Lecture #4 Flashcards
Thalidomide
Drug was developed in 1952 and studied by a German company. It was originally marketed as a sedative but was later found to be an effective antiemetic.
* It was studied extensively in animals for toxicity and found to have no adverse effects.
* It was marketed widely in Europe, and available over-the-counter, where many women used it to help with morning sickness
* At the time, there were no testing restrictions related to pregnant patients, as scientists of the day did not think drugs could pass the placental barrier of a pregnant patient.
1961: Thalidomide tragedy
Thalidomide was linked to phocomelia, a rare condition affecting the fetal formation of arms and legs.
* More than 10,000 children were born with serious birth defects worldwide, 40% of which died early in childhood.
* Frances Oldham Kelsey blocked the drug’s approval in the United States. She received the President’s Award for Distinguished Federal Civilian Service for saving countless American lives.
1962: Kefauver-Harris amendment
- Largely a result of the thalidomide disaster, Congress passed the Kefauver-Harris Amendment:
- Requiring medications to be demonstrated not only safe, but also effective (this applied to all drugs marketed between 1938 – 1962 as well as new drugs).
- Transferred jurisdiction of prescription drug advertising from the Federal Trade Commission (FTC) to the FDA.
- Established current Good Manufacturing Practice (cGMP) requirements.
- Added requirements to clinical investigations including informed consent
of research subjects and reporting of adverse drug reactions.
Current good manufacturing practices (cGMP)
Minimum requirements for the manufacture of drug products. Assures proper:
* Design
* Monitoring
* Control
Of manufacturing processes. Any manufacturer for drugs used in the United States must be registered with the FDA and undergo an inspection at least once every two years.
* If you don’t comply with cGMP, the product is adulterated!
* If you don’t register with the FDA, the product is adulterated and misbranded!
What 3 categories does making drugs fall in?
pharmacy or traditional compounding (503a)
outsourcing facilities (503b)
manufacturing
Pharmacy or traditional compounding (503a)
compounding according to prescriptions specific to particular patients on an as needed basis.
Outsourcing facilities (503b)
manufacturing large batches with or without prescriptions to be sold to facilities for office use only.
Manufacturing
mass production of drug products that have been approved by the Food and Drug Administration.
Pharmacy or traditional comounding (503a)
- Compound pursuant to a prescription only
- Compounding is for an individual patient
- Compounding is done by a pharmacist, physician, or another individual under their direct supervision
- Ingredients used in compounding are bulk substances which comply with USP-NF
- Compound cannot be a copy of a commercially available product
- Compounding can be done in advance, but only on a limited basis
Meeting these requirements is important, because compounding within these limits exempts the pharmacy from meeting regulations related to: - cGMP
- Misbranding (related to drug labeling)
- New Drug Requirements
Outsourcing facilities (503b)
- Compound without receiving a prescription for a specific patient
- Must register, pay annual fees, and be inspected by the FDA
- Compounding cannot be a copy of a commercially available product
Product labels must contain:
The statement “this is a compounded drug” - Name, address, and phone number of the
outsourcing facility - Lot number or batch number
- Established name of the drug
- Dosage or strength
- Quantity or volume
- Beyond use date
- Storage and handling instructions
- NDC
- The statement “not for resale”
- A list of active and inactive ingredients
Comparing requirements for making drugs - misbranding
pharmacy compounding (503a): NO
outsourcing facilities (503b): labeling/packaging requirements
drug manufacturer: YES
Comparing requirements for making drugs - cGMP
pharmacy compounding (503a): NO
outsourcing facilities (503b): YES
drug manufacturer: YES
Comparing requirements for making drugs - new drug requirements
pharmacy compounding (503a): NO
outsourcing facilities (503b): NO
drug manufacturer: YES
A new problem with old drugs
With the Kefauver-Harris Amendment came the new requirement that drugs had to be proven safe and effective.
* The Federal Food, Drug, and Cosmetic Act of 1938 only required drugs to be proven safe before coming to market…
* The Pure Food and Drug Act of 1906 didn’t even require drugs to be safe…
What do we do with the drugs that came out before 1962??
* If you came out before 1938, and you are still on the market, you must be safe and effective ̄_(ツ)_/ ̄. These drugs were grandfathered in. If you came out after 1938 though…
1968: drug efficacy study implementation (DESI)
The National Academy of Sciences investigates all medications approved between 1938-1962 for efficacy, and issues recommendations to the FDA.
* FDA reviews recommendations, and makes decisions on those products. Products may remain on the market until a decision is made.
* Some drugs are pulled off the market that were initially approved, although manufacturers can file for a hearing before the FDA in these cases.
The drug development process
Discovery and development of novel chemical for drug consideration.
