H D I N S I G H T S
HD Insights, Vol. 11 14
Copyright © Huntington Study Group 2015. All rights reserved.
H D I N S I G H T S
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Sasinowski, cont…
HD INSIGHTS: Are there current examples of this engagement in development of therapies for orphan neurological
conditions?
SASINOWSKI: One of my fellow NORD board members, Pat Furlong, is the founder of a group called Parent Project Muscular
Dystrophy. They devised their own draft guidelines on developing therapies for Duchenne muscular dystrophy and presented
them to the FDA, who published the guidelines for public comment. That is an example of a patient-driven, patient-initiated
effort to help define what key elements should be considered, what populations should be enrolled in studies, what kind of
endpoints should be considered, and what kind of safety risks should be prominently and sensitively monitored.
I'll give you one more example. About a year ago, the FDA published a guidance document on migraine that said in effect, "We
all know that the most prominent feature of migraine is pain, but we need to have other symptoms that will be relieved by any
therapy in development, because we do not want to approve drugs such as opioids that might treat only pain. There are three or
four other prominent symptoms such as photophobia, phonophobia, nausea, and vomiting. Why don't you, as a sponsor, let
each patient decide for themselves what is the most bothersome second symptom?" Why is this different? Let's say you have a
therapy and you need to come up with a second endpoint, aside from pain. Normally, you would say, "Well, maybe it's
photophobia, so I need only screen those who say that their most prominent second feature is light sensitivity." Thus, you enrich
your study population with those who are just light sensitive, and then ask, "How did you do on pain?" and "How did you do
on light sensitivity?" and hopefully show a difference. But you have severely limited who can enroll in your trials. The FDA is
saying, "Open the floodgates, let them all in, but let them define for themselves what is the most troublesome second symptom
after pain," demonstrating a sensitivity to letting patients drive the drug development system.
HD INSIGHTS: In 2012, you published an analysis of FDA approvals for rare and orphan diseases, demonstrating variability in
the application of evidence standards.
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What are the implications of your research for companies that are developing drugs for
rare and orphan diseases?
SASINOWSKI: The exchanges that I routinely heard at public advisory committee hearings for orphan drugs would baffle me.
Normally, sponsors need two adequate, well-controlled studies that each hit a P value of less than 0.05 on the primary endpoint
in order to even talk to the FDA about approval. For an orphan disease, the sponsor would often come in with something short
of that. The chairman of the committee would turn to the FDA and say, "We know that this is not a situation like a new drug for
treating hypercholesterolemia or high blood pressure, where you have an unlimited pool of potential subjects to enroll in trials.
We know that there are severe constraints on who can be enrolled. So what are we to do with this?" The FDA would answer,
"The Orphan Drug Act did not change the rules for how much evidence of treatment benefit needs to be presented for drug
approval." This left the advisory committee in a quandary, because it seemed that they should be more flexible, but the FDA said
that the law did not allow it. This bothered me. When the FDA held its first-ever public hearing on orphan drugs in June 2010, I
was invited to speak on behalf of NORD. I said that the FDA ought to articulate a policy that explains how they would deal with
this conundrum. The Orphan Drug Act did not change the quantum of evidence that is required for drug approval, but every
orphan drug is different and every rare disease patient population is different. I suggested that if they could not enunciate a
generalized statement of policy, at a minimum they could catalogue everything done with all the orphan drugs so that the world
could see what has happened over time and what the evidentiary basis had been for all prior orphan drug approvals by FDA.
The FDA approached me after the hearing and said, "We think your idea to catalogue it all is brilliant, but we do not have the
time." I knew then that if anybody were to do it, it would have to be me. I printed off all the labeling, medical reviews, and
statistical reviews for the 135 new chemical entities for rare diseases, other than cancer, that the FDA had approved from 1983
through June 2010. I took 27 boxes of documents with me to a secluded place in the mountains where I read and catalogued all
27 boxes, to see whether or not they met the usual criteria for approval for a prevalent disease. If they did not, I recorded
whether these approvals represented some flexibility in the quantum of evidence, demonstrating that the FDA exercises some
discretion while still relying upon good science. I found that two-thirds of all these orphan drug approvals showed some signs
of flexibility with regard to the number and scope of trials required. This was eye-opening to everyone, particularly to the FDA,
who did not realize they had been acting this way. I've since written an update that shows the same degree of flexibility. In
orphan drugs approved between June 2010 and July 2014, the same ratio of about two-thirds of all approvals show some
evidence of FDA flexibility.
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HD INSIGHTS: Is there any advice that you have for HD researchers or drug developers regarding current regulatory matters
in front of the FDA?
