Global Regulatory Requirements for Enrollment of Women of Child Bearing Potential in Clinical Trials

MARTA2013 Fall MeetingMary Ellen McNerney (Bristol-Myers Squibb)

Compelling Reasons to Enroll Women of Childbearing Potential (WOCBP) in Early Clinical Trials Women comprise slightly greater than half the

world’s population◦ If you double the number of available patients, you

can often accelerate clinical trial enrollment, thereby reducing development time and latency to treatment of unmet medical needs

Some diseases occur preponderantly in women◦ Autoimmune disorders (RA, LE, Crohn’s, IBD, etc)

Ability to discern gender differences in ADME early in drug development◦ Women have greater lipid, lower muscle stores than

men which may alter drug distribution, efficacy and target organ toxicity

3 Applicable Guidelines1. ICH M3(R2) December, 2009◦ Non-clinical Safety Studies for the Conduct of Human

Clinical Trials and Marketing Authorization for Pharmaceuticals

2. ICH S9 March, 2010◦ Nonclinical Evaluation for Anticancer Pharmaceuticals

3. ICH S6(R1) June, 2011◦ Preclinical Safety Evaluation of Biotechnology-Derived

PharmaceuticalsICH S5(R2) June, 1993 Detection of Toxicity to Reproduction for Medicinal Products and Toxicity to Male Fertility – this guidance deals with scientific content and study designs, not timing of nonclinical studies to support clinical trials

Historically…(c 1997, original M3) Inclusion of WOCBP varied by region◦ Japan: EFDs and female fertility required prior to

enrollment of WOCBP, as well as satisfactory evidence of effective birth control◦ EU: EFDs required prior to Phase I whenever

necessary to enroll WOCBP in SAD, MAD◦ US: EFDs and female fertility required prior to

Phase III. WOCBP “may be included in early, carefully monitored studies without reproduction toxicity studies,” with several provisos: Pregnancy testing prior to enrollment Highly effective contraception Entry after confirmation of menses Continued pregnancy testing and monitoring

M3(R2) 2009 [More] harmonized international agreement regarding timing of

EFDs for small molecules in non-life-threatening indications Cites concern for unintentional exposure of conceptus before

nonclinical data available to permit benefit-risk assessment◦ One approach: Get it all done early “…conduct reproductive toxicity studies to characterize risk…[then] take

appropriate precautions to prevent pregnancy during clinical trials.”

◦ 2nd approach: Prevent pregnancy in clinical trials while you don’t have supporting data “Limit the risk by taking precautions to prevent pregnancy during clinical trials”

Pregnancy testing prior to enrollment Use of highly effective forms of birth control (failure rate < 1% per year) Study entry only after confirmed menses Pregnancy testing throughout trial (and longer for drugs with long half-lives)

N.B. Many companies have the second approach in place, but the number of pregnancies in clinical trials remains surprisingly large

M3(R2) 2009 (cont’d)◦ Some circumstances envisioned for which

WOCBP could be always be enrolled without nonclinical data

“Intensive control of pregnancy risk over short-duration (e.g., 2 weeks) clinical trials”

Patient population is predominantly women Objectives of trial require WOCBP, with sufficient precautions

to prevent pregnancy MOA and/or extent of conceptus exposure well-

understood Placental permeability to mAbs during organogenesis

understood to be low

M3(R2) 2009 (cont’d)◦ Option 6: the expanded Range-finding Study Use of range-finding study with expanded scope

(“appropriate preliminary reproduction toxicity data”) to support inclusion of < 150 WOCBP for treatment durations < 3 months Includes fetal visceral evaluations, in addition to external

evaluations typically done in rf Notion based on low rate of pregnancy (0.1% per menses)

in Phase II clinical trials of this size and duration

◦ If Options 2-6 do not apply: US: EFDs can be deferred until Phase III EU and Japan: EFDs must be completed before

enrollment of any WOCBP

M3(R2) 2009 (cont’d) Female fertility study: all ICH regions permit

inclusion of WOCBP using highly effective contraception in Phase I and Phase II studies without fertility data Drug effects on reproductive tract organs evaluated

histopathologically in repeated-dose tox studies

PPND study: all ICH regions require PPND Study prior to marketing approval

Finally: ALL female reproduction toxicity studies AND standard genotoxicity battery are required for any clinical trial in which highly effective contraception is NOT employed, or in which pregnancy status of enrollees is unknown

S9 2010 Purpose: “…to facilitate and accelerate

the development of anticancer pharmaceuticals [for advanced cancers] and to protect patients from unnecessary adverse effects, while avoiding unnecessary use of animals, in accordance with the 3R principles…”◦ Corollary: perceived benefit/risk may be

skewed for developmental toxicants in advanced cancers

S9 2010: What’s an Advanced Cancer? Considered to be a serious and life-

threatening malignancy◦ Disease is refractory or resistant to available

therapies◦ No available therapies

So, guidance stipulations do not apply to Stage I indications, 1st line therapies, etc.

Guidance applies both to small-molecule and biotechnology-derived moieties that will be used in advanced cancers

S9 2010 (cont’d) “Embryofetal toxicity studies should be available when the marketing

application is submitted.”◦ Studies NOT needed to support clinical trials

Studies NOT needed for genotoxic pharmaceuticals Small molecules: if developmental mortality or teratogenicity confirmed in

a single species, use of second species unwarranted◦ Practical implication: if you can show developmental toxicity in the rat, you’re done.

