Basic principles Flashcards
1906 Pure Food + Drug Act
Beginning of drug regulation; prohibited adulterated, misbranded or poisonous drugs
1938 Federal Food, Drug, & Cosmetic Act (FFDCA)
- Truthfulness in labeling & documentation of safety
- Required to submit NDA before marketing (Toxicity studies to be conducted before marketing)
1962 Harris-Kefauver Drug Amendments to the Food, Drug & Cosmetic Act
- Preclinical trials before drug testing in humans
- 3 phase Investigation of New Drugs process (IND)
- Safety and efficacy
- Amendments: thalidomide for morning sickness
Drug Development Process
- Discovery + development
- Preclinical research
- Clinical research (phases 1, 2, 3)
- FDA review (New Drug Application/NDA)
- FDA post-market monitoring
- Discovery and development
- $$
- Goals:
- ID new viable compounds or drug targets
- Eval interaction with biologic targets
- Eval efficacy, potency, selectivity
- Preclinical testing
Testing
- In vitro: artificial environment
- Ex vivo: viable cell/tissue after removal from an organism
Identify potential risks and toxicity in animals (2 species)
- Acute and chronic toxicity
- Reproductive and carcinogenic effects
- Mutagenic potential
Identify key concentrations
- No-effect dose: Maximum dose where toxicity not seen • Minimum lethal dose:
- Smallest dose observed to kill experimental animal
Evaluate pharmacokinetic profile and pharmaceutical properties
- Clinical research (phases 1, 2, 3)
Clinical Trials
- Phase 1: 20-100 healthy volunteers
- Length: months
- Eval safety/dosage
- Blinded or open label studies
- Phase 2: Hundreds of pts with disease/condition (“perfect pt”)
- Length: months to 2 years
- Eval efficacy, side effects
- RCT, comparing placebo
- Short term SE
- Phase 3: Thousands of pts with disease/condition (“everyone”)
- Length: 1-4 years
- Confirm efficacy and safety
- RCT, double-blinded
- Long term SE
- FDA Review/Submit new drug application (NDA)
Must include EVERYTHING (preclinical data to Phase 3 trial data):
- Proposed labeling; Directions for use
- Safety updates
- Drug abuse information
- Patent information
- Data from studies conducted outside the US
- Institutional review board compliance information
- Proprietary naming
- Post-marketing monitoring (“phase 4”)
Reporting of adverse reactions
- Harmful or unintended response to a medication
FDA’s MedWatch program allows practitioners, pharmacists, and consumers to report adverse reactions www.fda.gov/medwatch
• Resources
- FDA website for drug safety updates, shortages, changes in labeling…
Risk Evaluation and Mitigation Strategies (REMS)
REMS are required risk management plans that use risk minimization strategies beyond the professional labeling
- allows necessary medications to be prescribed while appropriately monitoring the patient
Ensure benefits of certain prescription drugs outweigh their risks
Elements
- Medication Guide
- Communication Plan
- Elements to Assure Safe Use (ETASU)
- Most extensive
Biosimilars
- Biological products approved if highly similar to FDA- approved biological product (reference product)
- Has no clinically meaningful differences in safety and effectiveness
- Only minor differences in clinically inactive components are allowable
- Abbreviated licensure pathway to establish products to be “biosimilar” to or “interchangeable”
- Interchangeable biological product may be substituted for the reference product by a pharmacist without intervention of health care provider
Barriers to Pediatric Studies
Financial Issues
- Few incentives for pharmaceutical companies • Small market share
- Low profit margins
Ethical Issues
- Potential exploitation of children by drug researchers
- Need parental consent & child assent
Scientific Issues lead to practical difficulties
- Higher complexity due to physiological difference
- Dosing can be extrapolated from adult data
- Pharmacokinetic data and safety/toxicities can not
- MUST study children of different ages
- Small number of children with certain diseases
- Different dosage formulations
- Stability data
- Difficulties involved in recruitment of patients
Chloramphenicol
Hexachlorophene topical cleanser
Sulfonamide use in neonates
Chloramphenicol
- Pediatric dosing extrapolated from adult data
- Neonates given chloramphenicol developed “gray baby syndrome” leading to shock and death
Hexachlorophene Topical Cleanser
- Used routinely & safely in adults
- Lead to vacuolar encephalopathy of the brain stem in premature neonates after bathed in a 3% solution
Sulfonamide use in neonates
- Kernicterus reported
FDA Regulation of Pediatric Therapy 1979-1994
FDA 1979 Pediatric Information Requirement
- “Pediatric Use” subsection on medication labels & package inserts
- Information based on substantial evidence from adequate & well controlled studies in pediatric population
- Problem: most medications continued to lack information:
- “Safety and efficacy below age X have not been established”
- Section itself is required, information is not required
1994 Pediatric Use Labeling Rule
- Provided a broader basis for inclusion of pediatric data on label
- Allowed companies to obtain information if established dosing regimen in children where course of disease similar to adults - extrapolate data from adults (asthma, pneumonia)
- No requirement to conduct new pediatric studies
- Impact: Did not result in more pediatric labeling
1994 Pediatric Pharmacology Research Unit (PPRU)
- Established by NIH to provide guidance for clinical trials in pediatric patients
- C/s on what adult drugs need pediatric versions
FDA Regulation of Pediatric Therapy (1997-2019)
1997 Food & Drug Administration Modernization Act (FDAMA)
- Incentives for new drug testing in pediatrics “the carrot”
- Pediatric Exclusivity Provision:
- 6-month extension on drug patent IF the medication label included indications & dosing for pediatrics based on pediatric studies
- Did not apply to medications that lack marketing exclusivity or patent protection
- 2002: Replaced by Best Pharmaceuticals for Children Act (BPCA) – extends 6mo rule to 2007; still voluntary
1998 Pediatric Rule
- FDA requirement for pediatric studies “the stick”
- Pharmaceutical companies required to conduct pediatric studies as part of new drug development if the drug had potential for use in the pediatric population
- Study time would lag behind adult studies
- Finally: Requirement to conduct new pediatric studies
-
2002: Pediatric Rule overturned
- Federal District Court of DC ruled FDA overstepped its authority (Made medications more expensive, delayed release of new drugs)
-
2003: Pediatric Research Equity Act (PREA)
- Pediatric studies mandatory; requires pediatric assessments to support pediatric use info in labeling
2007 FDAAA*
- Est PeRC (pediatric review committee): c/s for general review of pediatric info for studies/labeling changes/exclusivity applications
- Reauth’ed BPCA, PREA (made permanent in 2012)
2007 PMDSIA
- Incentives for manufacturers to create peds medical devices
- Reauth’d in 2012, 2017
