Enhancing the Collection, Analysis & Availability of 
 

Demographic Subgroup Data
 

Barbara Buch, MD 

Chair, 907 Steering committee 

Associate Director of Medicine, FDA/Center for Biologics
 
 What is a biological product?
 
 

 

 

Blood Derivatives 

Whole Blood 

(

Vaccines 

preventive & therapeutic) 

Blood Components 

Worldwide Collaborations 

in Public Health 

Emerging Infectious Diseases 

Counter-Terrorism 

Allergenic 

Products 

Selected 

Devices 

Cell & 

Gene 

Therapies 

Human Tissues 

Xenotransplantation 

products 
 

 

 

 

 

Part I – Report Findings
 

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Clinical trial composition for age, sex and 

race was included in the labeling and/or 

clinical reviews of the five products and 

thus the information is publicly available. 

The issue of subset analyses was 

addressed but in some applications, not all 

subsets were fully analyzed and the 

reasons varied 
 

 

 

Quality Actions
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Modified Clinical and Statistical IND/BLA reviewer 

templates, to include demographic subgroup 

participation and analysis 

Incorporated demographic subgroup analysis in benefit 

risk/review discussion 

Incorporated the importance of demographic subgroup 

data inclusion, analysis, and communication into CBER’s 

New Reviewer Training Course 

Education and training courses for experienced reviewers 

and other staff to better clarify FDA’s data collection 

and analysis expectations related to demographic 

subgroups. 
 

 

 

Quality Actions
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Post market: 

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Strengthened systems and infrastructure for making better use of 

data once products are broadly available on the U.S. market. 

CBER- changes made to e-submission and CDISC programs 

to receive data by subgroups in marketing/licensing 

applications 

CBER Sentinel processes and AERS have incorporated 

demographic subgroup information into those systems to 

enhance analyses 

CBER requests an outcome analysis by sex, age, and 

ethnicity in the final clinical report or annual report
 

Expanding language in labeling to reflect valid notable 

demographic subgroup differences 
 

 

 

 

Participation Action Items-CBER
 Implementing efforts to enhance appropriate use of
 

enrollment criteria in clinical trial protocols
 

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CBER pre-submission documents/meetings with 

Industry to encourage greater demographic subgroup 

representation in clinical trials, subgroup analysis and 

communication of results 

Enhance discussions with sponsors: 

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Enrollment criteria to include all subgroups 

Analysis/trends of outcomes by demographic 

subgroups 

Language added to response letters for presubmission meetings
 
 

 

 

 

 

 

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Guidance Updates
 

•	 W ith CDER and CDRH continue to review, update, 

and/or finalize relevant industry guidance 

ISE final guidance (published 2015) 

Final Guidance for Industry and FDA Staff: Evaluation of 

Sex-Specific Data in Medical Device Clinical Studies. 

(August 2014) 

Draft Guidance for Industry and FDA Staff: Leveraging 

Existing Clinical Data for Extrapolation to Pediatric Uses of 

Medical Devices (April 2015) 

ICH Efficacy/Safety guidelines (ongoing) 
 
 

 

 

Transparency

Lets give them something to talk about
 

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907 Steering Committee 

Barb’s Blogs / Scientific Publications 

AC Public Meetings 

IOM 

Workshops 

Feb 29th Public Meeting 
 

 

 

 

 

 

 

 

 

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Meetings/Workshops
 IOM /OM H Roundtable on the Promotion of Health Equity and the Elimination of Health 

Disparities meeting April 9, 2015 

Workshop on “Clinical Trials: Assessing Safety and Efficacy for a Diverse Population” -- cosponsored by FDA & JHU CERSI December 2, 2015 

Vaccines and Related Biological Products Advisory Committee November 13, 2015 

Open session: discussed considerations for evaluation of the safety and effectiveness of 

vaccines administered to pregnant women to protect the infant 

Cellular, T issue, and Gene T herapies Advisory Committee February 25, 2014, discussed 

“oocyte modification and assisted reproduction for the prevention of transmission of 

mitochondrial disease or treatment of infertility” 

In collaboration with OW H, CBER scientists held a symposium on the thrombosis during 

pregnancy during the T eratology Society Annual meeting. September 2015 

Workshop: New methods to Predict Immunogenicity of Therapeutic Coagulation Proteins 
 

