Drug Safety – Is It Different For Men and Women?

1. Drug Safety – Is It Different For Men and Women? Emmanuel Olutayo Fadiran, R.Ph., Ph.D. Senior Health Program Coordinator Office of Women’s Health Food & Drug Administration ACCP 2011 Chicago, IL September 12, 2011

2. DISCLOSURE Emmanuel Olutayo Fadiran, R.Ph., Ph.D., Senior Health Program Coordinator, has been working at FDA for the past 18 years and have no disclosure or conflicts of interest.

3. OUTLINE • Studies/surveys/reports on participation of women in clinical trials • Drugs with sex related difference in safety • Survey of FDA review of safety analysis- 2007-2009

4. BASIC PREMISE • WOMEN AND MEN ARE NOT THE SAME • Problems with terminology – • Sex vs. gender • Sex- biological • Gender- societal/cultural

5. 1992 GAO Report

6. 1992 GAO STUDY • ~25 % of drug manufacturers do not deliberately recruit women • > 60% of drugs, the representation of women was less than in the disease population • Enough women to detect gender-related differences • Data were not analyzed for gender differences • Low representation of women: • Early phase (Phase 1) studies • Some therapeutic areas, e.g., cardiovascular

7. 2001 GAO Report

8. 2001 GAO STUDY • NDAs include appropriate numbers of women • Sponsor & FDA analysis by sex was NOT consistently present • Participation of women is similar to that of men except : • Earliest phasesof clinical trials • Some therapeutic areas (e.g., cardiovascular)

9. “Being male or female is an important basic human variable that affects health and illness throughout the lifespan.” Study of sex differences is evolving into mature science Barriers to the advancement of knowledge about sex … exist and must be eliminated BOTTOM LINE: Sex Matters 2001 IOM Report:

10. GAO Report on Prescription Drugs WITHDRAWN from the US Market 1997-2000 aSeldane-D was also withdrawn from the market. Terfenadine was the active ingredient in both Seldane and Seldane-D; Seldane-D also contained the decongestant pseudoephedrine. bPropulsid remains minimally available on a patient-by-patient basis for those with severely debilitating conditions. Source: GAO analysis in GAO-01-286R Drugs Withdrawn From Market

11. Fracture Risk - ADOPT • A Diabetes Outcome Progression Trial (ADOPT) was a randomized controlled clinical trial in type 2 diabetes patients comparing the efficacy and safety of rosiglitazone to metformin and glyburide. • Patients were titrated to the maximum effective daily dose of hypoglycemic drugs. Patients were well matched at baseline and the median duration of follow-up was 3.3 years (glyburide) and 4 years (rosiglitazone and metformin)

12. FRACTURE RISK ADOPT Study *Majority of fractures in upper arm (humerus), hand or foot. Number with hip or spine fractures was similar among the 3 treatment groups. AUTHOR et al NEJM. 2006;355 (23):2427-43 GSK Dear HealthCare Professional Letter, February 2007

13. Product Labeling • Pioglitazone: The fracture rates in women were twice as compared to placebo in type 2 diabetes patients at 3 years of follow up in a randomized clinical trial and no difference was observed in men • Rosiglitazone and Pioglitazone: Advise that the fracture risk in treating female patients should be considered and attention given to maintaining bone health in accordance to current standards of care

14. Cardiovascular Risk - Tedisamil • Class III antiarrhythmics • Indication: rapid conversion of new onset atrial fibrilation/flutter • Causes QT prolongation • Torsades de Pointes (TdPs) is a major safety concern • Increased risk in women: • Bradycardia, hypotension, ventricular arrhythmias • Thromboembolic events ?

15. Cardiovascular Risk - Tedisamil • Cardiovascular and Renal Drugs Advisory Committee Meeting, December 12, 2007 • PK similar between men and women • Meta analysis of 5 Phase III studies • Good efficacy in men and women

16. Incidence of TdP in women and men

17. DEATHS

18. AC Decision • Sponsor proposed sex-specific dosing regimen • “Should tedisamil be approved for the conversion of atrial fibrillation?” • Advisory Committee members voted unanimously NO

19. Cardiovascular Risk - Dofetilide • Class III antiarrhythmics • Indication: rapid conversion of new onset atrial fibrilation/flutter • Dose-Response and Concentration Response for increase in QT Interval is directly related to dofetilide dose and plasma concentration • A linear relationship between mean QTc increase and dofetilide dose was also seen in patients with renal impairment in patients, with ischemic heart disease, and in patients with supraventricular and ventricular arrhythmias.

20. Sex differences in the PK and PD of Dofetilide

21. Cardiovascular Risk - TdPs • There are well documented differences in QT effect and incidence of TdPs between males and females. • Women tend to have longer QT intervals between puberty and at least 55 years of age, perhaps due to lower parasympathetic tone, or estrogen- or metabolic-related changes. • Women are more susceptible to malignant arrhythmias than men, and there is an increased incidence of TdPs among women when treated with Class III antiarrhythmics, which is a consistent finding with all Class III agents approved for atrial fibrillation. • The reason for the female predominance in drug-induced TdP remains unclear.

