Drug Safety – Is It Different Drug Safety – Is It Different For Men and Women? For Men and Women?

Emmanuel Olutayo Fadiran, R.Ph., Ph.D.Emmanuel Olutayo Fadiran, R.Ph., Ph.D.Senior Health Program CoordinatorSenior Health Program Coordinator

Office of Women’s HealthOffice of Women’s HealthFood & Drug AdministrationFood & Drug Administration

ACCP 2011ACCP 2011Chicago, ILChicago, IL

September 12, 2011September 12, 2011

DISCLOSUREDISCLOSURE

Emmanuel Olutayo Fadiran, R.Ph., Ph.D., Emmanuel Olutayo Fadiran, R.Ph., Ph.D., Senior Health Program Coordinator, has Senior Health Program Coordinator, has

been working at FDA for the past 18 years been working at FDA for the past 18 years and have no disclosure or conflicts of and have no disclosure or conflicts of

interest.interest.

OUTLINEOUTLINE

Studies/surveys/reports on participation of Studies/surveys/reports on participation of women in clinical trialswomen in clinical trials

Drugs with sex related difference in safetyDrugs with sex related difference in safety

Survey of FDA review of safety analysis- Survey of FDA review of safety analysis- 2007-20092007-2009

BASIC PREMISEBASIC PREMISE

WOMEN AND MEN ARE WOMEN AND MEN ARE NOTNOT THE SAME THE SAME

Problems with terminology – Problems with terminology –

– Sex vs. genderSex vs. gender

Sex- biologicalSex- biological

Gender- societal/culturalGender- societal/cultural

1992 GAO Report1992 GAO Report

1992 GAO STUDY1992 GAO STUDY

~25 % of drug manufacturers ~25 % of drug manufacturers do notdo not deliberately deliberately recruitrecruit women women

> 60% of drugs, the > 60% of drugs, the representation of women was representation of women was lessless than in the disease population than in the disease population

EnoughEnough women to detect gender-related women to detect gender-related differencesdifferences

Data were Data were not analyzednot analyzed for gender differences for gender differences

Low representation of women:Low representation of women:– Early phase (Phase 1) studiesEarly phase (Phase 1) studies– Some therapeutic areas, Some therapeutic areas, e.g.,e.g., cardiovascular cardiovascular

2001 GAO Report2001 GAO Report

2001 GAO STUDY2001 GAO STUDY

NDAs include NDAs include appropriate numbersappropriate numbers of of women women

Sponsor & FDA Sponsor & FDA analysis by sexanalysis by sex was was NOTNOT consistently presentconsistently present

Participation of women is similar to that Participation of women is similar to that of men of men except :except :

– Earliest phasesEarliest phases of clinical trialsof clinical trials

– Some therapeutic areas (Some therapeutic areas (e.ge.g., ., cardiovascular)cardiovascular)

““Being male or female is an Being male or female is an important basic human important basic human variable that affects health variable that affects health and illness throughout the and illness throughout the lifespan.”lifespan.”

Study of sex differences is Study of sex differences is evolvingevolving into mature science into mature science

BarriersBarriers to the advancement of to the advancement of knowledge about sex … exist knowledge about sex … exist and must be and must be eliminatedeliminated

BOTTOM LINE:BOTTOM LINE: Sex Matters Sex Matters2001 IOM Report:2001 IOM Report:

GAO Report on Prescription Drugs GAO Report on Prescription Drugs WITHDRAWNWITHDRAWN from from

the US Market 1997-2000the US Market 1997-2000

Drug Type of Drug Patient Population

Primary Health Risk

Prescription Drugs with Evidence of Greater Health Risks In Women Pondimin Appetite

suppressant Women Valvular heart

disease Redux Appetite

suppressant Women Valvular heart

disease Rezulin Diabetic Women Liver failure

Lotronex Gastrointestinal Women Ischemic colitis Seldanea Antihistamine Women and Men Torsades de Pointes Posicor Cardiovascular Women and Men Lowered heart rate in

elderly women and adverse interactions with

26 other drugs Hismanal Antihistamine Women and Men Torsades de Pointes Propulsidb Gastrointestinal Women and Men Torsades de Pointes

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

Fracture Risk - ADOPTFracture Risk - ADOPT

A Diabetes Outcome Progression TrialA Diabetes Outcome Progression Trial (ADOPT) (ADOPT) was a randomized controlled clinical trial in type was a randomized controlled clinical trial in type 2 diabetes patients comparing the efficacy and 2 diabetes patients comparing the efficacy and safety of rosiglitazone to metformin and safety of rosiglitazone to metformin and glyburide. glyburide.

