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CMBM exam 5 > Drug development > Flashcards

Drug development Flashcards

0
Q

Top selling drug worldwide in 2013?

A

Humira - adalimumab
exceeded 11 billion
anti-TNF drug for RA

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1
Q

average cost of developing a new drug

A

802 million to several billion

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2
Q

Some meds that saved more than 1.5 million lives and 140 billion in costs for treatment

A

TB
poliomyelitis
Coronary artery disease
cerebrovascular disease

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3
Q

new drugs caused a post 1995 decline in

A

HIV mortality

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4
Q

Percent of USA healthcare dollar spent on Rx?

A

10%

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5
Q

Some approaches to Drug discovery

A
  1. identification or elucidation of new drug target
  2. Rational design of new molecule based on understanding biologic mechanisms and drug receptor structure
  3. Screening for biologic activity of large #s of natural products, banks or previously discovered chemical or large libraries of molecules
  4. Chemical modification of known active molecule , resutling in a me too analog
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6
Q

Drug screening

A

sequence of experimentation and characterization

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7
Q

Pharmacologic profile

A

molecular
cellular
organ system
whole animal levels

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8
Q

Lead compound

A

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

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9
Q

ALL drugs are _____ in some individuals at some dose

A

toxic

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10
Q

NO chemical can be certified as

A

completely “safe” (free of risk)

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11
Q

Preclinical toxicity

A

Identify potential human toxicities
Designing tests to further define the toxic mechanisms
Predicting the most relevant toxicities to be monitored in clinical trials

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12
Q

No effect dose

A

max dose which a specified toxic effect is not seen

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13
Q

Minimum lethal dose

A

smallest dose that is observed to kill any experimental animal

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14
Q

Median lethal dose (LD50)

A

dose that kills approx 50% of the animals

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15
Q

What is used to calculate the initial dose?

A

No effect dose
Minimum lethal dose
Medial lethal dose (LD50)

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16
Q

Limitations of preclinical testing

A
  1. Toxicity testing is time consuming and expensive. Take 2-6 years to collect and analyze data before drug is considered for human testing
  2. Large #s of animals may be needed for valid data
  3. Extrapolations of therpeutic index & toxicity data from animals to humans are reasonably predictive
  4. rare adverse effects are unlikely to be detected
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17
Q

Amount of drugs tested that never reach market

A

less than 1/3

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18
Q

3 Major confounding factors

A
  1. 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
  2. presence of other diseases and risk factors
  3. Subject and observer bias and other factors - Placebo response - placebo adverse effects and toxicity also occur
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19
Q

Single blind design

A

involved use of a placebo administered to same subjects in crossover design or to separate control group of well matched subjects

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20
Q

Double blind design

A

identity of medication being used - placebo or active form - disguised from both subjects and the personnel evaluating subjects responses

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21
Q

Adherence

A

confirmation of compliance

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22
Q

FDA

A

oversses drug evaluation process
grants approval for marketing of new drug products
authority derived from specific legislation

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23
Q

Pure Food & drug act of 1906

A

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

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24
Q

Food, Drug and Cosmetic Act of 1938

A

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

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25
Q

USP

A

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

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26
Q

USP standard for Aspirin

A

tablets must contain not less than 90% and not more than 110% of the labeled amount of aspirin

27
Q

Provisions of the Food, Drug and Cosmetic Act

A

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

28
Q

what makes a drug adulterated?

A

if it does NOT meet USP standards or if it is not manufactured according to defined “good manufacturing practices”

29
Q

Durham-Humphrey Amendment

A

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

30
Q

Examples of reclassified Rx drugs

A

Prilosec (omeprazole) - proton pump inhibitor for treating acid refulx
Claritin ( Ioratadine) - antihistamine

31
Q

Kefauver Harris Amendments

A

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

32
Q

Orphan drug Amendments

A

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

33
Q

Drug Price competition and Patent restoration act of 1984

A

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

34
Q

Accelerated Drug approval

A

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

35
Q

Harrison Narcotics Act of 1914

A

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

36
Q

Comprehensive drug abuse prevention and control act of 1970

A

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

37
Q

Controlled substances Act

A

classified drugs into 5 schedules

based on their potential for abuse and clinical use

38
Q

Schedule I drugs

A

high abuse potential and no legitimate medical use

distribution and possession are prohibited

39
Q

Schedule II drugs

A

high abuse potential but a legit medical use and distribution is highly controlled thru requirements for inventories and records and thru restrictions on prescriptions

40
Q

Schedule III, IV and V

A

have lower abuse potential but a legit medical use and distribution is highly controleed thru requirements for inventories and fewer restrictions on distribution

41
Q

CSA requires of manufacturers, distributors, physicians and medical researchers using controlled drugs to register with

A

Drug enforcement administration (DEA)

42
Q

Once a drug is judged ready to be studied in humans …

A

a notice of claimed investigational exemption for a new drug (IND)

43
Q

IND includes:

A

-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

44
Q

Phase 1

A

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

45
Q

Phase 1 expected outcomes

A

predictable toxicities are detected

pharmacokinetic measurements of absorption, half-life and metabolism are done

46
Q

Phase 2

A

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

47
Q

Phase 3

A

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

48
Q

If phase 3 meets expectations, an application is made for a new agent, requires submission of

A

New drug application (NDA) to the FDA

duration of FDA review leading to approval of NDA may take months to years

49
Q

Priority approval

A

designated for products that represent significant improvements compared with marketed products
median time: 6 months

50
Q

Standard approvals

A

which take longer, are designated for products judged similar to those on the market.
Median standard approval time = 10.2 months

51
Q

For serious diseases, FDA may permit extensive but

A

controlled marketing of a new drug before phase 3 studies are completed

52
Q

For life threatening diseases, FDA may permit

A

controlled marketing even before phase 2 studies have been completed

53
Q

Once approval to market a drug has been obtained

A

Phase 4 begins

54
Q

Phase 4

A

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

55
Q

Important drug induced events have an incidence of

A

1 in 10,000 or less and that some adverse effects any become more apparent only after chronic dosing

56
Q

Time from filing a patent to approval for marketing of a new drug may take

A

five years or much much longer

57
Q

Lifetime of a patent ?

A

20 years

58
Q

Because the patent review process can be lengthy, time consumed by review is

A

sometimes added to the patent life

59
Q

However, the extension (up to 5 years) cannot

A

increase the total life of the patent to more than 14 years after NDA approval

60
Q

As of 2005, average effective patent life for major pharmaceuticals was

A

11 years

61
Q

How is a generic drug licensed?

A

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

62
Q

Adverse drug reaction

A

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

63
Q

In the process of confirming and approving a drug, when are ADRs reported?

A

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

64
Q

In 2008, The FDA started

A

to publish a list of drugs (quarterly) being investigated for potential safety risks

65
Q

The prescription Drug use fee act of 1992, reauthorized in 2007

A

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

CMBM exam 5 (19 decks)

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