Assessing Risk in Drug Development

1. Assessing Risk in Drug Development David M. Benjamin, Ph.D. Clinical Pharmacologist & Toxicologist Adjunct Assistant Professor - Tufts Medical School Fellow, American Academy of Forensic Sciences (Toxicology) Fellow, American Society for Healthcare Risk Management Fellow, American College of Clinical Pharmacology Fellow, American College of Legal Medicine

2. Goals of the Presentation • Provide Criteria for Assessing Risk in Drug Development • Describe Theories of Drug Product Liability • Examine Omniflox, Baycol and other Recent Drug Withdrawals • Identify Reasons for Drug Withdrawal • Review Criteria for “Adequate” labeling

3. What Got Everything Started? • The Institute of Medicine issued: To Err is Human which reported that 44,000 - 98,000 patients died each year as a result of “Medical Error” (e.g., medication errors, surgical errors, missed diagnoses) • At an estimated cost to the US economy of $17-$29 billion

4. Major Findings of the IOM Study • Based on two reports from three states: New York (1984), Utah and Colorado (1992) • NY study sampled 30,000 charts from 51 state hospitals and found: • 3.7% of pts suffered injury severe enough to disable them or prolong hospitalization • 58% of these injuries were due to error; 13.6% were fatal

5. Major Findings of the IOM Study-2 • The 98,000 number was extrapolated from the NY study, based on the number of hospitalizations for 1997 • Based on reports from Utah and Colorado (1992) • 15,000 charts were sampled and a value of 44,000 deaths was extrapolated from these data • The IOM report has been criticized by one of the investigators, Troyen Brennan, MD, JD, MPH of the Harvard School of Public Health

6. Drug Product Liability:Murphy’s Law Rules • “Often, however, the benefits to the many come at a high cost to the few, for there are increasingly more opportunities for mishaps, not only in the manufacturing process, but also in the marketing and use of the finished products.” Page Keeton, Former Dean, U. of Texas School of Law, (Michigan Law Review, 1966)

7. What About Investigational Drugs During Development? • Chemical • Animal Pharmacology • Animal Toxicology • Clinical Phases I-III: 2,500-5,000 patients only detects ADRs of 1/1000 (0.1%) • Post-Marketing: hundreds of thousands to millions

8. Types of Adverse Drug Reactions (ADRs) Frequently Encountered • Overmedication • Side Effect • Secondary Effect • Allergic • Idiosyncratic • Drug-Drug Interaction • Investigational Drugs - Fewer pts. studied; less info available to IRBs; e.g., Investigator’s Drug Brochure

9. Evaluating ADRs for Causation • Does alleged ADR: (1) follow a reasonable temporal sequence from drug administration • Does alleged ADR represent a known effect of the drug? • Could the alleged ADR be caused by: (1) the patient’s pathophysiological (clinical) condition or (2) an intercurrent illness? • Could alleged ADR be caused by: (1) prior exposure to another agent or (2) concomitant medication?

10. Evaluating ADRs for Causation -2 • Is there a prior History of Sensitivity? • What were the: Dosage, Frequency and Route of Administration? • What was the patient’s Cardiac, Pulmonary, Hepatic and Renal Status? • Was the patient receiving any Concomitant Medications, OTC meds, herbals or alternative medical products? • Was suspect drug D/C’d? Was suspect drug restarted? With what effects on ADR?

11. Theories of Drug &Device Product Liability: • Defective Warning (Failure to Warn) • Inadequate Testing (Animal or Human) • Overpromotion (Lack of Fair Balance) • Defectively Designed Drug or Device(Unfit for intended purpose) • Adulterated or Contaminated Drug

12. Communication of Information Pharmaceutical Company ---warns--> Physician of known adverse effects Physician serves as “Learned Intermediary” for patient Physician provides patient with Informed Consent Including reasonablyforeseeable, materialrisks Once fully informed, the patient either: accepts treatment or states informed refusal

13. VicariousDefendants in Drug & Device Product Liability Suits • Pharmaceutical Manufacturer is Primary, vicarious defendants include: • Physician Prescribing Medication • Distributor • Pharmacist Dispensing Medication • Nurse Administering Medication • Hospital Employing MD, Reg.Ph., or RN • Apparent or ostensible agents of entity or medical school, e.g., IRB members

14. Defenses for Vicarious Defendants • Not negligent, or negligence was not a “Proximate Cause” of injury to patient (e.g., Bad Outcome) • Cannot warn when not informed or misled • Cross-Claim against manufacturer • Subrogation claim by insurance company • Claim for injury to MD’s reputation see: Washington State Physicians Ins. Exch & Ass’n v. Fisons Corp. 858 P.2d 1054 (Wash. 1993)

15. Legal Theories of Liability, aka What the lawyer says to the . . . • Physician: “Shouldn’t have prescribed it” • Nurse: “Shouldn’t have administered it” • Pharmacist:“Shouldn’t have dispensed it” • Hospital: “Shouldn’t have had it in your formulary ” • IRB: “Should have monitored more closely or not approved protocol”

17. Federal Food, Drug, and Cosmetic Act 1938 • Replaced US Pure Food and Drug Act of 1906 • Enacted as a result of the 1937 sulfanilamide crisis • Ensured that: (1) Foods were pure and wholesome, and produced under sanitary conditions, and that (2) Drugs were safe for their intended use (i.e., not adulterated).