Biopharmaceuticals: one pharmacologically relevant species is sufficient ◦ Exposure during organogenesis is critical◦ Alternative approaches may include:

Expanded study designs Assessment of placental transfer Literature assessment Consideration of direct and indirect actions of pharmaceutical

◦ Little Big-Pharma experience with submission of literature evaluations or paper arguments or placental transfer data in lieu of a monkey study

S9 2010 (cont’d) Fertility and Early Embryonic Development

study unnecessary to support clinical trials or marketing approval◦ Effects on potential for impaired fertility can be

inferred from [Histopathology] data in repeated-dose toxicity studies

PPND study unnecessary to support clinical trials or marketing approval◦ Presumption of positive risk-benefit◦ Life expectancy of untreated patients frequently

too short for future pregnancy outcome to be of concern

S6(R1) 2011 Original guidance (1997) gave little direction

regarding testing for toxicity to reproduction◦ Allowed that if a class effect well-known and only

NHP is relevant species (e.g. interferons), this may “…obviate the need for formal reproductive developmental toxicity studies.”

MANY questions arose in the interim, specifically with respect to species selection and the use of homologous proteins in rodents

S6(R1) 2011(cont’d) Two Guiding principles

◦ Biotherapeutics are generally highly-specific in their MOAs, and without toxicity that is not extension of pharmacology

◦ Many are active only in NHPs, and there is concern for ethical use of animals before success of drug development program is assured

When WOCBP are included in clinical trials before data on embryo-fetal development available, use highly-effective contraception

If biopharmaceutical only active in NHP and precautions to prevent pregnancy observed, WOCBP may be enrolled without EFD/ePPND◦ Use of clinical candidate preferred

Alternative model (use of homologue or transgenic animal) may be proposed if appropriate scientific justification is provided Timing of such a study not specified

◦ NHP study deferred to coincide with Phase III Report submitted with marketing application

If sponsor cannot commit to rigorous pregnancy prevention measures, complete EFD or interim ePPND report required prior to Phase III

If biopharmaceutical only active in NHP and MOA suggests grave concern for pregnancy outcome, drug should be labeled accordingly and administration to WOCBP avoided◦ No study in NHP warranted under this circumstance

S6(R1) 2011 (cont’d) Species selection is critical to study timing “Pharmacologically-relevant” is the mantra◦ If no relevant species identified, use of homologous

molecules or transgenic models may be considered Timing of EFD-like study not specified Only appropriate for hazard ID, not quantitative risk assessment Since only hazard ID possible, 2 experimental groups (one control and 1

drug-treated) acceptable

◦ If a single pharmacologically-relevant species is identified, it is not necessary to conduct studies in a second species

◦ If clinical candidate is active in rodents and rabbits, EFDs in both species are required Exception: demonstration of developmental mortality or

teratogenicity in one species obviates need for 2nd species Timing of rodent and rabbit studies as per M3

S6(R1) 2011 (cont’d) Fertility assessments◦ If pharmacologically-active in rodents, then S5 should be

adopted Amend study design as appropriate to address immunogenicity,

half-life, etc.◦ Mating “not practical” for NHPs If NHP is only relevant species, use histopathology of

reproductive tract organs from subchronic or chronic toxicity studies to assess potential for effects on fertility If cause for concern, assessments of menstrual cyclicity, sperm, circulating

levels of gonadotropins and sex steroids should be incorporated into study design

If MOA suggests adverse impact on conception or implantation and NHP is only relevant species, consider use of homologous protein or transgenic study Timing not specified

In absence of data, risk to patient communicated through clinical trial management, informed consent, product labeling

S6(R1) 2011(cont’d)

Choice of EFD vs ePPND in NHPs◦ Relevant for mAbs, since carrier-mediated

transport increases throughout gestation Exposure to conceptus low during organogenesis,

but increases to ~ maternal levels at end of pregnancy Implication: EFD, for which dosing limited to GD 20-50, may

not be adequate to characterize effects of drug on fetal growth and development

Final Thoughts on Study Timing to Support Enrollment of WOCBP in Clinical Trials HAs may be open to negotiation

regarding strict interpretation of M3 regarding need for 2 species◦ If drug is active in rodents, and MOA highly

suggestive of developmental toxicity, demonstration of same in rodents may be adequate S9 approach for non-cancer pharmaceuticals◦ Extensive discussions in EU around deferral of

rabbit study, if 2nd species is required, until registration

Phase of Development

Data Needed to Support

Therapeutic Target/Indication

Registrational Filing Developmental toxicitydata from NHP ePPND

Therapeutic proteins activeonly in NHP

EFD studies in 1-2 species (rodents and rabbits)

Life-threatening indications

PPND in Rodents

All other targets and indications

Phase III Fertility and Early Embryonic Development in Rodents

Phase IIPhase I (outpatient)

Tx Duration≥ 3 months in ≥ 150 WOCBP

EFD Studies in 2 species (non-rodent and rodent)

Tx Duration≤ 3 months in ≤ 150 WOCBP

Range-finding studies in 1-2 species

Phase I (inpatient) None