Patients were titrated to the maximum effective Patients were titrated to the maximum effective daily dose of hypoglycemic drugs. Patients were daily dose of hypoglycemic drugs. Patients were well matched at baseline and the median well matched at baseline and the median duration of follow-up was 3.3 years (glyburide) duration of follow-up was 3.3 years (glyburide) and 4 years (rosiglitazone and metformin)and 4 years (rosiglitazone and metformin)

FRACTURE RISK ADOPT StudyFRACTURE RISK ADOPT Study

AUTHOR et al NEJM. 2006;355 (23):2427-43GSK Dear HealthCare Professional Letter, February 2007

RosiglitazoneRosiglitazonen (%) n (%)

rate/100PYrate/100PY

MetforminMetforminn (%) n (%)

rate/100PYrate/100PY

GlyburideGlyburiden (%) n (%)

rate/100PYrate/100PY

MALEMALE 32 (3.95)32 (3.95) 29 (3.36)29 (3.36) 28 (3.35)28 (3.35)

1.161.16 0.980.98 1.071.07

FEMALE*FEMALE* 60 (9.30)60 (9.30) 30 (5.09)30 (5.09) 21 (3.47)21 (3.47)

2.742.74 1.541.54 1.291.29

*Majority of fractures in upper arm (humerus), hand or foot. Number with hip or spine fractures was similar among the 3 treatment groups.

Product LabelingProduct Labeling

Pioglitazone: Pioglitazone: The fracture rates in women were twice as The fracture rates in women were twice as compared to placebo in type 2 diabetes compared to placebo in type 2 diabetes patients at 3 years of follow up in a patients at 3 years of follow up in a randomized clinical trial and no difference was randomized clinical trial and no difference was observed in men observed in men

Rosiglitazone and Pioglitazone: Rosiglitazone and Pioglitazone: Advise that the fracture risk in treating female Advise that the fracture risk in treating female patients should be considered and attention patients should be considered and attention given to maintaining bone health in given to maintaining bone health in accordance to current standards of care accordance to current standards of care

Cardiovascular Risk - TedisamilCardiovascular Risk - Tedisamil

Class III antiarrhythmics Class III antiarrhythmics

Indication: rapid conversion of new onset atrial Indication: rapid conversion of new onset atrial fibrilation/flutterfibrilation/flutter

Causes QT prolongationCauses QT prolongation– Torsades de Pointes (TdPs) is a major safety Torsades de Pointes (TdPs) is a major safety

concernconcern– Increased risk in women:Increased risk in women:

Bradycardia, hypotension, ventricular Bradycardia, hypotension, ventricular arrhythmias arrhythmias

Thromboembolic events ?Thromboembolic events ?

Cardiovascular Risk - TedisamilCardiovascular Risk - Tedisamil

Cardiovascular and Renal Drugs Cardiovascular and Renal Drugs Advisory Committee Meeting, Advisory Committee Meeting, December 12, 2007 December 12, 2007

PK similar between men and womenPK similar between men and women

Meta analysis of 5 Phase III studies Meta analysis of 5 Phase III studies – Good efficacy in men and womenGood efficacy in men and women

Incidence of TdP in women and Incidence of TdP in women and menmen

DEATHSDEATHS

TedisamilTedisamil PlaceboPlacebo

ALLALL 0.6%0.6%

6/9316/931

0.6%0.6%

3/4703/470

MaleMale 0.2%0.2%

1/5281/528

0.9%0.9%

2/2312/231

FemaleFemale 1.2%1.2%

5/4035/403

0.4%0.4%

1/2391/239

AC DecisionAC Decision

Sponsor proposed sex-specific Sponsor proposed sex-specific dosing regimendosing regimen

““Should tedisamil be approved for Should tedisamil be approved for the conversion of atrial the conversion of atrial fibrillation?” fibrillation?”

