In recent years, there has been a growing concern of gender-based differentials and differences in health and pharmacotherapy with reasons yet to be ascertained. There are diseases that are specific to, more prevalent or exhibiting different pathophysiological mechanisms in women necessitating newer ways to enhance gender linked research.

Women's health is traditionally programmed to be associated with reproductive and child health leading to female participation predominantly with research in these areas. However, it is argued that research in non reproductive areas where disease profile is as sustained in women as in men also needs to be encouraged. Ensuring safety of female participants is an extremely important, sensitive and integral aspect of conduct of a clinical study, taking priority over the benefits that society or science would derive from validity of data especially if the product entails specific risks to female patients. Regulated post marketing surveillance is structured around meticulously planned risk minimization programmes to generate data stratified by gender.

Wherever women participation is expected in India, regulatory, ethical, social, cultural and environmental requirements are to be understood and respected by pharma MNCs in global trials more, so with those involving bio-similars, vaccines, epidemiologics and genetics.

Female research participants are broadly considered as either premenopausal or post menopausal. In the premenopausal group or women of child bearing potential (WoCBP) the participant has attained menarche and not undergone successful surgical sterilization with the possibility of an inadvertent pregnancy despite taking adequate protective measures. The aim here is to obviate broad risks and ensuing adverse consequences associated with unintentional harm to the woman herself, to fetus, child and in the long term on fertility and future progeny. Post menopausal population described as those without menses for 12 consecutive months or longer without any other alternative cause, factored with age and quantification of follicle stimulating hormone if on hormone replacement therapy; however, advances in assisted reproductive technologies with alterations to reproductive capacity need to be additionally comprehended.

Clinicians are cautious about the therapeutic class of medications administered in WoCBP group and take educated decisions, preferring safe authenticated drugs. Nonetheless, at times the physician has to face an unconscionable dilemma whether to prescribe or not due to insufficient product information.

Drug safety in women
To enable the unabridged use of pharmaceutical and non pharmaceutical interventions, the role of women participants in clinical experimentation is of paramount importance to assure gender specific analyses, nevertheless seldom performed.

The entity Normal Pregnant Women in clinical trials does not exist. Pregnancy in women is considered a special situation. The physiologic ante partum changes are categorized for treatment purposes into three semesters and post partum for variations that can occur due to pharmacokinetic and pharmacodynamic effects of medications considering hormonal interactions, receptor binding, drug metabolism, vascular, hepatic and renal dynamics and subsequent data assimilated being different from those obtained from the rest of human population with respect to changes in dosage, frequency and toxicity.

As teratogenic effects on fetus by drugs are mostly expected during the first trimester, clinical experimentation is preferred in the 2nd and 3rd trimesters. Postpartum status being equally significant as the infant is being nursed necessitating evaluation of paediatric pharmacology and anticipated effects.

Data collation from pregnant women is insufficient as they get actively excluded from trials by being dropped or discontinued. Accessible safety data in pregnancy status provides wider treatment options to clinicians. This was particularly noted in the recent H1N1 flu pandemic where the highest mortality and morbidity rates were observed in pregnant women with barely any available treatment data. Presently, as benefits of vaccination seem to far outweigh the risks, additional studies on pregnant women following immunization are continuing.

Nonetheless, even information derived from female participation is scarcely updated into the product information labels. On the contrary, studies exclusively with women as target population provide adequate information for confident treatment.

Clinical studies done with pregnant women preferably should consist of longitudinal study designs where she serves as her own control through each of the trimesters with the postpartum period as the control or comparator depending on duration, type and requirements of product therapy.

To an extent excluding pregnant women participants from clinical studies results in women healthcare being compromised by lack of sex-specific information about dosing and unique uses of drugs, devices and biologicals.

Ethics
It is acknowledged that the last word expected from trials is Good Science.
Ethical acceptability of studying women in research depends predominantly on the medical or scientific necessities of the study.

The concerns in premenopausal research participants must be combined with respect for women and their ability to make decisions for themselves and to the fetus following unintended drug exposure. The ever looming shadow of unhappy post marketing experimentation with thalidomide, diethylstilbestrol and Dalkon Shield, have made all concerned to be wary of products even little toxic for humans can when used by WoCBP, induce serious teratogenicity in the neonates to delayed malignant disorders in progeny. Even preclinical studies with these products did not predict or yield relevant human toxicity data on the maternal/placental/fetal unit.

Ethical issues weigh heavily here, with pregnant women being considered as vulnerable population and hence qualifying for greater protection rights to herself and the fetus.

Safety measures
Optimizing and tailoring treatment goals in women are requisite tools; it is envisaged to aid physicians in improving female patient compliance and also to minimize adverse events. Hence personalized dosing to pregnant women to maximize efficacy is a challenge by itself as the available collated data is insufficient.

During trials following judicious inclusion, clear concise instructions and education provided to female patients by clinical investigators on preventive measures to circumvent pregnancy and expedited communication with site personnel if pregnancy is suspected. This information along with extent of follow up of pregnancy or its termination, post natal and neonatal status for study participants is to be elaborated in appropriate trial documents.

Applicable forms of effective contraception measures include established use of but not limited to:

• Oral, injected, hormonal methods.


• Placement of intrauterine devices or intrauterine systems.


• Barrier or preferably double barrier methods with spermicides.


• Surgical male sterilization for more than 6 months.


• Exposure to partners during the study duration - true abstinence inclusive of male subjects whose partners are pregnant and no sperm donation.


