skipping” of specific exons. This is a very promising technology in development for Duchenne muscular dystrophy (DMD), which is caused by the lack of the muscle protein dystrophin. Because it is a large structural protein, dystrophin is somewhat tolerant of being truncated through the removal of specific exons in that, when the reading frame is restored, often a shorter but still functional protein can be produced. One of the major regulatory concerns surrounding this new use of AONs has do with the fact that deletions in the dystrophin gene can occur anywhere along its length and different sets of AONs are required to skip different exons to bring these mutations back into frame. As things stand, the FDA will likely default to treating each set of AONs as a completely new drug due to concern about sequence-specific toxicities. For a rare disease market to be parsed even further by the need to do a complete NDA development package for as many as five to eight different sets of AONs is simply not feasible. It would be useful to have a specific investigation around the question of sequence-specific toxicity, which right now is purely speculative but is slowing progress in this area. That is the kind of regulatory science study that might make a nice joint RFA for FDA and NIH.

Until the regulatory path for sequence-specific drugs can be smoothed, the FDA should consider streamlining the process of testing drugs under individual INDs in such a way that approval can be obtained without a large phase II/III study.

Risk-Benefit Analysis

Every review decision for a drug under development for a rare disease should have, not just lay input, but input either from a person affected by the specific disease in question or family members of a person affected by the specific disease in question. You cannot separate the process from the end goal, which is to help those affected by disease—the perspective of these lay participants from the disease community is every bit as valid as those of trained ethicists and experienced regulatory officials and should serve to augment the standard review process at all stages.

These really hit the nails on the head. Do you think there would be any benefit in submitting our own uniquely worded versions of your four main points as comments, including some brief personal stories?
Absolutely and the comment period is still open...

Paul Cliff said:

These really hit the nails on the head. Do you think there would be any benefit in submitting our own uniquely worded versions of your four main points as comments, including some brief personal stories?

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