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Target product profiles for novel medicines to prevent and treat preeclampsia: An expert consensus



Preeclampsia and eclampsia are a leading cause of global maternal and newborn mortality. Currently, there are few effective medicines that can prevent or treat preeclampsia. Target Product Profiles (TPPs) are important tools for driving new product development by specifying upfront the characteristics that new products should take. Considering the lack of investment and innovation around new medicines for obstetric conditions, we aimed to develop two new TPPs for medicines to prevent and treat preeclampsia.

Methods and findings

We used a multi-methods approach comprised of a literature review, stakeholder interviews, online survey, and public consultation. Following an initial literature review, diverse stakeholders (clinical practice, research, academia, international organizations, funders, consumer representatives) were invited for in-depth interviews and an online international survey, as well as public consultation on draft TPPs. The level of stakeholder agreement with TPPs was assessed, and findings from interviews were synthesised to inform the final TPPs. We performed 23 stakeholder interviews and received 46 survey responses. A high level of agreement was observed in survey results, with 89% of TPP variables reaching consensus (75% agree or strongly agree). Points of discussion were raised around the target population for preeclampsia prevention and treatment, as well as the acceptability of cold-chain storage and routes of administration.


There is consensus within the maternal health research community on the parameters that new medicines for preeclampsia prevention and treatment must achieve to meet real-world health needs. These TPPs provide necessary guidance to spur interest, innovation and investment in the development of new medicines to prevent and treat preeclampsia.


Hypertensive disorders of pregnancy are responsible for approximately 14% of maternal deaths globally, 99% of which occur in low- and middle-income countries (LMICs) [1,2]. Preeclampsia and eclampsia affect 4.6% and 1.4% of pregnant women respectively and account for the majority of maternal deaths and stillbirths due to hypertensive disorders of pregnancy [3]. The underlying aetiology of preeclampsia is incompletely understood; however, it involves abnormal placental development, imbalance in placental angiogenic factors and a pro-inflammatory response leading to uncontrolled maternal hypertension accompanied by either maternal organ failure (usually kidney or liver dysfunction), neurological symptoms and/or fetal growth restriction [4].

There are currently few effective medicines for the prevention and treatment of preeclampsia. In women at risk of preeclampsia (such as women with diabetes, chronic hypertension or a previous history of preeclampsia), low-dose aspirin can reduce the risk of preeclampsia by 10–20% [5]. For women living in regions with low calcium intake, high-dose calcium supplementation can also prevent preeclampsia [6]. In women who develop preeclampsia, anti-hypertensive medications can prevent severe complications, such as stroke or heart failure [7]. Magnesium sulfate is recommended for women with preeclampsia with severe features to prevent or treat eclamptic seizures [8], though some health care professionals lack confidence or knowledge in how to use magnesium sulfate, or consider it a complex or high risk medication to use due to side effects [9]. While birth of the baby and delivery of the placenta can cure preeclampsia, it can still occur postpartum. In light of the global burden and significant morbidity and mortality caused by preeclampsia, there is an urgent need to not only improve implementation of the few available medicines, but also to identify new agents that can prevent or treat it. However, previous research has identified considerable under-investment in in pharmaceutical research specific to maternal health conditions, including preeclampsia [10,11].

The Accelerating Innovation for Mothers (AIM) project was established in 2020 by Concept Foundation, with funding support from the Bill & Melinda Gates Foundation. The AIM project has co-ordinated a number of parallel research activities, including mapping the maternal health medicines development pipeline; identifying the scientific, financial, legal and regulatory barriers to maternal health medicines research; and developing new target product profiles (TPPs) for priority conditions [12].

