Time to take stock of Indian regulatory guidelines regarding drug use in pregnancy and lactation.

Sir,

On February 9, 2018, valproate was expelled from the first-line antiepileptic category in the UK for pregnant and childbearing age group and reserved for resistant cases only. Controversial opinions exist on the use of valproate in pregnancy. Its use as a bipolar medication is growing, while it is declining in epilepsy treatment in this population. Similar controversies exist for antidepressants, antiretrovirals, misoprostol and many more drugs.[1] This is because of the misinterpretation of A, B, C, D, and X categories of drugs in pregnancy which is continued in India as adoption from the US FDA. Almost 60% of the marketed drugs are placed in single category C. In the definition of category C, drugs with data supporting adverse effects in animals, as well as medications with no data from animal studies, are included. Such type of ambiguity in definitions makes risk–benefit assessment challenging.[2] In another scenario, there are false-positive associations of cleft lip and palate in mice with hydrocortisone, which has not been replicated in humans. On the other hand, false-negative associations also exist where no strong signals are obtained in animal studies, e.g., thalidomide and no teratogenesis in rats. Risk categories are commonly mistaken as an ordered structure, with medications in the same class having an equal threat.[3]

There is much concern among healthcare providers regarding the safety of prescribing drugs during pregnancy and lactation. For the majority of drugs, the labeling should provide relevant information available in a way that enables decision for treatment. The age-old categories A, B, C, D, and X, have, for many years, posed a challenge for doctors by making risk–benefit assessment difficult. This is because these categories are defined not by the severity or incidence of risk but by the amount and quality of available data. That has led to a lot of misinterpretation and misuse of drugs during pregnancy and lactation over the last few decades. Most importantly, it has led to unnecessary avoidance of drugs when the mother would have potentially benefitted, in fear of an unproven effect on the fetus.[2]

The US FDA printed the matter and structure of labeling for human prescription medications and biologics; requirements for pregnancy and lactation labeling mentioned to as the “Pregnancy and Lactation Labeling Rule” (PLLR) in December 2014 which was later amended in 2015. PLLR provides healthcare providers and subjects with relevant information for critical decision-making about the use of drugs when treating pregnant and lactating women. This rule provides complete knowledge about the known risks based on the available data, puts into consideration the disease factors, and also states clearly when no data is available.[4] PLLR works toward eliminating pregnancy risk categories and emphasizes on updating the information from time to time. Section 8.1 and 8.2 deals with risk benefit evaluation during pregnancy and lactation respectively. The section 8.3 which is new to the revised PLLR rule focuses on male and female reproductive potential. It include information on the need for pregnancy check up and contraception before, during or after medication use. It also elaborate on animal and human studies suggesting about an influence on fertility. The revised PLLR has been declared mandatory for implementation worldwide by the FDA from June 2015, and complete implementation is expected to occur over 3–5 years. Overall, PLLR provides a more structured approach to labeling drugs and is undoubtedly the need of the hour for the doctors involved in the care of pregnant and lactating women.[2]

Recruitment of pregnant and lactating mothers is avoided in clinical trials considering them as a vulnerable population. There are specific codes in the USA in the CDER Data Standards Manual like Code 030 which says – A human study is needed to capture and evaluate birth outcomes in women exposed to marketed drugs during pregnancy. Currently Indian drug regulatory does not have a similar provision to address the risk with drug use in pregnancy and lactation. Another robust way of establishing safety and efficacy is by performing the pharmacokinetic pharmacodynamic study in this population because of the physiological differences in pregnant and nonpregnant population. Metronidazole is an example of a drug that was first marketed for use in adults and when found to be used extensively in pregnant population the company then at the request of FDA conducted pharmacokinetic studies to define the kinetics of the drug in this condition. Involvement of all stakeholders such as the pharmaceutical industry and regulatory and healthcare providers is necessary to build a platform on designing advocacy norms and precautions for Indian pregnant and lactating population.[3] Since most of the current drug discoveries happening are carrying this PLLR information on their labels, the import of such medicines for conducting a clinical trial or for therapeutic use needs sound regulatory guidance.[5] Although limitations exist for PLLR such as the omission of over-the-counter drugs and drugs approved before 2001, the replication of this rule in India has tremendous potential to expand the level of care standard and hazards management of pregnant, breastfeeding and childbearing patients in India.[2]

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