* Step 1: Preclinical Research
* In Vivo Animal Studies
* Step 2: Submission of Investigational New Drug (IND)
* Step 3: Clinical Research
* Phase I
* Phase II
* Phase III
* Step 4: New Drug Application Process (NDA)
* Step5:Post-MarketSafetyMonitoring
* Phase IV
Step 1: preclinical research
Before a drug can ever be tested on humans, it must undergo testing to determine toxicity of the potential drug, as well as dosing levels.
* In vivo animal testing is utilized to record data on toxicity and pharmacology of the product.
* These studies are often small, but contain enough data to make an informed decision on whether or not to apply the chemical as an Investigational New Drug.
Step 2: investigational new drug (IND)
If the drug shows the possibility for safe and effective use, the manufacturer may submit an IND.
* The IND must contain the following information:
* Animal Pharmacology and Toxicology Studies
* Manufacturing Information
* Clinical Protocols and Investigator Information
* Once the IND is submitted, the sponsor must wait 30 days before initiating any clinical trials to allow the FDA to review the IND for safety and unreasonable risk.
Step 3: Clinical research phase 1
In the first phase of clinical trials, 20 to 100 healthy human volunteers receive the drug to evaluate the safety and dosage of the compound.
* Baseline human pharmacokinetic and pharmacologic properties are also reviewed and reported.
* Phase 1 continues for several months.
* 70% of drugs move to Phase 2.
Step 3: Clinical research phase 2
Phase 2 of clinical trials include several hundred human volunteers who have the disease or condition that is being studied.
* Primary goal of this phase is to expand information about safety and adverse effects of the drug, and to determine the effectiveness of the therapy.
* Phase 2 continues for up to 2 years.
* About 33% of drugs move to Phase 3.
Step 3: clinical research phase 3
The drug is given to hundreds or thousands of patients in several geographic locations who have the disease or condition that is being treated.
* Drug is compared to placebo in trials that are usually double blinded.
* Goal is to demonstrate efficacy at a higher power, and to expand
information around adverse effects.
* Phase 3 continues for 1 to 4 years.
* About 25-30% of drugs are submitted as a New Drug Application
(NDA).
Step 4: New drug application (NDA)
NDA is submitted by the sponsor to the FDA, including everything from the preclinical data to the Phase 3 trial data. Must also include:
* Proposed labeling
* Safety updates
* Drug abuse information
* Patent information
* Any data from studies that may have been conducted outside the United States
* Institutional review board compliance information
* Directions for use
* FDA can take 6 to 10 months to review data and make a decision on drug approval.
Step 5: Post-marketing surveillance phase 4
Even the exhaustive process to an approved NDA cannot provide a complete view of drug safety. With that in mind, there are additional requirements for these drugs.
* FDA reviews MedWatch for trends among adverse events reported by health professionals and patients.
* Routine manufacturer inspections are conducted to ensure appropriate quality and purity standards.
* FDA regulates prescription drug promotions and advertising to ensure accurate effectiveness, adverse effect, and prescribing information.
New drug application timeline
Drug discovery: 6 months – 5 years
* Preclinical research: 3 months – 1 year
* Investigational New Drug Application: 1 month
* Phase1:6–9months
* Phase 2: 6 months – 2 years
* Phase3:1–4years
* NDA:6–10months
* TOTAL TIME: 3 1⁄2 to 13 1⁄2 years…success rate about 3%…seems like a long time with a lot of risk…
1983: orphan drug act
After passage of the Kefauver-Harris Amendment in 1962, medications became much more costly to develop. As a result, most drug manufacturers only developed medications for common diseases to ensure they could recoup development costs and maintain profitability.
* Many rare diseases were ignored in this period of development, or “orphaned.”
* The orphan drug act provided lower statistical burdens for proof of safety and efficacy when appropriate, and also allowed:
* Tax incentives for orphan drug production
* Enhanced patent protection and marketing
* Clinicalresearchsubsidies
* Government incentive to engage in drug research
1984: Hatch-Waxman act
Another result of the time and expense required to complete an NDA, the Drug Price Competition and Patent Term Restoration Act of 1984, or Hatch-Waxman Act, was passed to reduce the requirements for approval of generic prescription drugs.
Before Hatch-Waxman Act
FDA approval for generic can’t be started until patent expires for brand
* Generic companies had to perform own safety and efficacy studies
After Hatch-Waxman Act
Generic companies can prepare for approval without impinging on patent
* Generic companies only had to prove bioequivalence and proof of acceptable manufacturing practices and controls
Abbreviated new drug application
Pathway for generic drug approval.
* Termed abbreviated because applicant does not need to include animal or human clinical trial data to establish safety and effectiveness.
* Bioequivalence: demonstration that the rate of absorption of the generic drug is equivalent to that of the innovator drug. Must deliver the same amount of ingredient in the same amount of time.
* This process dropped the standard approval time for generic drugs from 3 years to 3 months.