TPPs are an important resource for funders, researchers, product developers, manufacturers and regulators [13]. They guide product developers on the characteristics required to meet clinical and public health needs. They inform research and development (R&D) strategies, help frame product dossiers, streamline communication with regulatory agencies, and help funders set targets [14]. Therapeutics approved by the US Food and Drug Administration (FDA) that addressed a pre-specified TPP have been linked to more rapid regulatory review [15]. WHO and UNICEF have a number of TPPs publicly available to stimulate development for a range of health products, including vaccines for endemic diseases (such as COVID-19, herpes simplex and malaria), point-of-care diagnostic tests (tuberculosis, yellowfever and HIV), devices for newborn care as well as antibiotics and therapeutics for neglected diseases [16,17]. Despite 295,000 maternal deaths and 1.9 million stillbirths occurring worldwide each year, WHO’s Health Product Profile Directory has no TPPs for obstetric conditions. In this study, we used evidence synthesis, interviews, surveys and expert consultations to develop new TPPs to understand the requirements needed to be achieved to drive innovation in medicines for preeclampsia prevention and treatment.


A TPP describes the minimum and preferred (or optimal) characteristics of a target product, such as clinical indication, target population, desired efficacy, safety, formulation/presentation and stability and storage [18]. We prepared a study protocol on TPP development, which was informed by methods used in recent TPPs for HIV cures and sexually transmitted infection diagnostic tests, and adopted the five-step process used by Lewin et al. [1921] This protocol was reviewed and approved by the Alfred Ethics Committee for Human Research (project number 108/21), and formal consent was obtained from all participants prior to their participation.

Step 1: Initial drafting phase

The AIM project convened a multi-disciplinary expert advisory group, comprising 11 experts from research, obstetrics, patient advocacy, programs implementation, social enterprise, donors, WHO and global health systems with diversity in gender and geographical location. In consultation with this group, developing TPPs for preeclampsia was prioritised amongst five conditions (postpartum haemorrhage, preterm birth, fetal growth restriction and fetal distress), as well as the development of separate TPPs for 1) agents for preventing preeclampsia in women at increased risk; and 2) agents to treat women with preeclampsia.

We then sought to answer the following questions: What would the intended use-case scenario be for prophylactic and therapeutic medicines for preeclampsia? What are the key variables that would need to be considered for TPPs for new medicines to prevent and treat preeclampsia, and what would be the acceptable minimum and preferred targets for each of these variables? Through consultation and literature review, intended use-case scenarios were developed which were revised in subsequent project phases (Box 1). As a guiding principle, given the considerable burden of preeclampsia affecting women in low- and middle-income countries (LMICs), we specified that a primary focus of the TPPs were to drive development of medicines that could be used safely and effectively for women living in limited-resource settings. For example, variables would need to meet the temperature and humidity stability, and route of administration that are practical in low-resource settings. We collated TPP templates and guidance produced by several reputable organizations (FDA, Gates Foundation, WHO, PATH and others) [13,18,22] and developed a TPP template with 21 domains. We conducted literature reviews and developed draft minimum and preferred targets for each domain, along with additional annotations including the rationale and supporting evidence.

Box 1. Use case scenarios for TPPs in prevention and treatment of preeclampsia

Prevention of preeclampsia:

An affordable drug that can be administered to pregnant women identified as being at increased risk of developing preeclampsia. The drug will prevent the development of preeclampsia, have a good safety profile, can be commenced early in pregnancy (i.e., before 20 weeks’ gestation) and can be continued throughout pregnancy, as required.

Treatment of preeclampsia:

A therapeutic agent that can be administered by skilled health personnel to pregnant women diagnosed with preeclampsia of any severity, accompanied by monitoring of maternal and fetal well-being in antenatal care settings. The therapeutic agent will delay or prevent maternal disease progression, and ideally improve outcomes for the baby.

Step 2: International stakeholder survey

In parallel with the stakeholder interviews, we conducted an international online stakeholder survey using the same version of the TPPs. We used the approach of Pelle et al in developing TPPS for new point-of-care diagnostic tests [23]. The survey was conducted using the online survey platform Qualtrics ( and was pre-tested on three individuals prior to launch. Respondents were asked to rate their agreement with the minimum and preferred targets for each domain using a Likert scale (1 equals strongly disagree and 5 equals strongly agree). Optional comments were invited for each domain.