18. Chloramphenicol - Approved 1949 • June 1952 JAMA article describes aplastic anemia - sometimes fatal • Jan 1967 Cal Med Assoc & Dept of Health reported an incidence of aplastic anemia of: 1:25,000 in chloramphenacol users vs 1:524,000 in the general population (21X) • Lesson to be learned: Post-Marketing Surveillance is essential to identify rare, previously unrecognized ADRs

19. Thalidomide 1960 • FDA’s Dr. Frances Kelsey will not approve thalidomide for US market • Mass Torts on teratogenic effects postponed till Bendectin/Daubert • 1962 Harris-Kefauver Amendment to FDCA required: (1) animal testing prior to human administration, (2) filing of an IND, and (3) manufacturer must prove efficacy (in addition to safety) - NAS/NRC DESI Studies

20. 1970s DES IUDs DPT/MMR 1980s Oraflex, Zomax, Suprofen Generic Drugs Bendectin 1990s L-Tryptophan - EMS Omniflox - 5-month life Toradol - 5-day labeling Imitrex - First-Year Effect Silicone Breast Implants Fen-Phen - “Off-Label” use Duract - Where is Dr. Kelsey when we still need her? Post-1960s Withdrawals We Have Known and Loved

21. Omniflox (temofloxacin) - PM • Introduced: Jan 1992 • First Rx: February 24 • Voluntarily withdrawn: June 9th - 15 weeks • US Clin Trials 4,600 pts • Mkt’d in 8 countries Est. 300,000 pts rec’d drug worldwide

22. Post-Marketing fewer than 300,000 pts 1,700 non-fatal ADRs reported to FDA 54 cases of Acute Renal Failure, 113 cases of hemolytic anemia 60 deaths, 25-50 may be related; Globe 1/94 Pre-Marketing 4,261 pts Incidence > 1% N,V,D, headache, rash, itching Labs: Incr. BUN & creatinine Renal Failure <0.1% Pre- vs Post- Marketing Adverse Drug Reaction Reports

24. Recent Withdrawn Drugs • Posicor - too many interactions • Rezulin - liver toxicity • Raxar - cardiac arrhythmias • Propulsid - too many interactions • Seldane/ Hismanyl - drugs inhibit metabolism--> - long QT syndrome • Rotashield - infant bowel obstruction • Lotronex - off Nov 2000 GI ADRs & deaths; Re-instituted 2002 w/pt FU • Baycol (are other “statins” to follow?)

26. Why are Drugs Withdrawn From the Market? • Examples: Posicor, Propulsid, Seldane, and Hismanyl • Removed because of too many drug-drug interactions • Manufacturers & FDA tried to minimize interactions by revising labeling - BUT • How do physicians view (and use) labeling?

27. FDA Studies on Practitioners’ Views About Drug Labeling • 1992 Focus Groups • Oct 1993-March 1994: FDA-sponsored phone interview surveys of office-based MDs to determine: • How physicians perceive & use drug labeling, and • How labeling could be made more useful

28. “Survey Said:” • Office-based MDs used labeling primarily to answer specific questions, rather than as a general educational tool • Labeling is typically consulted after a prescribing decision has been made • Physicians wanted: important information summarized in the front of labeling, and • More graphs, larger print, abstracting of important data

29. Re: Clinical PharmacologySection Survey Said: • Among the least useful section • Information in this section is used less often than other labeling information • Physicians wanted it “moved toward the end of labeling”, and • Important data from Clinical Pharmacology Section should be put under other sections like “Special Populations” or “Drug Interactions”

30. Revising Labeling Will Not Reduce Drug-Drug Interactions • Labeling is not read • Dear Dr. Letters are not read • See Yarrow v. Sterling Drug Inc, (on a subsequent slide) regarding Aralen (chloroquine) and labeled retinal damage

31. Where’s the Proof ? • Cisapride (Propulsid) withdrawal • Marketed August 1993 • By 1995, 5 million OutPt Rxs and FDA had received reports of: 34 cases of torsade de pointes 23 cases of prolonged QT interval including 4 deaths • 1995 “Black Box” warning added to labeling contraindicating use in pts also receiving drugs that block the CYP 3A4 enzymes, e.g. macrolides, “conazole” antifungals, & indinavir/ritonavir for HIV

32. More Proof • 1998 “Black Box” warning expanded to contraindicate concomitant use of agents that caused prolongation of QT interval due to reports of serious arrhythmias, e.g., class IA or III antiarrhythmics, tricyclic anti-depressants, and antipsychotics, or in pts with “other conditions” that predispose to cardiac arrhythmias, e.g., vent. arrhythmia, CHF, ASHD, electrolyte imbalance, renal failure and respiratory failure.

