Drug Development 1 - Drug, Drug Development, and Approval Process

LADME

L - Liberation

A - Absorption

D - Distribution

M - Metabolism

E - Excretion

1848 Mexican War

- laced Quinine (imported drugs) used to treat yellow fever

Drug Importation Act 1848

- medications were inspected for quality and purity

- recognized USP (standards for medication)

1901 Death of Children

- diphtheria antitoxin

- contaminated smallpox vaccine

- all within country

1902 Biologic Act

- premarket approval

- NIH agency

- beginning of federal regulation of biologics in the U.S

Pre 1906 Vin Marini

- 140 mg/bottle laced with cocaine; unregulated distribution (32,000)

Pure Food & Drug Act 1906

- can't sell misbranded or laced food or drugs

Sulfanilamide Crisis

- non-soluble powder for strep throat

- only dissolved in diethylene glycol (anti-freeze)

- caused nephrotoxicity

FDC Act of 1938

- must demonstrate safety and preapproval before marketing

- NDA process required

Thalidomide Crisis

- sedative for morning sickness that caused birth defects

- 2 million tablets distributed

- Dr. Frances Kelsey refused NDA approval in the US

Kefauver-Harris Amendment

- drug must present SAFETY & EFFICACY before marketed

Post Marketing Crises

- Rezulin caused life-threatening liver dysfunction

- Vioox (good for arthrites) --> long term use caused heart problems and strokes

- Prozac (SSRI) increased suicidal tendencies, esp in children (was not disclosed to public)

Gov't Accountability Office (GAO) - watches over FDA processes and criteria for drug review --> slowed down evaluation

Grassley-Dodd Bill - companies must carry out studies on drugs in market; Independent Safety Board

Durham-Humphrey Amendment

difference between prescribed and over the counter drugs

FDC Act Amendment 1962

- tests for drug SAFETY and EFFICACY

- NDA approved before marketing

- IND required for NEW drugs

- informed consent

- labelling has right directions, not misleading

Parallel Track

patients have access to pre-approved drugs on the side of clinical trials (ex. drug for AIDS instead of AZT treatment)

Accelerated Approval

drug for life-threatening disease has priority for being in review (ex. drug for reducing HIV viral loads)

Prescription Drug User Fee Act 1992 (PDUFA)

fee for companies to apply for NDA

- increased resources for FDA

- sped up application review

- reinstated every 5 years

FDAMA (Modernization Act) 1997

broader reform law that modernized FDA regulations (focus = clinical trial flexibility, patient access, innovation) and also reauthorized PDUFA.

Orphan Drug Act 1983

- incentivizes drug development for rare disease affecting less than 200,000 people

- grants 7 year exclusive patent protection

- granted tax credits and grants to finance clinical trials

Exclusivity Protection

- gives manufacturer exclusive marketing rights

- FDA can't approve other generic/biosimilars

- standard 3 years (+0.5 if pediatrics)

Patent Protection

- 20 years to make drug work and earn $ from it

- ownership and property

- separated from FDA; usually before or with IND submission