The population of interest for the survey was professionals working in the field of maternal and perinatal health. This includes clinicians, researchers, funding agency staff, international public organization staff, programme implementers, policymakers, representatives of consumer advocacy organizations and other relevant maternal health systems stakeholders. Diverse representation from high-, middle- and low-income countries was sought. Survey invitations were sent to approximately 270 individuals using several databases: 1) AIM project database of relevant maternal health R&D experts; 2) a database of all individuals who had participated in WHO maternal and perinatal health guideline development groups in the past 12 years; [24] and 3) members of the WHO Multi-Country Survey on Maternal and Newborn Health research network [25]. To increase participant diversity, we distributed the survey through other clinician-researcher networks and listservs, including the Cochrane Pregnancy and Childbirth network and the Perinatal Society of Australia and New Zealand. The study protocol pre-specified a minimum of 50 responses per domain to evaluate the degree of consensus. We defined agreement as <25% of respondents selecting disagree or strongly disagree for a specific variable.

Step 3: Stakeholder interview phase

We identified 39 stakeholders from clinical, research, academia, international organizations, funder backgrounds, as well as consumer representatives, with a particular interest on preeclampsia and eclampsia. This sample size was selected to include numerous participants in all stakeholder groups and to ensure gender and geographical diversity. Inclusion criteria for participants was that they had experience in preeclampsia research or clinical practice, maternal medicines development, procurement, or implementation. Stakeholders were identified from a database of individuals who have participated in WHO maternal and perinatal health guideline development, an AIM project database of preeclampsia, maternal medicine and maternal programs implementation experts, and other salient clinical, research, advocacy, and professional networks (such as the International Federation of Gynecology and Obstetrics, the International Confederation of Midwives and the Perinatal Society of Australia and New Zealand). Stakeholders were selected in such a way as to ensure appropriate expertise for the topic of interest, with diversity of gender, geographical and technical expertise.

Stakeholders were initially contacted via email by a member of the research team (AM) and invited to participate in an interview. The goal of these interviews was to seek their input on use-case scenarios and minimum and preferred targets for each TPP domain, across both profiles. Stakeholder interviews were semi-structured through use of a pre-tested interview guide (S1 Appendix). Interviews included discussing the TPP domains sequentially, with particular emphasis on those relevant to their area of expertise or interest. For example, we focused interviews with obstetricians on target population, clinical efficacy, safety, administration route, among others and programme implementors on stability and shelf life, product presentation, affordability and WHO prequalification. We explicitly sought interviewee’s views on applicability across different country contexts. We asked participants to contextualise their feedback on the TPPs in terms of what they considered to be areas of disagreement with current text, and “major” and “minor” issues for revision or clarification in future versions of the TPP.

Interviews were conducted between April–June 2021, over Zoom by an AIM project researcher; they commenced with obtaining informed consent and lasted approximately 60 minutes. All interviews were conducted in English and audio- and video- recorded with permission. Participant feedback on the TPPs was captured through reflexive field notes and cross referenced with the recordings when needed. Participants were invited to submit further written comments after the interview if they wished.

Step 4: Public consultation

The draft TPPs were made available online for public comment via the Burnet Institute and Concept Foundation websites. The call for public consultation was disseminated via the Burnet Institute Twitter account. The public consultation period lasted approximately 4 weeks (concurrent with the international online survey) and was disseminated via social media.

Step 5: Synthesis and finalisation

We used a qualitative content analysis approach to analyse the interviews [26], aiming to identify the major and minor issues with the TPP domains, and any challenges to implementing or using the TPPs in practice for product development. We used combined directed and summative content analysis approach, meaning that we used our experience with TPP development and issues related to TPP development to develop an initial coding structure (directed), followed by counting and comparisons of major and minor issues with TPP domains (summative). Issues identified by the interview participants were then classified into key themes and “major” or “minor” concerns. The results of the international online survey were analysed descriptively, with a particular focus on areas where consensus was not reached, defined as variables with >25% of respondents indicating they disagreed or strongly disagreed. Variables where consensus was not achieved were modified based on feedback from expert interviews and survey respondent’s comments. The final drafts were shared with the AIM expert advisory group for final comments before finalisation and publication.


Overall, 23 stakeholders (15 females and 8 males) participated in interviews between April–August 2021. Interviewees were from Africa, Asia/Pacific, Europe, USA and South America (Fig 1A), and included 10 obstetrician/researchers, two neonatologists, two drug development researchers, one WHO staff member, two staff of funding organisations, two midwives, two medicines procurement experts, and two women with lived experience of preeclampsia.

