Transcript Evaluation & Categorization of Drugs

Evaluation & Categorization of Drugs
September 13, 2007
Frank F. Vincenzi
Learning Objectives
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FDA, DEA
Toxicity testing,
Clinical trials
Crossover design
Safety, efficacy
Single, double blind
Controlled trials
Specific outcome vs.
surrogate markers
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Placebo effect
Orphan drugs
Phase I, II, III, IV
IND, NDA
Use in pregnancy
ratings
Preclinical testing
Controlled substances
- Schedules I-V
Over-the-counter, Rx
Off-label use
Evaluation of drugs
• Good drugs?
• Bad drugs?
Legal status of drugs
• Non-prescription drugs (over-the-counter, OTC), often
previously Rx only (e.g., ibuprofen)
• Rx only (approved by FDA for at least one application
only after rigorous clinical trials - your responsibility
on/off label
(may prescribe by generic or Trade® name but the,
pharmacist may fill with generic in most cases)
• Investigational New Drug (IND) (in clinical trials),
submitted to FDA based on preclinical trial data.
• Schedule drugs (including controlled substances)
Dietary supplements and other anomalies
• No FDA regulation of dietary supplements
(extremely controversial); protected by the
Dietary Supplement and Health Education Act of
1994 (DSHEA)
• FDA regulation of tobacco ??
A cigarette IS a drug delivery device...but
• FDA regulation of alcohol (Not yet?) State & local
control plus Bureau of Alcohol, Tobacco & Firearms
Rx Drug Labeling (FDA regulations)
• Description
The
PDR
is
a
• Clinical pharmacology
'CYA’ document
useful for a quick review
• Indications and usage
official labeling does not include off-label uses
• Contraindications
seldom absolute, but important to understand why
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• Adverse reactions
immense health problem, now being documented
Adverse Drug Reactions
• One of the leading causes of death in the U.S.
• Accounted for 11.4% of hospital admissions
• 3.0% were therapeutic failures
(mainly from non-compliance)
• Some drugs more troublesome than others:
anti-rheumatics & analgesics (27%)
cardiovascular drugs (23%)
psychotropic drugs (14%)
anti-diabetics (12%)
antibiotics (7%)
corticosteroids (5%)
Adverse Reactions - Some Numbers
• Admissions per million doses dispensed:
nitrofurantoin
617
insulin
182
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diuretics
10
benzodiazepines
7
Hallas et al, Br. J. Clin. Pharmacol. 33: 61-68, 1992
Common causes of adverse drug reactions
• Failure to:
– Observe pre-existing drug allergies
– Avoid drug interactions
– Adjust dosing rate to account for
• Body mass
• Abnormal renal/liver function
• Patient age
An in-hospital computer monitoring program, verified by nurse or pharmacist,
identified 410 adverse drug events in one year compared to 9 the previous
year.
Proc. Ann. Symp. Comput. Appl. Med. Care, 1991, pp. 23-27
Drug Development
• Discovery of natural or synthetic molecules of potential
interest - now specific molecular design
• In vitro testing - determine potency & selectivity in test
systems, including tissue culture
• Initial pharmacological testing in animals
• Toxicity testing in animals
acute, subacute & chronic (multiple species)
• Use patent - 20 years of protection from approval
• Submit IND (Investigational New Drug) application to
FDA, if approved Clinical Trials.
• Submit CT data: New Drug Application (NDA), if
approved - marketing (Phase IV)**
Clinical Trials: Phase I
First Administration to Humans
• Normal human volunteers; 20-100
• Subjects in a Clinical Pharmacology Unit
• Determines safety and dosage to produce minor
toxicity in humans
• Preliminary estimates of pharmacokinetic
parameters in humans
Clinical Trials: Phase II - Dose Finding and
Preliminary Efficacy Testing
• Patients with target illness(es); 100-200
• Determining appropriate dosing schedules for
treatment of target illness(es) in patients
• May involve non-blinded or single blind trials
Clinical Trials: Phase III
Controlled Trials of Efficacy
• Patients with target illness(es) - 500 - 1000+
• Usually performed in multiple clinics
• Double blind, controlled trials to establish efficacy;
randomized, crossover design usual
(monitored; may be terminated early)
• Many disappointments; and some surprises
e.g., sildenafil (Viagra®)
Where is clinical research conducted?
Catchy acronyms for clinical trials
The drug approval
process summarized
“Phase 0” a new concept
Human ‘microdosing’,
usually with radiolabeled
drugs - useful to predict
PK and metabolites
New Drug Application (NDA)
• Submission of all pre-clinical and clinical trial
data.
• If approved, drug may be marketed with labeling
specifically approved by FDA and only for
conditions in which the drug has been shown to be
effective.
• Labeling may be altered later, based on wider
experience.
• Once a drug is approved, you may prescribe it for
a non-approved use - this is ‘off label’ prescribing.
Phase IV - Postmarketing Surveillance
• Patients in clinical practice - many thousands
cross exposure to other diseases and drugs
identification of low incidence effects
• MedWatch - voluntary reporting health
professionals of adverse events and product
problems http://ww.fda.gov/medwatch/safety.htm
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sometimes results in many reports of the same event
likewise events are often under reported
• Occasionally results in altered labeling or
withdrawal of a product
Drug approval vs. Drug Monitoring
• Bruce Psaty (Professor of Medicine and
Epidemiology, UW) said (as quoted in the NY
Times, March 4, 2005):
“In the office of new drugs, more than 1,000
employees work to review a few dozen new drugs
per year. In the office of drug safety, 109
employees work to evaluate the safety of
thousands of drugs currently on the market.”
