Pharmacology 1: Drug Discovery & Development – An Overview – Flashcards

- Food, Drug, and Cosmetic Act of 1938 - Kefauver-Harris Amendments (1962) - Orphan Drug Amendments of 1983 - Drug Price Competition and Patent Restoration Act of 1984 - Expedited Drug Approval Act (1992) - Food and Drug Administration Amendments Act of 2007

Required that NEW DRUGS SAFE AS WELL AS PURE (but did not require proof of efficacy). Enforcement by FDA.

REQUIRED PROOF OF EFFICACY AS WELL AS SAFETY FOR NEW DRUGS and for drugs released since 1938; established guidelines for reporting of information about adverse reactions, clinical testing, and advertising of new drugs

Amended Food, Drug, and Cosmetic Act of 1938, providing INCENTIVES FOR DEVELOPMENT OF DRUGS THAT TREAT DISEASES WITH LESS THEN 200,000 PATIENTS IN USA

Abbreviated new drug applications for generic drugs. (Required bioequivalence data. Patent life extended by amount of time drug delayed by FDA review process. Cannot exceed 5 extra years or extend to more than 14 years post-NDA approval.)

Allowed accelerated FDA approval for drugs of high medical need. (like in AIDS or cancer, Required detailed postmarketing patient surveillance.)

enhanced postmarket authorities of the FDA

- brings together the regulatory and industry authorities of Europe, Japan and the United States - purpose: harmonize the interpretation and application of technical guidelines - Objective: + economical use of human, animal and material resources, and elimination of unnecessary delay in development and availability of new medicines while maintaining quality, safety and efficacy, and regulatory oversight to protect public health. • Studies done in other countries may be submitted for approval

C. Safety & efficacy in patients are proven.

- 0-2-4 years: in vitro: biological products and chemical synthesis lead to a compounds then animal testing for efficacy selectivity mechanism (see which of the compounds found has best efficacy and safety) - then send IND (investigational new drug) to FDA for approval (if does not receive no in 30 days can begin trials) - phase 1: is it safe? (normal volunteers) - phase 2: does it work in patients - phase 3: does it work double blinded or is it not inferior to existing therapy? - collect all data and submit NDA (new drug application) to FDA for approval - phase 4: postmarketing surveillance - patent expires 20 years after filling application -> generics become available

- for ~10,000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials and about 1 compound receives regulatory approval by the US Food and Drug Administration - The mean time from synthesis of a new compound to marketing approval in the US is 14.2 years

• In Vitro • In Vivo • Other Studies

- Molecular target - high affinity - Pharmacologic profile - selectivity (how selective is drug for target) - Metabolism - drug interactions

- Disease model - efficacy (does it work on disease models (animals)?) - Pharmacological profile/ safety - (2 species) (need to do in 2 species to demonstrate safety)

Other Studies include: (look at other organ systems, if you see something that looks suspect you have to follow up) - Core - CNS, CV, Respiratory, GI, Kidney, etc. - F/U Suppl- CNS, CV, Resp., Renal, GI, other - Metabolism - drug interaction

- Usually 2 species, 2 routes. - determine the no effect dose and the maximum tolerated dose. - In some cases determine the acute dose that is lethal in ~50% of the animals (in the old days we would do LD50, that is not done anymore bc it takes many animals in order to determine. now it just takes 1 male and female of a species, and keep increasing doses)

- 3 doses, 2 species. - 2 weeks to 3 months of testing may be necessary before clinical trial. - the longer the duration of expected clinical use, the longer the subacute test. determine biochemical, physiological effects

- rodent and non rodent species for > or = 6 months. - required when drug is intended for use in humans for prolonged periods. - usually run concurrently with clinical trials - determine same end point as subacute toxicity tests

• Data from preclinical studies • Synthesis of chemical • Formulation for clinical use • Description of planned clinical trial(s) • IRB approval of clinical study protocol • FDA has 30 days to review IND before trials can begin. (If the FDA does not say halt, trial may begin)

?C. Long term (>6 mo.) safety studies in 2 species.

• First dosing of drug in man to determine SAFETY and TOLERABILITY in normal volunteers (10-30) (or in patients for drugs to treat cancer and AIDS). • Identification of predictable toxicities. • PK may also determined.

• Studies in small # of patients (50 to 100) to provide EVIDENCE of EFFICACY in TARGETED DISEASE. (Studies are not powered [large enough] to prove efficacy, but data suggest it might be effective.) • Dose-range finding studies. Different doses are used to obtain dose-response relationship to select doses for Phase III clinical studies

• Usually, at least 2 double-blinded studies in which 1-3 dosages of the drug are given to large # of patients (100-1000) to ESTABLISH EFFICACY AND ADVERSE-EFFECT PROFILE. • Drug is compared to placebo and/or an active drug (standard of care). • These are the PIVOTAL studies for submitting an NDA

- New Drug Application - At the completion of Phase III studies and analyses of results, sponsor may choose to file an NDA to obtain MARKETING APPROVAL (if you get NDA approval, you are allowed to sell the drug over state lines, so if you are only selling in MA, you probably do not need NDA approval)

- P: Priority review drug - S: standard review drug - O: orphan drug

a drug that appears to represent an advance over available therapy (it is a drug of the class, or is it a much better drug?)

drug that appears to have therapeutic qualities similar to those of an already marketed drug

a product that treats a rare disease affecting fewer than 200,000 americans (may be able to get approval doing just one clinical study. )

- Clinical studies to be conducted after a drug has been approved by the FDA. - Focus on Drug Safety & Adverse Effects • Drug given to patients in real-world clinical practice • In subpopulations of patients (geriatric, pediatric, etc.) not included in Phase III trials

?D. Phase 3 studies?

Abbreviated New Drug Application

- At patent expiration, generic drug manufacturers may submit an ANDA only referencing the toxicology studies submitted in original NDA. • Few, if any, clinical studies are needed. • Generic biologics ("Biosimilars") - authorized under BPCI (2009) and ACA (2010) - regulations and guidelines are being developed.