Evaluation & Categorization of Drugs

1. Evaluation & Categorization of Drugs September 13, 2007 Frank F. Vincenzi

2. FDA, DEA Toxicity testing, Clinical trials Crossover design Safety, efficacy Single, double blind Controlled trials Specific outcome vs. surrogate markers 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 Learning Objectives

3. Evaluation of drugs • Good drugs? • Bad drugs?

4. 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)

5. 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

6. Rx Drug Labeling (FDA regulations) • Description • Clinical pharmacology useful for a quick review • Indications and usage official labeling does not include off-label uses • Contraindications seldom absolute, but important to understand why • … • Adverse reactions immense health problem, now being documented The PDR is a'CYA’ document

7. 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%)

8. Adverse Reactions - Some Numbers • Admissions per million doses dispensed: nitrofurantoin 617 insulin 182 . . . diuretics 10 benzodiazepines 7 Hallas et al, Br. J. Clin. Pharmacol. 33: 61-68, 1992

9. 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

10. 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)**

11. Clinical Trials: Phase IFirst 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

12. 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

13. Clinical Trials: Phase IIIControlled 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®)

14. Where is clinical research conducted?

15. Catchy acronyms for clinical trials

16. The drug approval process summarized “Phase 0” a new concept Human ‘microdosing’,usually with radiolabeled drugs - useful to predict PK and metabolites

17. 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.

18. Phase IV - Postmarketing Surveillance • Patients in clinical practice - many thousandscross 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 • 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

19. 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.”

20. 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

21. 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

22. Clinical Trials are unlikely to identify rare adverse reactionsExample, 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

23. Detection of a drug-induced (DI) eventCritical Ratio = freq DI event/freq spont event • Incidence in Relative risk to detectcontrol group 2.0 5.0 • 0.0001 3.8*105 3.9*104 • 0.001 3.1*104 # 3.9*103 • 0.01 3.1*103 3.9*102# Means 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.

24. 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

25. Preclinical selection of mibefradil Test system Desired propertyisolated heart no decr. contractility CV in animals no reflex tachycardia GI transit time no constipation P’kinetics in animals long duration BP in SHR decreased BP Modified & adapted from Clozel et al., 1997

26. Clinical trial results with mibefradil • 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’

27. 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 beta-blockers, 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)

28. Drug development - an imperfect system but better than it used to be • 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)

29. Filings for Standard New Molecular Entities Adapted from the Center for Drug Evaluation and Research, Report to the Nation, 2003

30. 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

31. Conditions in patient-initiated discussions prompted by DTC advertising Berndt, E. R. N Engl J Med 2005;352:325-328

32. 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

33. FDA Use-in-Pregnancy Ratings • A - no risk shown in controlled studiesadequate studies fail to demonstrated risk • B - no evidence of risk in humans negative risk in animals or humans • C - risk can not be ruled outhuman &/or animal studies lacking or animals studies show risk • D - positive evidence of riskrisk to human fetus, but benefit may > risk • X - contraindicated in pregnancyrisk to human fetus > benefit

34. Categories of Controlled Substances • I - essentially illegal(research only, special license)the most interesting mind altering substances & political footballs • II - high potential for abusee.g., morphine • III - some potential for abusee.g., Tylenol®#3 • IV - low potential for abuse e.g., midazolam • V - local regulation & low potential for abusecodeine in cough syrup

35. Useful advice………. • Never prescribe a drug you don’t really understand... • Never take a drug you don’t really understand...