FDA and Rare Disease
Robert J. Temple, M.D.
Deputy Center Director for Clinical Science
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
PPMD Annual Conference
June 28, 2013
Basis for Approval
The principal legal requirements for drug approval take up
less than a page. They are, since 1962:
1. Effectiveness
There must be “substantial evidence that the drug will
have the effect it purports or is represented to have
under the conditions of use recommended in labeling.
Substantial evidence means evidence consisting of
adequate and well-controlled investigations (plural
was intended), carried out by experts, on the basis of
which it could be concluded that the drug will have
the effect it is represented to have when used as
suggested in labeling.
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Basis for Approval
Evidence of Effectiveness
This brief requirement has led to a regulation defining what a wellcontrolled study is (the 5 kinds of controls, need to specify design
and analysis precisely), as well as to a very large array of guidances
on the subject, including a detailed ICH guidance on statistical
principles, an ICH guidance on choosing the kind of control group
(active control non-inferiority study, historical control), ICH
guidance on reporting detailed results of studies, FDA guidance on
when we might rely on a single study (permitted by FDAMA in
1997) detailed guidance on how to use non-inferiority designs and
how to utilize enrichment and adaptive designs, and studies in
particular therapeutic areas.
There is probably no subject that has received more attention, both
formal (guidances) and less formal advice at meetings, action letters).
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Basis for Approval
The 1962 amendment requiring evidence of effectiveness
was, I believe, the most important therapeutic advance ever,
moving the US, and following our lead, the world, from a
standard of anecdote and rumor to real evidence. The rules
describing needed evidence for drugs moved gradually into
devices and even surgical procedures (not rules, but practice).
For unregulated products and practices, of course, we do not
get such evidence, a shame, in my view at least, and with a
considerable financial and, perhaps, health cost.
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Basis for Approval
Flexibility
The standard is high, and of immense value, but it has long been
recognized that a critical part of FDA’s job and mission is to actively
help expedite development of drugs to treat life-threatening and
debilitating diseases, especially where no satisfactory treatment exists.
Although the statutory standards of safety and effectiveness apply to all
drugs, including those for these important uses, regulations in several
places (312.80, subpart E, an IND rule related to these diseases; and
314.105(c), referring to application approval) state clearly that the many
kinds of drugs and wide range of uses “demand flexibility in applying
the standards. FDA is required to exercise its scientific judgment to
determine the kind and quantity of data and information an applicant
must provide for a particular drug.”
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Basis for Approval
Flexibility: illustrations (brief)
1. How much effectiveness data?
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Subpart E specifically urges early consultation to consider when
the controlled phase 2 studies can provide the basis for approval.
This requires close attention to study design, dose selection,
possible enrichment and adaptive maneuvers.
Under FDAMA, as explained in the 1998 guidance, FDA can rely
on a single adequate and well-controlled study (not 2). It is critical
to discuss this early. NORD analysis of orphan drug approvals
shows this is not uncommon. The studies are often quite small.
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Basis for Approval
Flexibility
• 
Subpart H (314.500, Accelerated Approval) allows approval
based on a surrogate endpoint “reasonably likely” to predict
clinical benefit. Common in oncology, less often elsewhere, but
always to be considered.
An issue that has arisen where approval of a drug has been
directed at a genomic subset of a disease (cystic fibrosis patients
with G551D mutation, hepatitis C type 1, and, of course,
Duchenne’s muscular dystrophy exon 51 abnormality), whether
different genetic subsets could be approved with less data.
Whether or not we could accept a surrogate endpoint (shortterm viral load, seat chloride) in those cases as a basis for
approval, has not been determined, but it is possible that after a
clinical benefit is found to track the surrogate in one or several
cases, it could be used for other genomic subsets.
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Basis for Approval
2. Safety
The law is not very detailed. An application must contain
“adequate tests by all methods reasonably applicable to
show whether the drug is safe” for its intended use; those
tests must not show the drug to be unsafe and they must
provide sufficient data to allow a decision.
It seems fairly obvious, but is never stated that way in
law, that safety is a benefit-risk determination; i.e., the
well-defined and demonstrated benefit must outweigh
the demonstrated risk as well as concerns one might have
regarding less than complete data.
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Safety in Practice
Subpart E (1988) is explicit about this: “FDA shall recognize the need
for a medical risk-benefit judgment in making the final decision on
approvability” and “consider whether the benefits of the drug
outweigh the known and potential risks and whether it is necessary to
answer remaining questions about risks and benefits, considering the
severity of the disease and the absence of satisfactory alternative
therapy.
It also recognizes that physicians and patients are generally willing to
accept greater risks or side effects from products that treat these
diseases.
Not surprisingly, the safety databases for orphan drugs are often very
small. In addition, treatments for serious illness, such as cancer,
inflammatory diseases, multiple sclerosis, psychosis, and epilepsy
regularly have quite sever adverse effects, tolerated because of the
important benefits.
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A Few DMD-specific Points
1. Obviously, I cannot discuss specific drugs and
there are no approvals for drugs for DMD to refer
to.
2. Apart from the question of whether the
production of a Becker-type dystrophin will be an
acceptable surrogate, for initial approvals, we will
certainly consider such issues with respect to
subsequent drugs for different genomic lesions,
particularly very rare ones.
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A Few DMD-specific Points
3. Accelerated approval is not a maneuver to “save” less than adequate clinical data
(approve under AA with good study to follow). I interpret the Putting Patients
First paper as suggesting that pathway in proposing “adaptive approval” and
several other changes. AA is appropriate when there is a credible surrogate
endpoint AND demonstrating clinical benefit is particularly difficult because effect
is quite delayed. I do not believe that is thought to be the case for the new DMD
treatments and sponsors are clearly seeking to show clinical benefit. Moreover,
many of the parents of children in trials clearly believe benefits are visible and not
greatly delayed.
4. There is no “adaptive approval” provision for drugs in US law. The threshold (with
some flexibility) is not to be waived, even for bad diseases with no treatment. I
note that Putting Patients First is clear in saying that the community does not want
ineffective drugs.
Its suggestion that we could experiment with “Adaptive Approval” or provisional
approval, meaning approval based on less than A& WC studies, apart from not
being legal, is would not be good for the patients we all want to see helped, in my
view. Also 312.85 does not allow FDA to REQUIRE post-marketing studies to
get the “good data,” as the paper suggests. Moreover, given the excitement
stimulated by the new treatments, I am somewhat surprised by the desire to
essentially the eliminate effectiveness standard. I do not believe, based on what
we’ve seen, that it is particularly difficult to carry out well-controlled studies in 11
DMD.
A Few DMD-specific Points
5. There is no required size for the studies intended to support
effectiveness, and large-scale randomized trials should not be needed
if the drugs work nearly as well as people hope.
For a very effective drug, the controlled trials can be quite small.
Further safety data can come from open follow-up periods.
6. We need to be clear on what risk/benefit means. As noted, we have
long recognized that people with untreatable serious illnesses will
accept considerable risk from an effective treatment. It is possible
they would also be willing to give up the effectiveness requirement
too, but that has not been part of our considerations.
7. We do not think 6 minute walk is the only credible endpoint and
have told sponsors this. Other measures are, in fact, in use. We
would like to see a broader array of patients in trials.
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