22. Sex Analyses Survey: Methods • List of NME drugs and biologics approved between 1/2007 and 12/2009 obtained from Drugs@FDA • Accessed FDA Medical and Statistical Reviews on Drugs@FDA • Sex analyses by safety was tracked using these coding criteria:

23. Results • 68 total NMEs approved 2007-2009 • 57 NDAs • 11 BLAs • 7 NME NDAs were excluded • No NME BLAs were excluded

26. Presentation of Sex Analyses in FDA Reviews Drugs (NDAs) *Of the sex analyses presented, 13% (safety) are exploratory

27. Presentation of Sex Analyses in FDA Reviews Biologics (BLAs) * Of the sex analyses presented, 29% (safety) are exploratory

28. Limitations/Future Directions • Sex analyses coding criteria dependent on limited information provided • Unclear if statistical analyses are conducted • Dependent on exact wording of reviewer’s comments • Further survey on sponsor’s presentation of sex analyses in clinical trial reports required.

29. Typical Review Examples • NDA21-856 - Febuxostat The overall incidence of adverse events during dosing was higher in females than males (63% and 25%, respectively). Similarly, the overall incidence of study drug-related adverse events was higher in females than males (54% and 13%, respectively). Female subjects had higher incidences of constipation and headache (38% and 13%, respectively) compared to male subjects (4% and 0%, respectively).

30. Typical Review Examples • NDA 22-074 - Lanreotide acetate Injection The percentage of males and females who reported > I TEAE (Treatment-Emergent Adverse Events) was similar: 178/205 (87%) and 178/211 (84%), respectively. The most commonly reported TEAE, diarrhea, was reported by a larger percentage of males (41%) than females (34%). Loose stools were also reported by a larger percentage of males (8%) than females (3%). However, some other GI disorders, such as nausea and constipation, were each reported by a larger percentage of females (nausea 16%, constipation 12%) than males (nausea 6%, constipation 4%). Cholelithiasis was reported by a larger percentage of males (26%) than females (15%). Urinary tract infections, arthralgia, and alopecia were all reported by a larger (>5%) percentage of females than males. A notably larger percentage of females (16%) reported TEAEs in the metabolism and nutrition disorders SOC compared with males (5%). The most common HLT within this SOC, diabetes mellitus (including subtypes), had a slightly higher incidence in females (5%) compared with males (2%). For other individual PTs, the difference between males and females was < 5%.

31. Typical Review Examples NDA 22-256 - Milnacipran Because of the observation of genitourinary AEs in the male population, the label should indicate that milnacipran should be used with caution in male patients with a history of dysuria, prostatic hypertrophy, prostatitis, or other lower urinary tract obstructive disorders. Notably, increased blood pressure was more frequent among male patients taking milnacipran versus placebo: whereas0% of male placebo patients experienced increased blood pressure, 8.7% and 12.5% of the MNL 100 mg/day and 200 mg/day patients, respectively, experienced this AE. Also, increased blood pressure was more frequent in male milnacipran-treated patients than female milnacipran-treated patients. Among females taking MLN 100 mg/day and 200 mg/day, the incidence of increased blood pressure was 3% and 2.2%, respectively.

32. Conclusions • “Sex” as variable matters in drug development • Complicated and confounded by: • Weight, body fat, renal function, CLcr • Rethink paradigm of one size fits all • Sex effect and “Personalized medicine” • “Right drug, right patient, right disease, right dose”– David Kessler, GWU, February 21, 2007

33. References • U.S. General Accounting Office. Women’s Health: FDA needs to ensure more study of gender differences in prescription drug testing, HRD-93-17. October 29, 1992; 1-39. http://archive.gao.gov/d35t11/147861.pdf, • U.S. General Accounting Office. Women’s Health: Women sufficiently represented in new drug testing, but FDA oversight needs improvement. 2001:1-36. http://www.gao.gov/new.items/d01754.pdf. • US General Accounting Report - Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women - http://www.gao.gov/new.items/d01286r.pdf • Avandia (rosiglitazone) Product Labeling http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=AVANDIA&x=17&y= 14 • Actos (pioglitazone) Product Labeling http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=actos • FDA Advisory Committee ref for tedisamil http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4327b2-01-solvay-backgrounder.pdf http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4327b2-02-fda-backgrounder.pdf http://www.fda.gov/ohrms/dockets/ac/07/minutes/2007-4327m-02-minutes-final-tedisamil-dec12.pdf • Tikosy Product Labeling: http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=tikosyn • Parekh A, Fadiran EO, Uhl K, Throckmorton, DC, Adverse effects in women: implications for drug development and regulatory policies. Expect Rev. Clin Pharmacol. 4(4), 453-466 (2011)

34. Acknowledgements • Rita Poon, ORISE Fellow, OWH, FDA • Onyeka Otugo, ORISE Fellow, OWH, FDA • Ameeta Parekh, R&D Director, OWH, FDA • Norman L Stockbridge, Director, DCRP, CDER, FDA