E1 Lecture 3 Flashcards
Thalidomide Tragedy
1961
What?
- thalidomide was linked to phocomelia (rare condition affecting fetal formation of arms/legs)
- led to large amount of children born with serious defects
- Frances Oldham Kelsey blocked thalidomides approval in the US
What did Frances Oldham Kelsey receive?
President’s Award for Distinguished Federal Civilian Service
Kefauver-Harris Amendment
1962
Characteristics:
- required medications to be demonstrated as safe but also EFFECTIVE (all drugs marketed between 1938-1962 + new drugs)
- transferred laws surrounding Rx drug advertising from FTC to FDA
- established current Good Manufacturing Practice (cGMP)
- added requirements to clinical investigations regarding informed consent of research subjects & reporting adverse drug reactions
Current Good Manufacturing Practices (cGMP)
provides the minimum requirements for the manufacturing of drug products to ensure:
- design
- monitoring
- control
Any manufacturer for drugs used in the US must:
- registered with the FDA
- undergo inspections at least once every 2 years
If failure to comply with cGMP?
adulterated
If failure to register with FDA?
adulterated-misbranded
3 Categories of Making Drugs
- Pharmacy/Traditional Compounding (503a) –> according to prescriptions specifics to particular patients on an as needed basis
- Outsourcing Facilities (503b) –> manufacturing large batches with/without prescriptions to be sold to facilities for office use only
- Manufacturing –> mass production of drug products approved by FDA
Pharmacy/Traditional Compounding (503a)
Requirements:
- compound pursuant to a prescription only
- compound for an individual patient
- compound done by pharmacist, physician, or another individual under their supervision
- ingredients are bulk substances complying with USP-NF
- compound cannot be a copy of a commercially available product
- compounding can be done in advance, but on limited basis
Why are the requirements for 503a important?
exempts pharmacy from meeting regulations related to:
- cGMP
- misbranding
- new drug requirements
Outsourcing Facilities (503b)
Characteristics:
- compound without receiving a prescription for a specific patient
- must register, pay annual fees, and inspected by FDA
- compounding cannot be a copy of a commercially available product
Product Labels in 503b must contain:
- “this is compounded drug”
- “not for resale”
- name, address, phone # of outsourcing facility
- lot number/batch number
- established name of drug
- list of active/inactive ingredients
- dosage or strength
- quantity or volume
- beyond use date
- storage and handling instructions
- NDC
Requirements for 503b
labeling/packaging requirements
cGMP
NO NEW DRUG REQUIREMENTS
Requirements for Drug Manufacturer
misbranding
cGMP
new drug requirements
Before 1938 & still on market
safe & effective (grandfathered in)
Drug Efficacy Study Implementation (DESI)
1968
National Academy of Sciences investigates all medications approved between 1938-1962 for EFFICACY & issues recommendations to FDA
FDA reviews recommendations and makes decisions
- products remain on the market until decisions are made
Drug Development Process
Discovery and development of novel chemical
Step 1: Preclinical Research
- in vivo animal studies
Step 2: Submission of Investigational New Drug (IND)
Step 3: Clinical Research
- Phase 1
- Phase 2
- Phase 3
Step 4: New Drug Application Process (NDA)
Step 5: Post-Market Safety Monitoring
- Phase IV
Preclinical Research
in vivo animal testing to provide data on toxicity and pharmacology of product
Investigational New Drug (IND)
if the drug shows possibility for safe & effective use
Must contain:
- Animal Pharmacology and Toxicology studies
- Manufacturing Information
- Clinical Protocols & Investigator Information
How long must the sponsor wait once the IND is submitted to start clinical trials?
sponsor must wait 30 days before initiating clinical trials to allow FDA to review IND for safety and unreasonable risk
Phase 1
20-100 healthy humans volunteer to receive the drug and evaluate the SAFETY and DOSAGE of compound
Obtain:
- human PK
- pharmacological properties
Phase 2
100-1000 with-disease human volunteer to receive the drug and evaluate the EFFICACY of compound
Phase 3
1000s in several geographic locations with-disease human volunteer to receive drug or placebo while being double-blinded and evaluate the EFFICACY and expand adverse effects
New Drug Application (NDA)
submitted by the sponsor to the FDA including everything from preclinical data to Phase 3 data
Must contain:
- proposed labeling
- directions for use
- safety updates
- drug abuse information
- patient information
- data from studies outside of US
- institutional review board compliance information
How long does it take FDA to make decision and review data of NDA?
6-10 months
Phase 4 (Post-Marketing Surveillance)
- FDA reviews MedWatch for trends among adverse events reported by patients & HC professionals
- FDA regulates Rx drug promotions & advertising to ensure accurate efficacy, adverse effects, and prescribing information
- routine manufacturer inspections to ensure appropriate quality and purity standards
Total Time for Drug Development
3.5 - 13.5 years
Success Rate: 3%
Orphan Drug Act
1983
Characteristics:
- provided lower statistical burdens for proof of safety & efficacy
- tax incentives for orphan drug production
- enhanced patent protection & marketing
- clinical research subsidies
- govt. incentive to engage in drug research
Hatch-Waxman Act
1984
reduced requirements for approval of generic prescriptions
Before Hatch-Waxman:
- FDA approval for generic can’t be started until patent expires for brand
- generic companies had to perform own safety & efficacy studies
After Hatch-Waxman:
- generic companies can prepare for approval without impinging on patent
- generic companies only had to provide bioeqivalence and proof of acceptable manufacturing practices & controls
Abbreviated New Drug Application
pathway for generic approval
Characteristics:
- does not need to include animal or human clinical trial data –> just bioequivalence
Bioequivalance
demonstration that the rate of absorption of the generic drug is equivalent to that of the innovator drug delivery the same amount of ingredient in the same amount of time
Affect of Abbreviated New Drug Application
3 years –> 3 months
