Pharmacology 1: Drug Discovery & Development – An Overview

Major US legislation regulating drugs
– 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
Food, Drug, and Cosmetic Act of 1938
Required that NEW DRUGS SAFE AS WELL AS PURE (but did not require proof of efficacy). Enforcement by FDA.
Kefauver-Harris Amendments (1962)
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
Orphan Drug Amendments of 1983
Drug Price Competition and Patent Restoration Act of 1984
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.)
Expedited Drug Approval Act (1992)
Allowed accelerated FDA approval for drugs of high medical need. (like in AIDS or cancer, Required detailed postmarketing patient surveillance.)
Food and Drug Administration Amendments Act of 2007
enhanced postmarket authorities of the FDA
International Conference on Harmonization (ICH) (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human
Use), Brings together what countries? Purpose? Objective?
– 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
Exam Type Question
Which ONE of the following statements best
describes the basic criteria the FDA uses to
approve a new drug?
A. It will help >200,000 patients.
B. Safety of the drug must be proven.
C. Safety & efficacy in patients are proven.
D. Studies submitted must be ICH approved.
E. Manufacturer pays a higher user fee.
C. Safety & efficacy in patients are proven.
Drug Development
– 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
Drug Development – USA
– number of compounds to get to final result?
– how long does it take on average?
– 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
Drug Discovery: Preclinical Studies
• In Vitro
• In Vivo
• Other Studies
Drug Discovery: Preclinical Studies • In Vitro
– Molecular target – high affinity
– Pharmacologic profile – selectivity (how selective is drug for target)
– Metabolism – drug interactions
Drug Discovery: Preclinical Studies • In Vivo
– Disease model – efficacy (does it work on disease models (animals)?)
– Pharmacological profile/ safety – (2 species) (need to do in 2 species to demonstrate safety)
Drug Discovery: Preclinical Studies
• Other studies
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
Preclinical Safety Tests
Acute toxicity
– 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)
Preclinical Safety Tests
Subacute os Sub chronic toxicity
– 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
Preclinical Safety Tests
Chronic toxicity
– 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
Investigational New Drug Application
• 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)
Exam Type Question
Your company has completed nonclinical studies on a new drug to treat life-threatening infections caused by a new antibiotic-resistant bacterium. You are checking that all
studies are included in the IND for a first in human clinical study of the drug. Reports for all of the following studies are
needed EXCEPT?
A. Acute single rising dose toxicology in 2 species.
B. Formulation of drug to be used in clinical studies.
C. Long term (>6 mo.) safety studies in 2 species.
D. Pharmacology profiling of the drug at other receptors.
E. Protocol for first clinical study.
F. Synthesis and chemical characterization of drug.
?C. Long term (>6 mo.) safety studies in 2 species.
Clinical Drug Development
Phase I Studies
• 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.
Clinical Drug Development
Phase II Studies
• 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
Clinical Drug Development –
Phase III 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
– stands for
– what is it for?
– 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)
NDA Review Classifications: letters and what they stand for
– P: Priority review drug
– S: standard review drug
– O: orphan drug
Priority review 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?)
Standard review drug
drug that appears to have therapeutic qualities similar to those of an already marketed drug
Orphan 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. )
Phase IV Studies
– 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
Exam Type Question
Which of the following best describes when
data are obtained, which provide proof of
efficacy, needed for submission of an NDA
(New Drug Application) to the FDA?
A. Nonclinical studies
B. Phase 1 studies
C. Phase 2 studies
D. Phase 3 studies
E. Phase 4 studies
?D. Phase 3 studies?
ANDA – Generics: stands for
Abbreviated New Drug Application
ANDA – Generics: general
– 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.