Working with and
Understanding the FDA
MARLENE E. HAFFNER, MD, MPH
HAFFNER ASSOCIATES, LLC
PARENT PROJECT MUSCULAR DYSTROPHY
CHICAGO, ILLINOIS
JUNE 27, 2014
Who is the FDA: What do they do and why?
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FDA is part of the administrative arm of government.
Must follow laws passed by the US Congress
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1938 – sulfanilamide
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1962 – Thalidomide – Kefauver Harris Amendments
strengthened both efficacy and safety
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Resulted in longer development time and
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Greater cost to drug development which then produced
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1982 Orphan Drug Act, which passed because of the
limited drugs for small prevalence diseases of which
Duchene Muscular Dystrophy is one
What did the Orphan Drug Act do?
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Created Incentives for sponsor of drugs for rare diseases
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Primarily financial incentives
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Designation - 7 years exclusive marketing for that drug for that disease for 7
years post FDA approval
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Created a grants program for support of Orphan Drug Development
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Tax credits to the sponsor of the approved orphan drug
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20 years carry forward and 1 year fall back
Waiver of the NDA Review filing fee - ~$2 million in FY 2014
Currently Orphan Drugs and their development are very “popular!”
Orphan Drugs Must Be Safe And Effective
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Orphan Drug Act does not change standards of safety and efficacy for
new drug approval
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Because of small patient numbers some flexibility will be exist
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Patients with rare diseases deserve to know the product they are using
is safe and effective for it’s intended use
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Safety and efficacy are measureable via clinical endpoints and
adverse events
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Drugs are approved based on risk/benefit for the disease
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A drug with significant side effects may still be approved if the disease
is serious and life threatening and no other treatment exists
How Are New Drugs Developed
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Concept
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Pre-clinical testing including animals – evaluation of mutagenicity,
carcinogenicity, other issues of side effects
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Is there an animal model of the disease
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Obtain an IND prior to any human testing in the US – establish endpoint for
efficacy
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Phases 1, 2, 3
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Approval – many products fail at each step beginning in Pre-clinical
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Why?? – side effects; lack of efficacy – risk benefit
Drug Development Process
How Are Drugs Developed?
Source: Nature.com
What Are Endpoints?
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Clinical endpoint - Relate to the disease
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e.g. inability/ability to walk a specified distance
Surrogate endpoint
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correlates with the disease but may not be related.
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Must be validated. Shortens approval time
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e.g. BP as a surrogate endpoint for end results of hypertension.
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Validation is complex and takes time on its own
Clinical endpoints preferred
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i.e. the patient can now walk farther/faster – but may not always be possible.
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Surrogate may be a change in laboratory test or biopsy – presence of dystrophin.
What About Compassionate Use?
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Governed primarily by the company
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Must be approved by FDA
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Must not jeopardize enrollment or the ongoing
efficacy study or studies
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Companies are wary – perhaps without cause
Patient and Family Involvement
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Patients are VERY important in the development of a new drug
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Get the Patient/Family involved early in the development
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Find out what endpoints might best meet patient needs
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Company and patients work together with the FDA to develop a meaningful
endpoint
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Does not mean patients and families get to have whatever they want. Why not?
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Companies and patients develop trust and understanding
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Patients will be involved with company and FDA well before an advisory
committee
How can patients/families become
involved?
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Work with company re “what is this disease?”
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No one knows the disease like the patient.
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Provide aspects of natural history of the disease
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Work with the company re mechanism of action of the drug and how that will
affect the patient
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What aspects of therapy are important to the patient
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Huntington’s chorea – Tetrabenazine for chorea
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Work with FDA and the company to establish meaningful endpoints and the
parameters around them – negotiated
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Establish credibility and realism
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Find patients for clinical trials
What cannot be done?
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Change requirements of safety and efficacy
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But can weigh in on tolerability of side effects and appropriateness of endpoints
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Perform review of the product within the FDA
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Demand access when company is unable to provide
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Some drugs are difficult to supply in sufficient quantity
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Can work with company re compassionate use if there is sufficient drug
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Get laws changed for “you”
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FDA cannot, by law, release for distribution a drug that has not been shown to
be safe and effective
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Public pressure – what works, what slows the process. FDA operates on
science.
EU has approved ataluren – what next
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EU granted conditional approval to PTC – US and EU frequently, but do not
always follow the same path
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Conditional approval does not exist in the US
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Many companies involved in treatment for DMD
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Clearly we are close to a break through on approvals – how close??
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What about Prosensa and Sarepta??
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What about post market commitments – almost always exist following and
orphan approval because of patient size.
Working together produces more than
the individual parts
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The more collaboration, the better for all
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There are some things FDA cannot tell patients – only the company can do
that
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Open and transparent dialogue is the best way
Questions
Marlene E. Haffner, MD, MPH
President & CEO
11616 Danville Drive
Rockville, Maryland 20852
[email protected]
301 984 5729 - office
301 641 4268 - cell
301 984 2272 - FAX