The challenges of licensing drugs for use in pregnancy

Abstract

Most recommended obstetric therapeutic agents are not licensed for their purpose. There is a lack of funding for research and little development of new therapeutic agents for use in the treatment of pregnancy-related disorders. Current therapeutics used in maternal health and their licensing status are reviewed and suggestions for these shortfalls together with possible solutions considered.

Keywords::

• drug licensing
• pregnancy
• therapeutics

1. Introduction

In 2011, there were over 700,000 live births in the UK [1]. During their pregnancies, approximately 75% of these women will have taken at least one drug for which safety data are insufficient [2]. The two big issues facing obstetric therapeutics are i) lack of industry research and development funding and therefore development of new drugs and ii) the use of marketed drugs for alternative therapeutic targets in pregnancy without a pregnancy-specific licence. This is in contrast with huge investment by the pharmaceutical industry into research and development of new drugs each year in many other areas. In the past 20 years, only one new drug, atosiban, has been licensed for primary obstetric applications in the UK [3]. Currently, many of the drugs in common use to treat medical disorders in pregnancy are used by clinician's without a licence, with a burden of responsibility falling on the clinician with both potential ethical and legal dilemmas. Licensing is part of a robust process promoting safety and efficacy; we explore the reasons why the system has failed pregnancy.

The reasons for this lack of pharmaceutical investment are complex. Reluctance to test drugs in pregnancy, the ‘thalidomide' effect, is common given the potential risks of teratogenicity or other foetal harm; even a small risk of adverse publicity and threat of litigation seems to outway most anticipated commercial advantage, which itself is limited by the cost of development. The safety profile of a drug in human pregnancy can really only be assured by post-marketing surveillance, which takes an average of 6 years, adding to costs. Another leading reason for this lack of investment lies in the current gaps in the medicines regulatory systems (UK Medicines and Healthcare products Regulatory Agency (MHRA) and US Food and Drug Administration [FDA]) that allow medication to be prescribed without a licence provided the potential risks are fully described and documented. This provides no incentive to drug companies or the health service to alter current practice and increase research both into new drugs and new applications of medicines already in use.

What common treatments are used in pregnancy, and how does their current licensing status affect their prescribing? There are few examples of drugs successfully licensed and commonly used. Folic acid is recommended internationally as supplementation in all pregnancies until 12 weeks' gestation for the prevention of neural tube defects [4]. It has held a licence for this purpose since 1987. Essentially, this is replacing a nutritional deficit and as such its acceptability to expectant mothers is good, and risk perceived to be less to a marketing company. Another large class of drugs that hold licences for use in pregnancy is the labour induction agents. Oxytocin was the first polypeptide hormone to be sequenced and synthesised way back in 1954 [5]. Its synthetic form, syntocinon, is used on a daily basis in maternity units around the world to augment labour. Given its unique use during pregnancy, it is not surprising that syntocinon, along with other induction agents such as prostin (a synthetic prostaglandin), holds a licence for this purpose. These examples, together with a handful of others (see magnesium sulphate for anti-convulsing prophylaxis below), demonstrate that the MHRA can and do license drugs for specific pregnancy indications, so why are there far more examples of obstetric treatments used without a licence?

Preterm labour occurs in 7 – 8% of pregnancies. Therapeutic management has considerable potential to help prevent and reduce adverse sequelae. Preterm births account for 75% of perinatal mortality and more than half the long-term morbidity [6]. There are many differing causes, but once symptoms are present, the therapeutic options available are limited in efficacy. They include maternal steroid injections to improve foetal lung maturation, antenatal magnesium sulphate for foetal neuroprotection, antibiotics to prevent or treat infection if suspected, and tocolytics to try and slow the progress of labour to aid other therapeutic options. Betamethasone or dexamethasone 12 mg given intramuscularly in two doses are the steroids of choice to enhance foetal lung maturation [7]. The evidence to reduce morbidity and mortality is robust. Indeed giving steroids is an auditable standard in obstetrics, and it is potentially negligent to fail to give them if the opportunity arises. Neither drug holds a licence for this purpose, but both are recommended by national bodies throughout the world. There is ongoing research into the possible long-term effects of steroids on child health and wellbeing, which may concern industry. However, a Cochrane review of 21 studies showed that treatment of women at risk of preterm birth with a single course of antenatal corticosteroids reduced the risk of neonatal death by 31%, respiratory distress syndrome by 44% and intraventricular haemorrhage by 46% [8], so clinician's have on balance felt that the risk of not treating outweighs the risks of treatment. Given the drug is relatively cheap and prescribed anyway, there is little incentive for industry to change the status quo.

Currently, there are two tocolytics frequently used in UK clinical practice to delay delivery in threatened preterm labour. Atosiban, a competitive antagonist of oxytocin, holds a licence in the UK, but not in the USA, partly due to insufficient safety data with limited efficacy in neonatal endpoints. Nifedipine is a calcium channel blocker that has been used for cardiovascular indications since the early 1970s. In more recent years, it has been used as a tocolytic, but it does not hold a licence for this purpose. Both drugs are currently recommended by the Royal College of Obstetricians and Gynaecologists for tocolysis [9], but given the cost variation and that safety data are available for both, nifedipine is becoming the first-line agent of choice in most UK National Health Service (NHS) maternity units.