Transparency
 

CBER Pilot
 

To improve the public availability of
 

demographic subgroup data
 

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•

Phase I Process and IT infrastructure 

– W ork process (FY2015) 

Phase II Public Posting Plan 

– launched January 2016 
 

 

Transparency 

For new approved BLAs posted on CBER’s Approval Page 

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts 

Refer to Section 1.1 of the clinical 

review memo for information about 

participation in the clinical trials and 

any analysis of demographic 

subgroup outcomes that is notable 
 

 

 

 

 

 

Transparency
 Pregnancy and Lactation Labeling Final Rule 

•	 CDER/CBER Published Dec 2014 – in effect June 2015 

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Applies to biological products subject to the Physician Labeling 

Rule. vaccines, allergenics and cellular and gene therapies. 

In assessing benefit versus risk and in subsequent counseling of 

pregnant women and nursing mothers who need to take 

– 

medication, 

New: Females and Males of Reproductive Potential subsection 

(8.3),includes information about the need for pregnancy testing, 

contraception recommendations, and information about infertility as 

it relates to the drug 

–	 The PLLR also requires the label to be updated when information 

becomes outdated. 
Research - Pregnancy
 

Non-clinical issues of 

thrombosis in pre gnancy 

Protecting and treating 

mother and ne onate s from 

v e rtical transmission of HBV,

HCV, and CMV during 

pre gnancy 

 

Pregnancy outcome s after

exposure to v accination 

cluding risk of spontaneous

abortion afte r influe nza 

v accine 

in

Influe nza Vaccines and 

Pre gnancy Outcome s 

PK/PD of CBER regulate d 

antibody therapies used 

uring pregnancy to be ne fit

the mother and the baby 

d

safe ty and e fficacy of IGIV

when use d to combat 

infectious disease s during 

pregnancy to be tter

understand transplacental 

transfe r of the antibody

during pre gnancy 

animal mode l of pre gnancy; 

whe n use d at the e nd of 

pre gnancy HBIG may be ne fit

the newborn & help pre v e nt

vertical transmission of 

he patitis B. 
Research - Age/Sex 

Differences
 

blood donors ’ 

travel &expos ure

behaviors by s ex

and ag e: different 

age groups donate

differently; s ample 

= accurate 

population data. 

RISK OF 

VENOUS 

HROM BOEM B 

OLISM AFTER 

GARDASIL 

VACCINATION 

T

 Examine 

diffe rent age 

groups & their

immune 

re sponse to 

influe nza 

v accine w/ &

w/out adjuvant 

Evaluating a 

biomark e r in ­

ne onate s –to 

distinguish who

experience 

thrombotic with

ne onate s with no

events 

Clotting Factor 

Product Us e And 

Same -Day Risk

For Thrombotic 

Adverse Events, 

As Re corde d I n 

Large He alth

Care Database 

 
 

Research - Ethnicity 

Differences 

T he genetic determinants 

of immunogenicity to 

Factor VIII used in the 

treatment of hemophilia A 

Examining different ethnic

groups and their risk

factors with developing

inhibitors to factor VIII 

X-linked bleeding 

disorders in carriers 

(women who carry

mutated genes ) may also

need proper treatment of

bleeding of hemophilia 
 

 

ResearchOutcomes in the Elderly
 Re trospective cohort study of

M e dicare beneficiaries to assess 

the relative effectiveness of high

dose inactivated influenza 

v accine among the elderly. 

Pilot case control study to evaluate

the effectiveness and duration of 

protection of the Herpes Zoster

Va ccine in persons >65+ yrs using

da ta from CMMS and CDC 

First population-based study of

transfusion-re late d a cute lung

injury show ed that elderly persons

receiving blood transfusions in

inpa tient fa cilities a re at 

significantly greater risk of

developing the disorder 

Compa rative effectiveness of high- dose versus standard dose 

influenza vaccines in US residents 

age d 65 years a nd older 

CBER conducte d comparative 

e ffe ctive ness study to compa re 

High-dose and Standard-dose

influenza vaccination in medicare 

population 65 years and older. 

