Transcript DRUG DEVELOPMENT 101 AKA I Have an idea to cure the world of

U of Arizona Innovation Conference
20 September 2011
Marlene E. Haffner, MD, MPH
Haffner Associates, LLC
1800’s – US Customs Laboratories were
established to administer the Import Drugs Act of
1848
--Mission – US should not be a dumping ground
– purity and potency standards of the USP
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Opium, morphine, heroin, and cocaine – no restrictions
Cows weren’t tested for TB
Victories over infectious diseases just beginning – Robert
Koch; Louis Pasteur
Agricultural to industrial economy
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Prohibited Interstate Commerce of misbranded and
adulterated foods and drugs and poisonous patent medicines
Specific labeling – morphine, cannabis, chloral hydrate, …
Did not address
◦ Food or drug standards
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Enforced by Division of Chemistry of the Department of
Agriculture
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1938 – Food, Drug, and Cosmetic Act
◦ Elixir of sulfanilamide
◦ Safety
◦ Safe tolerances
1962 Kefauver-Harris
◦ Thalidomide
◦ Efficacy and safety before marketing
◦ Adverse events
Further improvements to safety in subsequent years
Each added to the better and more costly products
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8000 + dedicated and talented employees across the US
~ 50% in the Washington, DC area
MDs, pharmacists, statisticians, nurses, dentists, policy
analysts, PhDs, engineers, and more
No one in the agency bites! They really wish to be
helpful
They are short staffed for the responsibilities they have
Listen carefully to what you are told in meetings
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Discovery
Screening – including product characterization, formulation,
PK, and drug disposition
Pre-Clinical Toxicology testing
IND Application
Phases 1, 2, 3 – clinical trials
New Drug Application (NDA)/ Biologics Licensing
Agreement (BLA)
Post marketing commitments (REMS – risk evaluation and
mitigation strategy)
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Often a stumbling block
Acute and long term toxicity in animals – one
rodent and one non- rodent
◦ Genetic
◦ Reproductive
◦ Carcinogenicity
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How is the drug absorbed, distributed, metabolized
and excreted in animals
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Apply to FDA to allow human exposure to the
experimental drug – Go to FDA website
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http://www.FDA.gov/cder/guidance/index.htm
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Qualification Process for Drug Development tools
(DDT)
IND describes for what the product is being
developed, safety issues as known, studies to be
undertaken – assures safety for first in humans
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Chances are you are not going to “cure” the disease
How will you show efficacy?
Is your endpoint a clinical endpoint, or a surrogate
endpoint?
Discuss with FDA. If you and FDA do not agree, why?
Further discussion with FDA
MEET WITH FDA REVIEW DIVISION – EARLY AND OFTEN
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Phases 1, 2, 3
Phase 1 –
◦ usually healthy volunteers
◦ 10 – 80 – determine safety of dosage (12 – 18 mos)
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Phase 2 –
◦ 100 – 300 patients volunteers (24 mos)
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◦ Dosage, adverse events (AEs), early efficacy
Phase 3 –
◦ 1000 – 3000 patient volunteers
◦ confirm efficacy,
◦ monitor AEs (30 – 40 mos)
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Begin 30 days following submission of IND providing
no “clinical hold”
20 – 80 volunteers
Duration: 1 year
Determine bioavailability and safety
Determine adverse events associated with increasing
doses
Gain early evidence of efficacy
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Consult with FDA – often
Assess efficacy in the disease or condition
Monitor safety and AEs
100 – 300 patient volunteers
Duration: 2 years
Less than 33% of INDs survive Phase 2
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Consult with FDA
1,000 – 3,000 patient volunteers
Multiple testing sites
Duration 3 – 4 years
Confirm safety and efficacy – no drug is ever
confirmed as completely safe
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Formal proposal to FDA for approval of a new drug to
be marketed in the US
Must provide sufficient evidence for the FDA to
determine:
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Benefits outweigh the risk of the product
Drug is safe and effective for its intended use
Proposed labeling is appropriate
Manufacturing methods and controls maintain drug identity,
strength, quality, purity and stability
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Must assure continued safe and stable production
Must continue to monitor AEs
FDA may determine need for REMS – especially if
study done on small number of patients
Must report significant Adverse Events to FDA
Adverse events may not be known for many years – e.g.
VIOXX
Preclinical
3 – 6 years
Phase 1
1 – 2 years
Phase 2
2 – 3 years
Phase 3
3 – 4 years
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9 – 15 years
FDA review
1 year
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Marlene E. Haffner, MD, MPH
301 984 5729
www.mhaffner.com
[email protected]