Drug development Flashcards
Top selling drug worldwide in 2013?
Humira - adalimumab
exceeded 11 billion
anti-TNF drug for RA
average cost of developing a new drug
802 million to several billion
Some meds that saved more than 1.5 million lives and 140 billion in costs for treatment
TB
poliomyelitis
Coronary artery disease
cerebrovascular disease
new drugs caused a post 1995 decline in
HIV mortality
Percent of USA healthcare dollar spent on Rx?
10%
Some approaches to Drug discovery
- identification or elucidation of new drug target
- Rational design of new molecule based on understanding biologic mechanisms and drug receptor structure
- Screening for biologic activity of large #s of natural products, banks or previously discovered chemical or large libraries of molecules
- Chemical modification of known active molecule , resutling in a me too analog
Drug screening
sequence of experimentation and characterization
Pharmacologic profile
molecular
cellular
organ system
whole animal levels
Lead compound
candidate for new drug
patent app filed for a novel compound (composition of matter patent) that is efficaciious or for new and nonobvious therapeutic use
ALL drugs are _____ in some individuals at some dose
toxic
NO chemical can be certified as
completely “safe” (free of risk)
Preclinical toxicity
Identify potential human toxicities
Designing tests to further define the toxic mechanisms
Predicting the most relevant toxicities to be monitored in clinical trials
No effect dose
max dose which a specified toxic effect is not seen
Minimum lethal dose
smallest dose that is observed to kill any experimental animal
Median lethal dose (LD50)
dose that kills approx 50% of the animals
What is used to calculate the initial dose?
No effect dose
Minimum lethal dose
Medial lethal dose (LD50)
Limitations of preclinical testing
- Toxicity testing is time consuming and expensive. Take 2-6 years to collect and analyze data before drug is considered for human testing
- Large #s of animals may be needed for valid data
- Extrapolations of therpeutic index & toxicity data from animals to humans are reasonably predictive
- rare adverse effects are unlikely to be detected
Amount of drugs tested that never reach market
less than 1/3
3 Major confounding factors
- Variable natural Hx of most diseases. Evaluate large pop over sufficient time. Crossover design, consists of alternating periods of administration of test drug, placebo prep and standard tx
- presence of other diseases and risk factors
- Subject and observer bias and other factors - Placebo response - placebo adverse effects and toxicity also occur
Single blind design
involved use of a placebo administered to same subjects in crossover design or to separate control group of well matched subjects
Double blind design
identity of medication being used - placebo or active form - disguised from both subjects and the personnel evaluating subjects responses
Adherence
confirmation of compliance
FDA
oversses drug evaluation process
grants approval for marketing of new drug products
authority derived from specific legislation
Pure Food & drug act of 1906
first legislation concerning food and drug
passed in response to sale patent meds by snake oil salesman which contained toxic or habit forming ingredients
Required accurate labeling of ingredients in drug products and sought to prevent adulteration of products thru substituttion of inactive or toxic ingred.
DID NOT regulate false advertising
Food, Drug and Cosmetic Act of 1938
response to incident in which over 100 ppl died after ingesting elixir that contained sulfanilamide, used to tx strept inf, in a solution of ethylene glycol
requires evidence of drug safety before the drug product could be marketed by establishing FDA to enforce requirements and gave legal authority to drug product standards contained in the USP
USP
united states pharmacopeia
first compiled 1820
contains info on the chemical analysis of drugs and indicates how much variance in drug content is allowable for each drug product
outlines standards for tablet disintegration and many other aspects of drug product composition and analysis
USP standard for Aspirin
tablets must contain not less than 90% and not more than 110% of the labeled amount of aspirin
Provisions of the Food, Drug and Cosmetic Act
prohibits distribution of drug products that are adulterated, misbranded or do not have approved NDA
requires label contain name, dosage, quantity of ingredients as well as warning
what makes a drug adulterated?
