Drug Discovery and Development Flashcards
Basic steps in Drug Discovery and Development:
Drug Discovery: target validation, assay validation, hit, hit to lead, lead optimization
Development: Pre-clinical trials, clinical trials, FDA review and approval, scale up to mfg., and surveillance
Steps of non-clinical safety studies:
Observe and describe the toxicity and target organs.
Identify & confirm the mechanism of toxicity.
Identify the toxic dose
NOAEL = No Observable Adverse Effect Level (“no-effect dose”).
MTD (maximum tolerated dose).
Investigational New Drug (IND) Application (Notice of Claimed Investigational Exemption for a New Drug):
Documents the composition and source of the drug.
drug chemistry, manufacturing, and controls (CMC)
ALL data from preclinical safety studies (really any study even relevant to safety).
clinical trials plans and protocols (especially Phase I)
names and credentials of clinical investigators and study sites
INVESTIGATOR’s BROCHURE - Report of the key data relevant to clinical use and investigation of the drug (for PIs and IRBs)
Interdisciplinary Review Board (IRB):
Must review and approve the scientific and ethical aspects of the clinical trial at the trial site
Clinical trial phases:
Phase I: 20-100 people, 1 year, main goal MTD.
Phase II: 100-300 patients with disease, 2 years: part a is Safety and Efficacy and part b is proof of concept.
Phase III: 1000 to 5000 people, 3 years, carefully designed to variables in I and II, small financial expense, final formulation.
Phase IV: post marketing surveillance.
New Drug Application (NDA) Sections:
1) Chemistry, Manufacturing and Controls (“CMC”)
2) Non-clinical Pharmacology and Toxicology
3) Human Pharmacokinetics and Bioavailability (“Biopharma”)
4) Microbiology (if required)
5) Clinical Data
6) Statistical Data
What is the purpose of nonclinical safety testing?
Acute Toxicity: usually two species, two routes, determine the no-effect dose and the maximum tolerated dose
Subacute or subchronic toxicity: three doses, two species, two to three months of testing before clinical trial; longer duration of use, the longer the test, determine biochemical physiological effects
Carcenogenic potential: two years, two species, required when the drug is intended to be used in humans for prolonged times; determine gross and histologic pathology
What is the Clinical Development Process?
- New Chemical Entity (NCE or NME) for preclinical and clinical studies from multiple sources, routes, impurity profiles
- NCE used in safety studies, clinical studies & and commercial product must me demonstrated to be equivalent or otherwise “bridged”
- optimizes and standardizes synthetic route to minimize steps, starting materials, mfg impurities, and maximize yield
What is New Drug Application (NDA)?
Submitted after Phase III
SAFE AND EFFECTIVE FOR ITS APPROVED INDICATION?
- Full reports of all preclinical and clinical studies
- preclinical safety assessment, chemical development, formulation development, environmental impact assessments, proposed label (i.e., package insert), proposed advertising
Clinical Trials can began after?
1) IND submission
2) Informed Consent of human subjects have been obtained
3) IRB decision
What is the Placebo Effect?
If the individual knows they are getting, they ACTUALLY get better
What is an Abbreviated New Drug Application (ANDA)?
Application for generic medication after brand patent has expired
Must demonstrate bioequivalence to branded medication
Differentiate between “brand” and “generic” drug products.
- Patent life for the innovator is 20 years after filing
- After loss of patent exclusivity anybody can market a generic product without compensation to the innovator; must file ANDA
- Generics represent about 3/4 of all prescriptions dispensed by retail pharmacies and long-term care facilities*
