1. Regulatory Considerations for the Development of Substantial Evidence of
Effectiveness
Marlene Haffner, MD MPH
Haffner Associates, LLC
World Orphan Drug Congress 2014
April 24, 2014

2. History of regulation in the drug industry
Sulfanilamide safety
Thalidomide safety and efficacy
PDUFA post marketing requirements
REMS stricter post marketing controls for safety and efficacy evaluation
Safety and Efficacy - risk/benefit - intertwined

3. Need for a path to drug development
What is the disease and what is known about the disease - Natural History
Is the disease life altering/shortening?
Is the disease of genetic origin or not? Is the gene known? Are you treating symptoms or affecting the gene?
Is the disease monogenic or heterogeneous?
Is there a support group for the disease? And what is their interest?
What is the drug and how will it affect the disease?
Do we know the mechanism of action of the drug?
What animal studies have already been done?
Is the drug approved for another use? - repurposing

4. ProActive engagement with patients/advocates and FDA
What does FDA need; What do patients want
Design the trial to show efficacy - work proactively with FDA
Listen to the patients/advocates
Codified in FDASIA
Know the disease and the natural history of the disease
Ongoing activities between FDA and patient groups - PPMD and development of guidance for endpoints in DMD
Increasing transparency of all involved - FDA and industry

5. New potential methodologies for preclinical and early clinical work
BioPontis Foundation
Other similar models
No need to continually reinvent the wheel

6. Development of Clinical Trials
Whenever feasible - placebo controlled.
Fastest way to get answers
Build in a follow-on with active drug - if appropriate
Involve the patient community
they know the disease and where patients can be found
Small populations have their own difficulties
no chance to perform multiple trials
Multicenter/multi country trials may be needed with very small populations. Always more than one center.
Always hard to find the patients

7. Endpoint and BioMarker Development
Constructive plans for endpoint and biomarker development
Validation of surrogate endpoints
Involve the patients
Expect long term follow-up
FDA becoming more involved and interactive
May/may not be necessary to utilize surrogates

8. Reaching the Goal - an Effective Product
Goal -to develop an effective and safe product as quickly as possible
Many orphan drugs will qualify for “Breakthrough status”
Keep the patients involved
Continual dialogue with FDA
Closely monitor the trials. No opportunity for errors

9. Orphan Drugs must be Safe and Effective for their intended use
FDA is flexible but risk/benefit is the golden rule
Orphan disease patients do not want to be exposed to unnecessary risk or lack of efficacy
Statistics must be clean - Figures don’t lie; but liars figure!
May need to evaluate previously unknown subgroups
Work with the patients

10. Marlene E. Haffner, MD, MPH
Questions
Marlene E. Haffner, MD, MPH
President & CEO
11616 Danville Drive
Rockville, Maryland 20852
(office)
(cell)