–Advisory Committee members Advisory Committee members voted unanimously voted unanimously NONO

Cardiovascular Risk - DofetilideCardiovascular Risk - Dofetilide

Class III antiarrhythmics Class III antiarrhythmics

Indication: rapid conversion of new onset atrial Indication: rapid conversion of new onset atrial fibrilation/flutterfibrilation/flutter

Dose-Response and Concentration Response for increase Dose-Response and Concentration Response for increase in QT Interval is directly related to dofetilide dose and in QT Interval is directly related to dofetilide dose and plasma concentrationplasma concentration

A linear relationship between mean QTc increase and A linear relationship between mean QTc increase and dofetilide dose was also seen in patients with renal dofetilide dose was also seen in patients with renal impairment in patients, with ischemic heart disease, and in impairment in patients, with ischemic heart disease, and in patients with supraventricular and ventricular arrhythmias.patients with supraventricular and ventricular arrhythmias.

Sex differences in the PK and Sex differences in the PK and PD of DofetilidePD of Dofetilide

ParameterParameter Women Relative to MenWomen Relative to Men

Clearance Clearance 12-18% lower12-18% lower

Plasma ConcentrationPlasma Concentration 14-22% higher14-22% higher

Risk of Torsade de Risk of Torsade de Pointes (TdP)Pointes (TdP)

3 times3 times

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

Sex Analyses Survey: MethodsSex Analyses Survey: Methods

List of NME drugs and biologics approved between 1/2007 and List of NME drugs and biologics approved between 1/2007 and 12/2009 obtained from Drugs@FDA12/2009 obtained from Drugs@FDA

Accessed FDA Medical and Statistical Reviews on Drugs@FDAAccessed FDA Medical and Statistical Reviews on Drugs@FDA

Sex analyses by safety was tracked using these coding criteria:Sex analyses by safety was tracked using these coding criteria: Sex Analysis Coding

Coded As: Criteria

Presentation of Sex AnalysisHas at least a one-line summary of safety or efficacy analysis by gender/sex

Exploratory Sex Analysis

Analysis followed by a qualifying state that analysis was “exploratory” or “not statistically powered to draw conclusions”

Conclusive Sex Analysis

Analysis had conclusions showing there is/ is not sex differences observed. No comments on the statistical power of analysis.

No Sex AnalysisAnalysis could not be located within FDA reviews

ResultsResults

68 total NMEs approved 2007-68 total NMEs approved 2007-20092009

57 NDAs57 NDAs11 BLAs11 BLAs

7 NME NDAs were excluded7 NME NDAs were excluded

No NME BLAs were excludedNo NME BLAs were excluded

Safety Analysis for NDAs N=50

Categories N (%)

Presentation of Sex Analysis 39 (78%)

Exploratory Analysis 5

Conclusive Analysis 34

No Sex Analysis 11 (22%)

Safety Analysis for BLAs N=11

Categories N (%)

Presentation of Sex Analysis 7 (64%)

Exploratory Analysis 2

Conclusive Analysis 5

No Sex Analysis 4 (36%)

Drugs (NDAs)

*Of the sex analyses presented, 13% (safety) are exploratory

Presentation of Sex Analyses in FDA Reviews

Sex Analysis Presented (Safety)

No Sex Analyses

22%

Sex Analyses Presented

78%

Exploratory Analyses Only*

13%

Biologics (BLAs)

No Sex Analysis

36% Exploratory Analysis Only*

29%

Sex Analysis Presented

64%

Sex Analysis Presented (Safety)

* Of the sex analyses presented, 29% (safety) are exploratory

Presentation of Sex Analyses in FDA Reviews

Limitations/Future DirectionsLimitations/Future Directions

Sex analyses coding criteria dependent on Sex analyses coding criteria dependent on limited information provided limited information provided – Unclear if statistical analyses are Unclear if statistical analyses are

conductedconducted– Dependent on exact wording of Dependent on exact wording of

reviewer’s commentsreviewer’s commentsFurther survey on sponsor’s presentation Further survey on sponsor’s presentation of sex analyses in clinical trial reports of sex analyses in clinical trial reports required.required.