if it does NOT meet USP standards or if it is not manufactured according to defined “good manufacturing practices”
Durham-Humphrey Amendment
passed in 1952
created legal distinction btw nonRx and Rx
Prescription drugs are labeled “Rx only”
FDA may reclassify drug as nonRx if found to be safe enough
Examples of reclassified Rx drugs
Prilosec (omeprazole) - proton pump inhibitor for treating acid refulx
Claritin ( Ioratadine) - antihistamine
Kefauver Harris Amendments
passed in 1962
largely in response to reports of severe malformations from Thalidomide for sedation during pregnancy
It was not approved in US because scientist, Frances Kelsey, held up approval
required demonstration of both SAFETY and EFFICACY
Orphan drug Amendments
Passed in 1983 to provide tax benefits and other incentives for drug manufacturers to test and produce drugs that are used in treatment of rare diseases and therefore unlikely to generate large profits
Drug Price competition and Patent restoration act of 1984
extended the patent life of drug products (at the time was 17yrs) by adding amt of time required for regulatory review of NDA
accelerates approval of generic drug products by allowing investigators to submit an abbreviated NDA
Therapeutic equivalence of the generic is demonstrated
Accelerated Drug approval
1992
authorized for new drugs to treat life threatening conditions such as AIDS and cancer
pts with these conditions can be treated with investigational drug before clinical trials have been completed
Harrison Narcotics Act of 1914
First major drug abuse legislation
prompted by growing problem of heroin abuse followed the synthesis of potent and rapid acting derivative of morphine
sought to control narcotics thru the use of tax stamps on legal drug products
Comprehensive drug abuse prevention and control act of 1970
during 1960s, prevalence of drug abuse increased especially among teens and young adults who were using a wide range of drugs that included Rx sedatives and stimulants as well as LSD, MaryJ, and other hallucinogens
also called Controlled substances Act
Controlled substances Act
classified drugs into 5 schedules
based on their potential for abuse and clinical use
Schedule I drugs
high abuse potential and no legitimate medical use
distribution and possession are prohibited
Schedule II drugs
high abuse potential but a legit medical use and distribution is highly controlled thru requirements for inventories and records and thru restrictions on prescriptions
Schedule III, IV and V
have lower abuse potential but a legit medical use and distribution is highly controleed thru requirements for inventories and fewer restrictions on distribution
CSA requires of manufacturers, distributors, physicians and medical researchers using controlled drugs to register with
Drug enforcement administration (DEA)
Once a drug is judged ready to be studied in humans …
a notice of claimed investigational exemption for a new drug (IND)
IND includes:
-information on the composition and source of drug
-chemical and manufacturing information
-all data from animal studies
-proposed plans for clinical trials
-names and credentials of physicians who will conduct the clinical trials
compilation of key data relevant to study drug in humans that has been made available to investigators and institutional review boards
Phase 1
effects of drug as function of dosage are established in small# (20-100) healthy volunteers
find max tolerated dose
volunteer pts with disease recruited if drug has severe toxicity in place of normal healthy pts
determine probable limits of safe clinical dosage range
may be non blind or open
Phase 1 expected outcomes
predictable toxicities are detected
pharmacokinetic measurements of absorption, half-life and metabolism are done
Phase 2
drug studied in patients with the target disease to determine its efficacy and the doses to be used in any follow on trials
100 -200 pts studied
single blind design often used, inert placebo, established active drug and new investigational drug
a broader range toxicity may be detected
Have the highest rate of drug failures and only 25% of innovative drugs move to Phase III
Phase 3
drug is evaluated in larger #s of diseased patients (thousands) to further establish and confirm safety and efficacy
double blind and crossover techniques are frequently used.
can be difficult to design and expensive
certain toxic effects especially those caused by immunologic processes become apparent
If phase 3 meets expectations, an application is made for a new agent, requires submission of
New drug application (NDA) to the FDA
duration of FDA review leading to approval of NDA may take months to years
Priority approval
designated for products that represent significant improvements compared with marketed products
median time: 6 months
Standard approvals
which take longer, are designated for products judged similar to those on the market.
Median standard approval time = 10.2 months
For serious diseases, FDA may permit extensive but
controlled marketing of a new drug before phase 3 studies are completed
For life threatening diseases, FDA may permit
controlled marketing even before phase 2 studies have been completed
Once approval to market a drug has been obtained
Phase 4 begins
Phase 4
constitutes monitoring safety of new drug under actual conditions of use in large number of patients
low incidence drug effects are NOT generally detected before phase 4
no fixed duration
Important drug induced events have an incidence of
1 in 10,000 or less and that some adverse effects any become more apparent only after chronic dosing
Time from filing a patent to approval for marketing of a new drug may take
five years or much much longer
Lifetime of a patent ?
20 years
Because the patent review process can be lengthy, time consumed by review is
sometimes added to the patent life
However, the extension (up to 5 years) cannot
increase the total life of the patent to more than 14 years after NDA approval
As of 2005, average effective patent life for major pharmaceuticals was
11 years
How is a generic drug licensed?
after expiration of a patent, any company can produce the drug, file an ANDA, demonstrate equivalence and with FDA approval market the drug as a generic
currently, 67% of prescriptions in USA are generic
Adverse drug reaction
harmful and unintended response
4th leading cause of death (higher than pulmonary dis, AIDS, MVA)
-overdose, excessive effects and drug interactions
-in susceptible pts, includes, intolerance, idiosyncrasy, allergy
In the process of confirming and approving a drug, when are ADRs reported?
during the IND and clinical phase 1-3 trials and before FDA approval
all MUST be reported
surveillance is kept up while drug in on the market
events that are both serious and unexpected must be reported to the FDA within 15 days
In 2008, The FDA started
to publish a list of drugs (quarterly) being investigated for potential safety risks
The prescription Drug use fee act of 1992, reauthorized in 2007
attempts to make more FDA resources available to the drug approval process and increase efficiency thru use of fees collected from drug companies that produce certain human drugs and biologic products