Fig 1. Stakeholders’ distribution by WHO global regions.

The proportion of stakeholders who participated in the (A) interviews (n = 23) and (B) survey (n = 46), in each of the WHO global regions. AFR = African region (yellow), AMR = Region of the Americas (blue), SEAR = South-East Asian region (light green), EUR = European region (red), EMR = Eastern Mediterranean region (dark green), WPR = Western Pacific region (black).

Survey and public consultation results

The survey was active for 31 days and 46 responses were received. Respondents were across all WHO geographical regions (AFR 19.6%, AMR 27.5%, EUR 15.7%, SEAR 11.8%, WPR 23.5%, EMR 2.0%; Fig 1B). Different professions were represented, including researchers (44.7%), clinicians (doctor, midwife or nurse, 23.4%), epidemiologists or public health specialists (10.6%), staff or consultants of a national or international NGOs (6.4%), staff of funding agencies (6.4%), employee or consultants of a normative body or civil society organisation (2.1%) or other (including educator, research student and combined clinician/researchers, 6.4%).

Survey results showed high agreement (>75%) across most domains for both TPPs (Fig 2). For preeclampsia prevention, agreement was less than 75% for both the minimum and preferred targets for companion diagnostics; for the minimum targets for administration and stability/shelf-life; and for the preferred target for volume estimates (Fig 2A and 2B). For preeclampsia treatment, agreement was less than 75% for the minimum and preferred targets for population unlikely to be treated; for the minimum targets for stability and shelf-life; and for the preferred target for treatment adherence (Fig 2C and 2D). One comment was received via the public consultation website.

Fig 2. Survey responses.

Results from international stakeholder survey (n = 46). Percentage of respondents that strongly agreed (dark green), agreed (light green), were neutral (grey), disagreed (orange) or strongly disagreed (red) in response to the minimum and preferred variable in the TPPs for new medicines to prevent (A = minimum criteria, B = preferred criteria) and treat (C = minimum criteria, D = preferred criteria) preeclampsia. Consensus was considered agreement greater than 75% (black dotted line).

Findings from stakeholder interviews and survey

Responses to the survey showed a high level of agreement with the target population definition for both prevention (90.2%) and treatment (96.3%). However, a major theme identified during interviews was whether the target population for preeclampsia prevention should be women with identifiable risk factors for preeclampsia versus a population-wide intervention targeting all pregnant women. Some interviewees felt a population-level approach was needed considering the difficulties in accurately predicting preeclampsia [27]. Other interviewees felt that a population-wide intervention required a very high safety profile (complicating or prolonging drug development) and may not be acceptable—most women will not develop preeclampsia, and a population-level prophylaxis approach has significant resource implications. In the TPP for drugs to treat preeclampsia, many interviewees disagreed with the inclusion of women indicated for immediate delivery in the population unlikely to be treated, citing the risk of post-partum preeclampsia. This was consistent with the survey results showing 29.6% of respondents either disagreed or strongly disagreed with the minimum and preferred requirements for population unlikely to be treated.

The feedback from the expert interviews on stability and shelf-life, particularly the inclusion of cold chain as a minimum acceptable target also strongly aligned with high disagreement (24% and 34.4%) in the survey for those domains in both TPPs. Many interviewees, particularly those with experience working in LMICs, highlighted the challenge of maintaining cold chain in these settings. Given the greater burden of preeclampsia in LMICs, ease of transport and storage, as well as stability in hotter or humid conditions is a priority [1]. However, other interviewees maintained that cold chain was an acceptable minimum requirement in order to not limit innovation of novel biological technologies, such as monoclonal antibodies or siRNA therapies [28].

