Table 4

Research gaps for over-the-counter (OTC) oral contraception

Clinical, programmatic, values-based or human rights question		Current WHO recommendation	Strength of recommendation	Source or quality of evidence	Critical human rights and equity considerations	Ideal study design(s)	Feasibility and practical constraints	Alternative study design	Methodological issues arising in the alternative study design
Benefits versus harms	PICO: should OTC contraception be made available without a prescription?	OTC oral contraception should be made available without a prescription.	Strong.	Very low.	Privacy and confidentiality; accessibility.	RCT conducted in LMIC with inclusion of outcomes to measure accessibility, privacy and confidentiality.	As a strong WHO recommendation exists, it would be unethical to repeat an RCT of the effectiveness of the intervention.	Repeated cross-sectional surveys (can be targeted to specific subgroups or of women in the general population including adolescent girls and young women) attending pharmacies to evaluate privacy and confidentiality and choice to obtain OTC contraception over time.	Selection bias: women who participate in the survey may have fewer concerns regarding privacy and confidentiality than those who would refuse to participate, limiting generalisability.
	Are there quality differences between OTC oral contraception medication and prescribed oral contraception medication?	Not applicable.		GDG.	Not applicable.	This is a quality assessment concern and requires laboratory analysis and is outside the scope of this article. WHO guidelines for national regulatory authorities exist to guide national regulatory control to ensure substandard products are not made available and that dosages are correct (see https://www.who.int/medicines/areas/ quality_safety/quality_assurance/GoodRegulatory_ PracticesPublicConsult.pdf).
	What are the optimal ways to provide advice on switching to different oral contraception or using other contraceptive options (eg, via text messaging, in person in pharmacy)?	Not applicable.		GDG.	Accessibility and informed decision making.	Comparative effectiveness research to compare different types of methods to provide advice.	A controlled trial that may or may not be randomised is feasible. Identification or development of modes of health literacy will be required prior to testing in a controlled manner. In LMIC, pharmacy technicians or cashiers may provide advice instead of pharmacists that requires consideration when planning real-world studies.		Fidelity bias: delivery of health advice is dependent on mode of advice. If given by pharmacists, community health workers or technicians, then monitoring the fidelity of the intervention will ensure the rigour of the results. Outcomes must include a measurement of accessibility such as requests for and uptake of advice.
	What adverse events arise from providing oral contraception OTC?	Not applicable.		GDG.	Acceptability, informed decision making and non-discrimination.	Convenience sample and cross-sectional survey of women obtaining OTC contraception at pharmacies to elucidate if they have experienced adverse events related to the OTC nature of the contraception.	This is a feasible study design.	Not applicable.	Selection bias: such a sample would only include women who are willing to provide information and who feel sufficiently confident to voice their concerns; women who have already experienced stigma or who fear it are less likely to return to the pharmacy and so are less likely to be represented in the sample.
Values and preferences	What are the values and preferences of women living in low-income and middle-income countries related to OTC oral contraception?	Not applicable.		GDG and survey.	Accessibility, privacy and confidentiality, and non-discrimination.	Qualitative study using key informant interviews with women seeking and/or using contraception and who live in LMIC regarding their values and preferences to elucidate their experiences and observations. A question regarding receipt of appropriate screening for contraindications will be essential to include.	This is a feasible study.	Not applicable.	Selection bias: as with all qualitative studies, participants are purposively selected. However, this is an advantage in this study design as those women who have considered this issue will have rich experiences and observations to share.
Human rights and equity	Will women of all ages be able to access OTC oral contraception? What barriers remain in the healthcare sector?	Not applicable.		GDG.	Availability, accessibility and non-discrimination.	Unannounced standard patient (simulation) study where women of different ages pose as users wishing to procure OTC contraception in different settings, regions and countries.	This is a feasible study design.	While this design is feasible, current obstacles to conducting standard patient research include automated electronic medical records and creation of believable identities. However, this should be less relevant for OTC studies than medical practice studies where simulation is widely used.	Measurement error: the presentation and responses of the 'standard user' may differ between scenarios and settings leading to overestimating or underestimating the accessibility of the OTC contraception. This can be addressed by ensuring adequate training for 'standard users' and developing templates for different responses.
Acceptability	What do healthcare providers know, think and feel about provision of OTC oral contraception, especially in low-income and middle-income settings?	Not applicable.		Survey.	Accessibility, privacy, the right to seek, receive and impart information.	Online global cross-sectional survey of healthcare providers with delivery through relevant organisations.	In many settings of deprivation, and especially in LMIC, online accessibility is limited by costs, inadequate technology and lack of knowledge on how to use tools.	Focus groups in purposively sampled healthcare provider populations and regions. Focus groups are most suitable to drive conversations and elicit responses among participants with shared lived experiences and is less confrontational as the aim is not to gather in-depth personal experiences but assess current cultural and social norms, practices and concerns with respect to OTC contraception. Specific questions can be directed regarding attitudes towards vulnerable populations, for example, trans-men and bisexual women.	Social acceptability bias: given that experiences are shared in a group, there may be a reluctance to disclose stigmatising behaviours; however, development of semistructured interview questions in consultation with local healthcare providers to best reflect local beliefs for interrogation can reduce this bias. In addition, a skilled focus group leader can create a safe space for disclosure.
Resource use	Who bears the cost of OTC oral contraception – is the cost shifted from the health system to the user?	Not applicable.		GDG.	Accessibility.	Regional patient costing study using cross-sectional survey of women obtaining OTC contraception at pharmacies to determine 'user cost pathway' (including transport; loss of income) and identify financing sources (eg, user pays, tax-based or contributory health insurance scheme pays).	This is a feasible study.		Generalisability: the results of any costing study will be specific to the context; however, the method of data collection can be replicated in other regions to determine locally specific costs. Measurement bias: much of the data will be dependent on participant recollections (recall bias may be a risk) and their own assumptions about what constitutes opportunity cost, for example.

GDG, Guideline Development Group; PICO, Population, Interventions, Comparison and Outcomes; RCT, randomised controlled trial.