The study suggested that HD is

more e ffective in preventing

influenza infection and influenza 

related hospitalization in elderly 

CBER conducted e ffectiveness 

study to investigate the

effectiveness of Herpes Zoster

vaccina tion in medicare population

65 ye ars a nd older 
 

 

 

 

 

 

 

Observations
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Demographic information is routinely included in submissions 

Many sponsors have presented the results by demographics; if they 

leave it out, we do the calculations and include them in the review 

(descriptive) 

W e look at these factors post hoc in completed phase 3 trials & we 

consider potential safety issues based on demographics in planning 

future clinical trials 

Have considered demographic issues in labeling, in the few 

products that we have labeled 

Vaccines are regularly analyzed by age, and often stratified by 

sex/gender 

–	 Elderly may have a lower response to a vaccine and safety profiles 

could vary by age 

HPV vaccines: studies done by gender/sex 
 

 

 

 

 

 

 

 

Examples
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Ruconest (C1 -esterase inhibitor) showed regional and gender 

differences but they were hard to interpret. This was clearly spelled 

out in the label 

The Factor VIII products are primarily for males, but.... 

Prostate cancer vaccine is indicated for older men 

W e have asked sponsors to include efficacy and safety analyses by 

age, sex, race, and ethnicity in their final study reports. (e.g.) 

Glassia (Alpha-1 Proteinase Inhibitor) 

W e have seen different trends in analyses of deaths by sex with 

Prothrombin Complex Concentrates 

W e have seen differences in the magnitude of the placebo effect 

with C1-esterase inhibitor products between men and women 

(example: recombinant C1-INH) 
Challenges 

50 

45 

40 

35 

30 CBER 

25 Orphan 

Total Cber 20 

15 

10 

5 

0 

2014 2015 20 
 

 

 

 

 

Ongoing Challenges 

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Self identification for sex 

–	 confused with Gender identity 

Self identification for ethnicity 

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there is a lot of missing data on ethnicity (>half) 

Sentinel search on “ethnicity” generated 80 different responses 

Very few products have reached phase 3 or any trial with 

substantial numbers of subjects 

CBER products for small populations/rare diseases Indications 

for diseases with limited subgroup affected (e.g. Hemophilia) 

For >95% effectiveness, the high rate of effectiveness precludes the 

necessity of additional subgroup analysis (e.g. Vaccines) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CBER POSTERS
 Trans place ntal Trans fe r of He patitis B

Ne utralizing Antibodie s during

Pre gnancy in an Animal M ode l:

Implications for Ne wborn and 

M ate rnal He alth; 

Xu Y, Ma L, Zhong Z, Norton MG, Mahmood I,

Zhong L, Zhang P, Struble E

CBER/OCT GT /DCEPT
 

Up clos e and pe rs onal: The ge netic

de te rminants of immunoge nicity to

Factor VIII us e d in the tre atme nt of 

he mophilia A 

Zuben Sauna CBER/OBRR/DHRR/LH 

Efficacy of a Candidate Unive rsal
 

Influe nza Vaccine in M ice of
 

Diffe re nt Age s
 

Mayra Garc ía1 ,2 , J ulia A. Mis plon1, ChiaYun Lo1, Graeme E. Pric e1, Suzanne L.
 C B ER/O CTGT/DC G T a n d Epstein 

C DRH 

A pharmacoge ne tic approach to

immunoge nicity: Implications for

ove rcoming attrition owing to 

de ve lopment of anti-drug antibodie s

during clinical trials us ing a Factor

VIIa analog as a mode l

Zuben Sauna CBER/OBRR/DHRR/LH 

B iomarke rs of immune prote ction of

ge ne tically modifie d Live atte nuate d 

Le is hmania donovani paras ite s in

young and age d mice 

P arna Bhattacharya 

CBER/OBRR/DETTD
 

De ve lopme nt of a mous e mode l to

mimic the re s ponses of fe male and

pre gnant human s ubje cts to avian 

influe nza infe ctions and to e valuate
 

the prote ctive efficacy of pande mic

H5N1 vaccine s ; 

Hang Xie

CB ER/OVRR/DVP/LPRVD
 

Modulatory Effe cts of Proge s terone on

M ate rnal Immunity and The ir

Implications in Pre gnancy-as s ociate d

Sus ce ptibility to Avian Influe nza

Infe ctions in a M ous e M odel addressing 

sex differences in response to avian 

influenza infections Hang Xie

CB ER/OVRR/DVP/LPRVD
 
Thank you !