Drugs with unanticipated toxicity make it to
the market
• 1975-1999, 584 new chemical entities approved
– 7.4% received ‘black-box warnings’
– 2.7% were withdrawn
Rofecoxib (Vioxx®) approval process
• Animal studies
• Human studies
– 58 studies in 5771 patients
– 3629 received drug 1 day or more
– 752 received usual doses >= 1 year
Psaty, Medical Grand Rounds, UW
Clinical Trials are unlikely to identify rare
adverse reactions
Example, Stevens-Johnson Syndrome
• Occurs at a rate of ~ 1/300,000 treatments with a certain
antibacterial
• If you see SJS once it is unlikely that you will see it
again…but...
• Even if you have never seen SJS, you should not ignore the
potential for that reaction when choosing therapy
Detection of a drug-induced (DI) event
Critical Ratio = freq DI event/freq spont event
• Incidence in
control group
Relative risk to detect
2.0
5.0
• 0.0001
• 0.001
• 0.01
3.8*105
3.1*104 #
3.1*103
# Means
3.9*104
3.9*103
3.9*102
that for a 90% chance of detecting a drug-induced
event that occurs spontaneously at an incidence of 1/1000
in controls, if the risk of the event is doubled by the drug,
then about 31,000 patients need to be studied in the
experimental group.
Development of a new drug - an example
• mibefradil (Posicor®)
a unique blocker of Ca channels;
blocks T-type Ca channels
(all currently marketed blockers block so-called
L-type channels)
• Potential for treatment of angina pectoris and
hypertension
Preclinical selection of mibefradil
Test system
Desired property
isolated heart
CV in animals
GI transit time
P’kinetics in animals
BP in SHR
no decr. contractility
no reflex tachycardia
no constipation
long duration
decreased BP
Modified & adapted from Clozel et al., 1997
Clinical trial results with mibefradil
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Relaxation of vascular smooth muscle
Selective vasodilation of coronary vasculature
No negative inotropic effect on heart muscle
Antihypertensive and anti-anginal - possible promise in
minimizing cardiac hypertrophy in congestive heart failure
• No reflex activation of catecholamines, renin and
aldosterone
• ‘…a side effect profile similar to placebo’
Mibefradil - a short time line
• June 24, 1997 Approved in U.S.
• August 24, 1997 Approved in Europe
‘clinical trials show that Posicor® is very well
tolerated…similar to placebo’
• December 1997 ‘Dear Doctor letter’ - urges caution when
combining mibefradil with other medications such as betablockers, digoxin, diltiazem or verapamil
• December 22, 1997 FDA adds new Warnings regarding
cholesterol lowering drugs such a lovastatin or simvastatin
• February 10, 1998 FDA Warning regarding hismanal and
other medications (including mibefradil)
• June 8, 1998 Voluntarily withdrawn - based on the
potential for drug interactions - too complex to label
(est. 200,000 Americans were on mibefradil)
Drug development - an imperfect system
but better than it used to be
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Identify potential compounds
Select compound with promise
Demonstrate safety in animals & humans
Demonstrate efficacy in at least one clinical
condition (several hundred million dollars to this point)
• Market … and wait
(20 years of patent protection: initial investment and return profit)
Filings for Standard New Molecular Entities
Adapted from the Center for Drug Evaluation
and Research, Report to the Nation, 2003
International Committee of
Medical Journal Editors*
• Require, as a condition of consideration for publication,
registration in a public trials registry
• For any clinical trial starting enrollment after July 1, 2005
• Clinical Trial “Any research project that prospectively
assigns human subjects to intervention or comparison
groups to study the cause-and-effect relationship between a
medical intervention and a health outcome.”
• Studies to study pharmacokinetics or major toxicity (phase
1 trials) would be exempt.
*JAMA, N Engl J Med, N Zealand Med J, Norwegian Med J, CMAJ, Lancet,
MEDLINE, Ann Int Med, Croatian Med J, Dutch J Med, Med J Australia
New Engl J Med 351: 1250-1251, 2004
Conditions in patient-initiated discussions
prompted by DTC advertising
Berndt, E. R. N Engl J Med 2005;352:325-328
Trade Name® versus generic name
• Trade name (e.g., Inderal®, Wyeth-Ayerst), specifies a
particular manufacturer
• Generic name (e.g., propranolol, at least 9 different
manufacturers listed in 1998 PDR)
• Combination products
(Prinzide® = lisinopril + hydrochlorothiazide)
• Equivalence?
Dosage equivalence
Bioequivalence
Therapeutic equivalence
FDA Use-in-Pregnancy Ratings
• A - no risk shown in controlled studies
adequate studies fail to demonstrated risk
• B - no evidence of risk in humans
negative risk in animals or humans
• C - risk can not be ruled out
human &/or animal studies lacking or animals studies show risk
• D - positive evidence of risk
risk to human fetus, but benefit may > risk
• X - contraindicated in pregnancy
risk to human fetus > benefit
Categories of Controlled Substances
• I - essentially illegal (research only, special license)
the most interesting mind altering substances & political footballs
• II - high potential for abuse
e.g., morphine
• III - some potential for abuse
e.g., Tylenol®#3
• IV - low potential for abuse
e.g., midazolam
• V - local regulation & low potential for abuse
codeine in cough syrup
Useful advice……….
• Never prescribe a drug you don’t really
understand...
• Never take a drug you don’t really understand...