In the TPP for medicines to prevent preeclampsia, many interviewees indicated that they were not comfortable with injectables (i.e., intramuscular or intravenous administration) being included as a minimum requirement for administration, highlighting the greater cost and access barriers if a preventive medicine required injection. Similar to the inclusion of cold chain as acceptable as a minimum in the stability/shelf-life variable, some interviewees felt it was important to include injectable administration as an eligible route of administration within the minimum criteria, so as to not limit the potential innovation around novel biological prevention agents [28]. In all cases, interviewees stated that if injectable was to be included in the minimum requirement, the frequency of injection was vital to its acceptability, with most agreeing that a long-lasting (>1 month) injectable medicine was potentially preferable to once daily oral medication. In addition, multiple interviewees stated that adding administration by non-invasive routes should be considered in both profiles, including options like inhaled, transdermal and vaginal administration. There was some disagreement from other interviewees regarding the inclusion of vaginal administration in specific populations of women. Many interviewees felt that the vaginal route offered benefits over other modes of administration, including localized drug delivery to the uterus, avoiding systemic side-effects, and increased ease of administration compared to injection. In contrast, some interviewees did not support the inclusion of vaginal administration, stating that for some women this would be unacceptable.

In the TPP for medicines to prevent preeclampsia, survey respondents did not reach consensus for the minimum and preferred requirements for companion diagnostics. In contrast, most interviewees agreed with the requirements specified for companion diagnostics. Stakeholders from LMICs specifically highlighted the importance of no special tests being needed to accompany use of the preventive medicine, as this could become a barrier to use in low-resource settings. However, two interviewees proposed that use of newer biomarker tests be included as part of assessing risk factors for preeclampsia. A minor issue identified with both TPPs was that the volume estimates were based on current use of preeclampsia medicines. Multiple interviewees expressed that volume estimates should be based on the incidence of preeclampsia and its risk factors rather than current use of medicines, given the inability to accurately assess current usage of medicines for preeclampsia.

Finalisation of TPPs

Following synthesis of findings from stakeholder interviews and surveys, the study group agreed that the target population for prevention of preeclampsia would remain as “women at increased risk of preeclampsia” (Table 1). In the TPP for medicines to treat preeclampsia, “women indicated for immediate delivery” was removed from the women unlikely to be treated (Table 2). Text acknowledging post-partum preeclampsia was also added throughout the TPPs. In both TPPs, the inclusion of cold-chain storage was removed from the minimum and preferred requirements and replaced with acceptability of cold-chain for biologicals only. Additional non-invasive administration routes—including transdermal, inhaled, and vaginal routes—were added to the minimum and preferred formulation, dosage and administration.

Table 1. Target product profile for medicines to prevent preeclampsia.

Table 2. Target product profile for medicines to treat preeclampsia.


Although TPPs have been widely used to stimulate innovation for high-burden health conditions (such as infectious diseases), these are the first TPPs to be developed for new obstetric medicines. Through extensive consultation with a wide variety of experts and stakeholders, we have defined the key characteristics that new medicines to prevent and treat preeclampsia should take, with an emphasis on meeting the needs of women living in LMICs. These TPPs will guide researchers, product developers and industry partners to achieve improvements in current therapies available to women at risk of and with preeclampsia.

During stakeholder interviews we identified disagreement on whether a population-wide (i.e. all pregnant women) or a targeted (i.e. a subset of pregnant women, such as women at increased risk) intervention is likely to be a more effective strategy for preventing preeclampsia. Predicting who will develop preeclampsia accurately is challenging—screening for preeclampsia using clinical risk factors, as proposed by the National Institute for Health and Care Excellence (NICE) and the American College of Obstetricians and Gynecologists (ACOG) have poor predictive value. The NICE guidelines have a detection rate of 41% and 34% for preterm and term preeclampsia respectively, whereas the ACOG guidelines have a detection rate of only 5% of preterm and 2% term preeclampsia [39,40]. This means 59–98% of women who develop preeclampsia are not identified with these screening algorithms. Some improvements in preeclampsia prediction algorithms have been made, particularly with the inclusion of biomarkers [41] however as these are not yet widely used—particularly in LMICs—they were not included as a minimum requirement in these profiles. A further consideration is that most of the promising candidates currently being investigated for prevention of preeclampsia would not be feasible as a population-wide intervention [28]. Preeclampsia diagnostics may themselves be a strong candidate for new TPPs in the future [42].

