barriers to large molecule drug developments
purifying molecules
immune response
modification of proteins or conformational differences may alter how the drug is absorbed, metabolized, or even where it targets
gene cloning
allows for production of large quantities of human or humanized protein
minimizes immunological reaction
genetic engineering
allows for customization and optimization of proteins
biosimilar
biological product is highly similar but not identical to a reference product
minor differences in clinically inactive components
no clinically meaningful differences between them in terms of safety, purity, and potency
goal of pre-clinical testing
estimating risk associated with exposure to the drug candidate
limitations: toxicity testing is time consuming and expensive
large numbers of animals
extrapolations of toxicity data from animals to humans are not perfectly predictive
rare adverse events unlikely to be detected
social and clinical value
outcome of the study should be important enough to justify the risk and/or inconvenience that study subjects are being asked to assume
scientific validity
question asked is answerable, the research methods are valid and feasible, and the study is designed with accepted principles, clear methods, and reliable practices
fair selection of subjects
recruitment based off the scientific goals of the study, groups not included/excluded without good scientific reason
informed consent
participants make their own decision about whether they want to participate
accurately informed and understand
consent may be withdrawn
favorable risk-benefit ratio
everything should be done to minimize the risk and maximize benefits, benefits proportional to or outweigh the risk
independent review
panel reviews proposal and asks important questions
study free from bias, ethically designed, etc.
phase 1 of clinical trials
first in human: is the drug safe?
20-100 healthy subjects
results establish safety and tolerability
success rate of 50%
open label study design
phase 2
first in patient: how does the drug work?
50-500 subjects with target disease
randomized controlled study design (may be blinded)
results establish efficacy and dosing ranges
success rate: 30%
phase 3
multisite trial
a few hundred to a few thousand patients with target disease
randomized controlled/uncontrolled study design (may be blinded)
confirmation of efficacy in larger population
success rate: 25-50%
phase 4
post-marketing surveillance
many thousands of participants
open label
delineate info regarding: new indications, risks, optimal doses and schedules, rare side effects
no fixed duration
Investigational New Drug (IND) Application
information on the composition and source of the drug
chemical and manufacturing information
all data from animal studies
proposed plans for clinical trials
the names and credentials of physicians who will conduct the clinical trials
a compilation of the key preclinical data relevant to study f the drug in humans that have been made available to investigators and their institutional review boards
safety endpoints in each phase
phase I - safe dosage range and predictable toxicities
phase II - side effects/toxicities (small population)
phase III - side effects/toxicities (large population)
phase IV - safety with typical use in the general population
efficacy clinical endpoint
measurable medical outcome
ex. heart attack, fractures
higher clinical trial costs, longer duration and more participants
reliable outcome
efficacy surrogate endpoints
outcome thought to be predictive of the relevant clinical outcome
ex. cholesterol levels, bone mineral density
lower clinical trial costs - shorter duration and likely fewer participants
predictor of an outcome, results should be interpreted with caution
rationale for current drug prices
high risk: huge costs and low success rates, limited patent timeframe, product liability, stringent regulation
potential for profits that can benefit further research and development
medication costs are rising at a slower rate other than healthcare costs
no well established approach to quantity value
counterargument for current drug prices
outcomes are not better in the US despite enormous healthcare costs
orphan drug act of 1983
provides incentives for development of drugs for rare diseases