Typical Review ExamplesTypical Review Examples

NDA21-856 - FebuxostatNDA21-856 - Febuxostat

The overall incidence of adverse events during dosing was higher in females than males (63% 63% and 25%,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).

Typical Review ExamplesTypical Review ExamplesNDA 22-074 - Lanreotide acetate InjectionNDA 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%.

Typical Review ExamplesTypical Review Examples

NDA 22-256 - MilnacipranNDA 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: whereas 0% 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.

ConclusionsConclusions

““Sex” as variable matters in drug Sex” as variable matters in drug developmentdevelopment– Complicated and confounded by: Complicated and confounded by:

Weight, body fat, renal function, CLcrWeight, body fat, renal function, CLcr

Rethink paradigm of one size fits allRethink paradigm of one size fits all– Sex effect and “Personalized medicine”Sex effect and “Personalized medicine”

““Right drug, right patient, right disease, right Right drug, right patient, right disease, right dose”dose” – David Kessler, GWU, February 21, 2007– David Kessler, GWU, February 21, 2007

ReferencesReferencesU.S. General Accounting Office. Women’s Health: FDA needs to ensure more study of 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. gender differences in prescription drug testing, HRD-93-17. October 29, 1992; 1-39. http://archive.gao.gov/d35t11/147861.pdfhttp://archive.gao.gov/d35t11/147861.pdf,,U.S. General Accounting Office. Women’s Health: Women sufficiently represented in U.S. General Accounting Office. Women’s Health: Women sufficiently represented in new drug testing, but FDA oversight needs improvement. 2001:1-36. new drug testing, but FDA oversight needs improvement. 2001:1-36. http://www.gao.gov/new.items/d01754.pdfhttp://www.gao.gov/new.items/d01754.pdf..US General Accounting Report - US General Accounting Report - Drug Safety: Most Drugs Withdrawn in Recent Years Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks for WomenHad Greater Health Risks for Women - - http://www.gao.gov/new.items/d01286r.pdfhttp://www.gao.gov/new.items/d01286r.pdf Avandia (rosiglitazone) Product LabelingAvandia (rosiglitazone) Product Labelinghttp://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=AVANDIA&x=17&y=14http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=AVANDIA&x=17&y=14 Actos (pioglitazone) Product Labeling Actos (pioglitazone) Product Labeling http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=actoshttp://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=actosFDA Advisory Committee ref for tedisamilFDA Advisory Committee ref for tedisamil

http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4327b2-01-solvay-backgrounder.phttp://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4327b2-01-solvay-backgrounder.pdfdfhttp://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4327b2-02-fda-backgrounder.pdfhttp://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4327b2-02-fda-backgrounder.pdfhttp://www.fda.gov/ohrms/dockets/ac/07/minutes/2007-4327m-02-minutes-final-tedisamilhttp://www.fda.gov/ohrms/dockets/ac/07/minutes/2007-4327m-02-minutes-final-tedisamil-dec12.pdf-dec12.pdf

Tikosy Product Labeling: Tikosy Product Labeling: http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=tikosynhttp://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=tikosyn Parekh A, Fadiran EO, Uhl K, Throckmorton, DC, Adverse effects in women: Parekh A, Fadiran EO, Uhl K, Throckmorton, DC, Adverse effects in women: implications for drug development and regulatory policies. implications for drug development and regulatory policies. Expect Rev. Clin Expect Rev. Clin PharmacolPharmacol. 4(4), 453-466 (2011). 4(4), 453-466 (2011)

AcknowledgementsAcknowledgements

Rita Poon, ORISE Fellow, OWH, FDARita Poon, ORISE Fellow, OWH, FDA

Onyeka Otugo, ORISE Fellow, OWH, FDAOnyeka Otugo, ORISE Fellow, OWH, FDA

Ameeta Parekh, R&D Director, OWH, Ameeta Parekh, R&D Director, OWH, FDAFDA

Norman L Stockbridge, Director, DCRP, Norman L Stockbridge, Director, DCRP, CDER, FDACDER, FDA