A clear challenge to addressing the global burden of preeclampsia is the need for more “end-to-end” thinking [12]. That is, ensuring that the medicines development pipeline, from pre-clinical research through to Phase III trials and implementation, is aligned with the real-world contexts that clinicians and women face in preventing and managing preeclampsia, particularly the challenges of low-resource settings. In the context of developing TPPs, these challenges were evident in our data related to stability, shelf-life and formulation variables. While novel candidates such as siRNA therapies and monoclonal antibodies are promising, the need for cold-chain transport and storage will likely limit their feasibility in many LMICs. This problem has been well-described in the context of postpartum haemorrhage [43]. IV/IM oxytocin is highly effective when used for postpartum haemorrhage prevention and treatment, however oxytocin requires cold-chain transport and storage. This requirement has not only limited its use in many LMICs, but also contributed to concerningly high rates of low-quality oxytocin in many settings [44]. Consequently, alternative agents such as heat-stable, oral misoprostol with greater side effects for women are necessary to increase coverage of uterotonics. While many novel molecular and antibody therapies require parenteral administration, stakeholders with experience in LMICs raised concerns that even though an injectable medicine may be effective, repeated injections requiring additional healthcare visits would be a significant barrier for many women, ultimately limiting their potential impact. To strike this balance, both TPPs contain non-invasive or injectable therapies as part of the minimum target for route of administration, and cold chain for biologicals only under the stability/shelf-life domain. It should however be acknowledged that new medicines for preeclampsia prevention and treatment may involve the development of novel products or repurposing of existing medicines for obstetric use. Metformin, a blood glucose lowering drug, shows promise as an effective preventive agent for preeclampsia. A recent clinical trial in women with preterm preeclampsia found metformin significantly prolonged gestation, compared to placebo [45].

Effective medicines to prevent and treat preeclampsia are vital to reducing maternal and newborn mortality and morbidity globally. However, significant challenges remain in place for the development of new maternal medicines. The lack of incentive and willingness to invest in development of new maternal medicines, both by drug developers and by governments, is a key barrier to progress in this field [10,46]. Without strong motivation for stakeholders to coordinate efforts and prioritise maternal and newborn medicines, the development of new medicines for preeclampsia is likely to remain haphazard, impeding more rapid progress [46]. The TPPs we have developed provide a first step in the development of new medicines for preeclampsia that meet specific characteristics defined to meet the global needs of pregnant women and the health care providers caring for them.

These are the first publicly available TPPs designed to address the lack of effective medicines for the prevention and treatment of preeclampsia. They were developed using multiple methods with diverse international participation, in accordance with a pre-specified protocol that was informed by product profile development approaches used in other health fields. Nonetheless, some limitations exist. All interviews were conducted online, and it is possible that face-to-face interviews may have yielded better quality data. While we sought a diversity of participants, it is possible that other members of the maternal health research community or other stakeholder groups may hold different views. Though the exact response rate of the survey cannot be determined (as it was disseminated through multiple channels and listservs), a larger number of responses may have yielded different levels of agreement, however given the already high level of agreement and the strong consensus between the survey results and the in-dept interviews we believe this to be unlikely. Some previous TPP development studies have used two survey rounds to reach consensus with stakeholders on TPP domains [20,23], which can be a useful strategy when there is high disagreement for a large number of domains. In this study, agreement was relatively high and the few areas of disagreement were explained by stakeholder interview data. We consider these TPPs to be “living” documents that may be updated or refined as the preeclampsia R&D field advances, and if further viewpoints or evidence is elucidated.


There is a lack of new medicines for preeclampsia in the drug development pipeline, and without significant R&D investment the global burden of this condition will likely persist. This TPP development study demonstrated clear agreement amongst diverse stakeholders on the requirements for new medicines in preeclampsia prevention and treatment, with particular emphasis on meeting the real-world needs of low-resource contexts. These TPPs can provide guidance to those involved in maternal medicine research and implementation, including drug developers, clinicians, researchers conducting clinical trials, donors and implementers. They can help stimulate renewed interest, innovation and resources for developing medicines–whether new or repurposed–that can prevent and treat preeclampsia.

Supporting information


The authors would like to thank the expert advisory committee to AIM30 and the stakeholders who participated in this study.


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