33. Still More Proof • June 26, 1998 - FDA circulated “Press Release” and manufacturer sent “Dear Healthcare Professional” letter to 800,000 MDs informing them of the changes in the labeling • July 2000 - Manufacturer terminated marketing of cisapride in US • December 20, 2000 JAMA 284:3036-3039: Smalley et al reviewed regulatory history of cisapride in Contraindicated Use of Cisapride Impact of FDA Regulatory Action

34. Smalley, Shatin, Wysowski, et al • Analyzed number of pts. at three centers who received cisapride when it was contraindicated • Received cisapride July 1997 - June 1998 (pre-warning revision) vs. • Received cisapride July 1998 - June 1999 (post-warning revision) • Pre-Warning Year 7/97-6/98: 26%, 30% & 60% • Post-Warning Year 7/98-6/99: 24%, 28% & 58%

35. Smalley, Shatin, Wysowski, et al • Conclusions: • “There was no material reduction in . . . use at any of the study sites following FDA regulatory action, which included a black-box warning . . . and a Dear Health Care Professional letter” page 3038 • “. . . no material change in contraindicated use even in the group most likely to be affected by the regulatory action” - pts. beginning new cisapride use.

36. Smalley, Shatin, Wysowski, et al • Conclusions: • “ . . . despite the prominent publication of case reports, label changes, and Dear Health Care Professional letters . . .” • “ . . . need to develop more effective methods for modifying practice to reflect new information about a drug’s risks and benefits.”

37. Ditto for Metformin • Metformin marketed for Type 2 DM in 1995 with “black box” warning regarding lactic acidosis • Contraindications included: renal dysfunction and CHF • In 2000, 25 million Rxs for metformin • Horlen, Malone, Dennis et al (letter in JAMA 287:2504-5) performed retrospective chart review of pts. who received metformin at UNC outpatient pharmacy between Jan 1, 2000 - Sept 30, 2000.

38. Metformin (continued) • Metformin was prescribed twice or more for 241 pts. - 100 charts randomly selected • 22% of pts. had either CHF or renal dysfunction; 14 CHF, 5 renal dysfunction, 3 had both CHF and renal dysfunction • Only 2 pts. had documentation in the medical record considered metformin contraindications • “. . . it is difficult to determine whether clinicians are aware they are prescribing metformin against a black-box warning.”

39. Yarrow v. Sterling re: Aralen Where the doctor is inundated with the literature and product cards of the various drug manufacturers . . . a change in the literature or an additional letter intended to present new information on drugs to the doctor is insufficient. The most effective method employed by the drug company in the promotion of new drugs is shown to be the use of detail men; thus, the Court feels that this would also present the most effective method of warning the doctor about recent developments in drugs already employed by the doctor, at no great additional expense. Yarrow v. Sterling Drug, Inc. 263 F. Supp. 159, 1963

40. What ADRs will this Drug Have? • Look to animal studies • Examine other drugs of the same pharmacologic or chemical class • Review SBA of other similar drugs • Toxicity is the interaction of frequency and severity, e.g., Severe but infrequent = OK, and Mild but common = OK • True frequency cannot be determined before marketing because “n” is too small

41. Assessing ADRs -1 Severity MildModerateSevere|<--------------------50%-------------->|100% Nausea, More Than Life- Rash? Annoying Threatening Red & Itchy vs. SJS/TEN

42. Assessing ADRs - 2 Frequency Rare: <1/10,000, e.g.,chloramphenacol & blood dyscrasias Rare, but life-threatening Frequent: >1/100, e.g.,headache & dry mouth Frequent, but not serious

43. Characteristics of Ideal Drug • Novel pharmacologic action or treats condition for which no acceptable alternative exists • Higher Therapeutic Index than other drugs in its class • Lower frequency & severity of reported reactions • Manufactured inexpensively • Secondary or multiple uses

44. What are the Most Common Processes Associated with Medication Errors? • Physician ordering: 39-49% • Nursing administration: 26-38% • Transcription error: 11-12% • Pharmacy dispensing error: 11-14% Source: Bates et al JAMA 1995;274(1):29-34 & Leape et al JAMA 1995;274(1):35-43.

45. Portrait of a Poor Prescription What is the name of the first drug written on this prescription? See next slide for discussion.

46. The Correct Drug was . . . • Final Answer:Isordil. NotPlendil,which was dispensed and caused fatal hypotension for which both the MD and RPh were held jointly liable for almost $500,000.

47. Why Computerize? • MD computerized order entry decreased serious medication errors 55% and • Potential undetected Adverse Drug Experiences (ADE) declined 84% • Bates et al JAMA 1998;280:1311-1316

48. Transcription Errors • Transcription Error • Data Entry Error • Verification Error Vigilance

49. Transcription Errors - 2 ConfusionOver:Drug Names orHandwriting • Larocin 250 vs. Lanoxin 0.250 (Larocin changed to Larotid after mix-up) • enalapril vs. Elderpryl • Lamisil vs. Lamictal

50. The “Name Game”: Risk Management Strategies • Select drug names that are not easily confused with other marketed products: e.g., Losec 50 mg vs. Lasix 50 mg, ultimately Losec changed to Prilosec • Packaging shoulddistinguishbetween different dosage strengths of the same drug • Size, shape and color of different dosage strengths of the same product should make it easy to tell the difference