Hypertension complicates over 10% of all pregnancies, this can be pre-existing, gestational or as part of the pregnancy specific disorder, pre-eclampsia (proteinuria and hypertension). Treatment of hypertension is critical as uncontrolled systolic blood pressure can lead to stroke, other end-organ damage and death. In the last Confidential Enquiry into Maternal Deaths triennial report [10], the importance of maintaining systolic blood pressure below 150 mmHg was again highlighted, but only one anti-hypertensive is licensed for use in pregnancy. Labetalol, an alpha and beta-blocker, has a licence for both oral and intravenous use in pregnancy, but frequently this drug alone is not adequate to control hypertension to the level required, and other agents such as methyldopa or nifedipine are then used without a pregnancy-specific licence. It is interesting that the 2010 National Institute for Health and Care Excellence (NICE) Hypertension in pregnancy guidance recommends non-licensed therapeutic agents [11]. This suggests that clinicians do not give credence to the value of licensing, perhaps because they have become so familiar with prescribing off licence or the limited therapeutic options force them to recommend unlicensed alternatives. There is evidence that both agents have limited foetal risks, but industry has not chosen to pursue licensing, as this would hold no financial gain for them. Other agents frequently used outside the pregnancy setting with much better efficacy and patient adherence are not being tested in pregnancy for similar reasons.

Pre-eclampsia, which complicates around 5% of pregnancies, can be catastrophic for both mother and baby. Currently, there is no cure other than delivery of the placenta and hence the baby. Magnesium sulphate is used intravenously for the prevention and treatment of eclamptic seizures [12]. It does hold a licence for this purpose again highlighting that industry does recognise the improved marketing ability when MRHA/FDA approval is held.

Aspirin is recommended by the NICE hypertension in pregnancy guideline for prevention of pre-eclampsia [11]. The evidence for the use of low-dose aspirin (75 mg/day) is consistent with a significant risk reduction for pre-eclampsia, and there are sufficient data on the safety of aspirin in the doses used in pre-eclampsia prophylaxis trials to make recommendations for clinical practice. Given that aspirin has been in clinical use since 1899 [13] and is cheap, it is again not perceived as financially viable to licence it for this purpose. Pravastatin has been proposed for amelioration of early onset pre-eclampsia [14] and is currently under UK national randomised controlled trial (StAmP). However, this study is encountering issues with recruitment. Patient anxiety relating to taking medication in pregnancy for which the safety data are incomplete plays a significant part. This again highlights the problems faced with the introduction of new treatments into maternal pharmacotherapy.

So what can be done to address these issues? Poor industry investment was highlighted in 2008 by searching the Pharmaprojects database to investigate current obstetric research and development drug advancement [3]. Significant underinvestment by pharmaceutical companies in maternal health was apparent and a ‘drug drought' in obstetric therapeutics demonstrated. Suggested solutions included providing incentives to encourage universities, small–medium enterprises and multinational pharmaceutical companies to invest in the development of maternal health therapeutics. This model has worked for other neglected diseases, especially when the treatments provide improved global healthcare, with the emphasis on improving morbidity and mortality in developing countries. Another suggestion was for the development of a non profitable entity, such as the Institute for One World Health [15], with specific dedication to maternal health.

A further aspect to be considered is the use of unlicensed drugs. In today's clinical practice there is occasional need for ‘off-label' use of therapeutics, particularly when a disease is rare and the evidence is emerging. However, once this use becomes long-term and the unlicensed use of a drug is endemic, as is the case for most obstetric drugs, the situation becomes unacceptable and the need for an alternative route for licensing becomes clear. If the licensing laws were tightened and financial allowances made for existing drugs to be licensed for obstetric use, this might stimulate industry investment further. As mechanistic understanding of pregnancy pathology increases, the potential for new drugs to impact on outcomes will increase, and this may also incentivise industry to invest.

Given the high number of pregnancies each year worldwide, new approaches to stimulate the research and development of new therapies for maternal health are of paramount importance. The systems of licensing and investment need an overhaul in order to offer these women and their babies the treatments they deserve.

2. Expert opinion

There is a need for therapeutics in pregnancy to be highly regulated because of the potential harm to the developing foetus and devastating long term consequences. Therapeutics on the other hand has considerable potential to ameliorate morbidity and mortality in pregnancy. The paradox of common off label prescribing in potentially high risk situations must change, and industry incentivised to invest in pregnancy. This will be a considerable challenge as maternity is already a highly litigious speciality and paradoxically clinicians are comfortable with risk and do not always respect the value of licensing. Communication between regulator, industry and clinicians may rectify the problem to a degree but a culture change to ensure all act to help our patients rather than to limit potential risk to themselves is needed. The reality is litigation in maternity research is negligible compared to that in clinical practice, especially in recent years. Perhaps a radical change in process is needed in pregnancy, such as funding of licensing coming through non-commercial institutions and academic institutions increasing their research and development role in drug development. Maybe crown indemnity should take on litigation costs. Pregnancy does not suit the current system; it will have to change to suit pregnancy if the licencing processes are to maintain any credibility in maternity care.

Declaration of interest

A Shennan is a Consultant to GSK regarding Tocolysis drugs. L Webster has nothing to declare.