• Abstinence by female participants including onset of menses prior to study commencement and following the last dose of trial medication.

The aforementioned details to preferably be made available in product literature.

Pregnancy testing in trials
All pregnancy tests are effective in determining whether a woman is pregnant, however, higher the sensitivity of test earlier the opportunity to detect pregnancy after conception. Patient should not be on fertility drugs.

Both strips and midstream tests based on monoclonal antibody technology detect hormone hCG (Human chorionic gonadotrophin) levels in urine; the detection thresholds range from 20mIU/L to 100mIU/L.

Precautions in interpretation
False negative results are more common than false positives and are primarily due to inaccuracies in timing of the test or carelessness in the procedure or presence of urinary tract infections. A positive result can only be determined within the time interval captured in kit literature. However, to confirm negative results, the complete reaction time is ideal.
The more sensitive and accurate testing for pregnancy is serum beta hCG immunoassay where quantification and detection of levels <10mlU/ml is possible.

Regulatory
Scientific and ethical ambiguity exists regarding female participation in non therapeutic research predominantly in early phase trials with no direct therapeutic benefits; apparently not encouraged to minimize preventable risks as per regulations. The trend now is towards greater regulatory and scientific acceptability of female inclusion in most drug development phases of therapeutic research to accrue gender specific scientific data.

The Schedule Y, Indian GCP and ICMR have provided guidance on female trial participation with due consideration of pregnant and nursing women as special population. If female gender participation in research is expected, then to be cautiously included supported by data accumulated from preclinical species specific reproduction studies and to be designed such that it protects and advances the health and carries no more than minimal risk to the woman, fetus or nursing infant with the object of the research expected to derive new knowledge about drug behavior in fetus, pregnancy and lactation. Clinical studies with products suitable to be used in this special population is permitted where data generated from other subsets of women is unsuitable.

Statutory drug authorities have classified pharmaceutical agents by an assessment of the established risks of causing fetal injury, if it is used as directed by the pregnant mother. It does not include risks conferred by the agents or their metabolites during lactation. Category X indicates evidence of fetal risk which outweigh any benefits.

Some regulatory authorities spearheaded by governmental and non governmental agencies accentuate the need and mandate female participation with cogitated inclusion of pregnant women meeting entry criteria in all phases of research whilst others maintain the cautious norm, safety for all and all for safety approach.

Statistically ensure that registered trials are powered to detect treatment versus gender or other interactions and meta-analyses of completed studies for deeper interpretations of subgroup differences to augment risk-benefit deliberations.

Reporting
The aim as part of investigator responsibilities is to safeguard the health of the individual, fetus or infant from immediate risks and to implement preventive interventions for expected and unexpected adverse outcomes. Authorities determine and estimate risks and also provide margins of reassurance regarding lack of risks.

Pregnancy does not fulfill definitions of AE or SAE. In majority of trials it is an event that needs expedited reporting and in this way is handled as an SAE (preferably on a pregnancy reporting form) unless otherwise mentioned in protocol and with relevance to the scientific objectives being studied and category of test product. In India, specific guidance on pregnancy reporting is unavailable.

The investigator is expected to report information pertaining to the course of the pregnancy, perinatal and neonatal outcomes and in the context of complications of spontaneous abortion, congenital abnormalities is to be considered an SAE.

The significance of data lock procedures to support new drug applications and tying patient pregnancy status as safety information to end of trial procedures need to be discerned.

Pharmacoepidemiology
It includes methods, designs with interpretation of post marketing surveillance involving specific pharmaceutical agents in female populations and utilization patterns with assessments of risk versus benefit in product therapies.

Comparative observational studies or randomized controlled clinical studies are initiated from the information obtained in areas of specific interest and support data stratification with standardization for women across demographics and physiological status for accumulation of sex linked data.

Industry, academia, regulatory maintain registries in the medical product's lifetime as prospective or retrospective dedicated databases collated for normal and abnormal pregnancies, congenital abnormalities, pediatric toxicology etc which are further linked to exposure data sets and additionally ensure dissemination of substantiated data to health care providers.

Pharmacovigilance
In real world setting, sex-linked safety monitoring in post marketing surveillance systems supporting safe, rational and appropriate use of products to diminish drug-related morbidity and mortality. As new drugs are reaching developing countries in greater numbers and more quickly because of funding from several international foundations, pharmacovigilance activities need to be scaled-up as gender specific data in the ethnic population is unavailable.

Spontaneous reports from pregnant women following exposure is the most important source of crucial pregnancy related safety data post authorization. Hence quantified pregnancy including paternal exposures to products is an essential requirement in the regulated country specific periodic safety updated reports from marketing authorization holders along with data evaluation and signal detection for trends in outcomes or specific adverse reactions.

Pharmacogenomics
Clinical trials are positively impacted by excluding those female subjects whose pharmacogenomic screening with appropriate consent would reveal that the drug being tested could be harmful, ineffective, or could predict drug interactions and largely helps in quantification and accurate elucidation of genetic determinants of drug response objectively.

The debate over inclusion of women in research is due to real time and theoretical concerns over effects of treatment on gender, genetic or biological factors and legitimate fears of exposing fetuses, infants or children to investigational products. There is a need to encourage dedicated national gender based comprehensive, accurate and reliable safety monitoring databases.

Enhanced methodologies to maximize extrication of data from research to eliminate dilemmas, discrepancies and disparities concerning women's health would be welcome.


(Author is senior medical advisor, Safety and Pharmacovigilance, Lotus Labs Ltd, Bangalore)