Only 17 drugs are in active development for maternal health indications, while only one new class of drugs for pregnant women has been licensed in the last 20 years, a study has found. Among the nine new chemical entities (NCEs) in preclinical or clinical development for maternal health, there are no new classes of drugs in clinical trials for primary obstetric applications.
The thin development pipeline for maternal health was identified in an analysis by Nicholas Fisk, director of the University of Queensland Centre for Clinical Research in Brisbane, Australia, and Rifat Atun, professor of international health management at Imperial College London in the UK. The published their findings on the open-access site PLoS Medicine.
The authors compared the obstetrics pipeline with those for a mainstream disease area (cardiovascular health) and a rare condition (amyotrophic lateral sclerosis/ALS). In both cases obstetric conditions came out worse, considerably so in the case of cardiovascular indications (660 compounds in preclinical/clinical development or pre-registration) and even significantly so versus ALS (34 compounds in active development).
Among the 17 drugs identified as under active development for maternal health indications as of November 2007, just three were in preclinical studies (all of them NCEs), five were in Phase I trials, five in Phase II, three in Phase III, and one was awaiting registration. All of the drugs in Phase III or awaiting registration were reformulations of existing compounds.
“Pregnancy has become a virtual ‘pharma-free zone’,” the authors comment. Nor is this just a market failure. The global drought of maternal health drugs has attracted little attention from international donor agencies, despite the marked impact of obstetric pathologies on the maternal and perinatal disease burden in the developing world, they point out.
Four main reasons – “all of them addressable” – are given for the current market failure in maternal health:
– The reluctance of pharmaceutical companies to test or develop drugs in pregnancy – in part due to the additional cost of reproductive toxicity studies but mainly because of risk aversion to the possibility of teratogenicity. While these barriers to entry are understandable, Fisk and Atun comment, teratogenicity “is really only an issue in early pregnancy and of little relevance to drug development in later pregnancy, where there is a genuine unmet need in treating pre-eclampsia, pre-term labour, growth restriction and the complications of labour”.
– The relatively small market size for conditions affecting pregnant women. These are mostly short-lived, while the number of children per woman is falling. Global markets are estimated at the lower end of US$0-US$500 million, “although this could rise many-fold with development of prophylaxis against pre-term labour or pre-eclampsia”, the authors add.
– The limitations of a shareholder-driven industry model for drug development in the case of rare or neglected diseases – even though, Fisk and Atun note, the disease frequencies outlined in the article and the untapped developed world market suggest “reasonable potential returns in obstetrics”. Nonetheless, they acknowledge, the “high degree of regulation of drug safety in pregnancy together with the paucity of pipeline drugs creates greater potential for revenue shocks, to which the industry is averse”.
– Gaps in the regulatory system, whereby most drugs used antenatally are not licensed in pregnancy. “A system that allows off-label use has advantages in accessing drugs for rare diseases and situations with an emerging evidence base, but becomes a major disadvantage where long-term off-label use becomes endemic, as it discourages pharmaceutical investment in clinical trials,” the authors comment. “This is clearly unacceptable, as lack of evidence on safety or efficacy places women at risk,” they say. Moreover, “the resultant impoverished evidence base creates additional regulatory risks for new entrants into the obstetric market”.
One way of providing committed funds for research and development in maternal health might be to replicate ‘push’ mechanisms that encourage investment in drugs for neglected diseases, such as the Medicines for Malaria Venture, the TB Alliance or the Drugs for Neglected Diseases Initiative, Fisk and Atun propose. Other options might include global ‘pull’ mechanisms along the lines of the Global Fund to Fight AIDS, Tuberculosis and Malaria, or creating a not-for-profit entity (e.g., the Institute for OneWorld Health) dedicated specifically to maternal health.
The paper on drugs for maternal health can be accessed at http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1.
