The history of mefloquine hydrochloride (Lariam™), and its adverse event profile in the British military, has been a long and complicated one. The origins of this drug, and some of the controversy surrounding its use in a military setting, have been well documented in the excellent commentary by Dr Ashley Croft , one of the earliest researchers to work on studies examining mefloquine use in the UK military . Perhaps the most important message from this paper is that the majority of safety studies for mefloquine were carried out after licensing, far from the usual process for release of any therapeutic to be used in human patients. As such, tolerability and safety studies have been heavily influenced by the requirement to keep mefloquine in the market place, rather than to support its introduction; a factor that must be taken into account when examining the variety of studies that have presented information both in favour of and against safety of the drug [3-8].
At its advent, mefloquine was widely reported by the manufacturer (Hoffman LaRoche) to be a convenient and effective antimalarial, with considerably greater ease of use in its weekly dosing regimen than the daily dosing required for efficacy of other commonly available antimalarials, such as doxycycline. An apparent lack of safety information, surprisingly, did not limit uptake of mefloquine in the British military, uptake that was likely influenced by positive reports of safety from trials undertaken in the early 2000s by an Australian Defence Force research establishment, the Army Malaria Institute [9-12], as well as use of the drug by other military organisations around the world .
After 2000, an increasing number of UK soldiers were prescribed mefloquine for routine training in malarious zones of East Africa, or deployment to malaria endemic areas such as Sierra Leone and Afghanistan. Indeed, from 1990 until 2012 mefloquine was the ‘first line’ of defence against malaria in the British military in all theatres of activity. These areas have included both training and conflict deployment in Sierra Leone, Kenya, Iraq and Afghanistan, including regions that Public Health England, the body with oversight of prescribing policy in the UK, does not identify as requiring mefloquine for effective prophylaxis. It is still unclear exactly how many UK soldiers have been exposed to mefloquine to date, but the numbers are likely to be in the tens of thousands.
The current Defence Select Committee Inquiry into the use of Lariam (mefloquine hydrochloride) in the British military is the culmination of a decade of work on the part of a very small group of individuals. It is a story which highlights how large organisations can avoid scrutiny for many decades when only small voices are calling for information, and the work and determination needed to exert enough pressure to bring them to be accountable. This commentary will outline the series of events that lead to the DSC inquiry in the UK, the outcomes of which we anticipate shortly.
Individual Stories: The Foundation for Institutional Change
This journey begins with two individuals: Lt Col Andrew Marriott MBE (now retired) and Major Cameron Quinn (now deceased). Both men were given mefloquine (Lariam™) for operational duties in the British Armed Forces between 2001 and 2003, both suffered severe and lasting consequences of that exposure. In the case of Lt Col Marriott this is a persistent nightmare disorder that prevents a single episode of uninterrupted sleep; in the case of Major Quinn it was his suicide in 2006 after suffering both personality change and sleep disturbances. In 2006, neither Lt Col Marriott nor Major Quinn’s widow, Dr Jane Quinn, knew each other but their paths would become inextricably linked in the following decade, along with others who had also been affected.
Major Quinn’s suicide was extraordinary, unexpected, out-of-character and of an extreme nature. This event was characterised by those professionals working to support his family after his death as a ‘psychotic episode’. The official who investigated his demise indentified it as a highly unusual event, even given his extensive experience of completed suicides in men of Major Quinn’s age. The only rational conclusion that could make sense of his untimely loss was that mefloquine had played a role in his death. His widow began investigating a possibly causal link between the drug he had been issued for routine exercise in Kenya, and his changes in behaviour and ultimate suicide. Already, in 2006, there was extensive evidence in the medical and scientific literature that mefloquine could induce severe adverse events in those who took it for malarial prophylaxis, including neuropsychiatric effects [9, 15-22] and was neurotoxic similar to other quinoline antimalarials [23, 24]. On the basis of this evidence she felt compelled to alert the military of her concerns as she knew that her husband was far from being the only soldier who had received this drug. The exercise he had been deployed on had involved two entire battalions, and it was likely all of these individuals had received mefloquine, as well as many others prior to that date.
In response to her concerns, and his own, in May 2006, the Procurator Fiscal (the Scottish High Legal Officer) investigating Major Quinn’s death wrote to the Ministry of Defence, to ask for information around the prescribing of mefloquine for deployment in military personnel. Surprisingly, the response from the MoD did not come from the individual to whom the original letter had been addressed, but from a spokesperson for the Army Medical Directorate, Medico-Legal branch. This stated, for the first of many times in this story, that ‘the Ministry of Defence follows medical practice as laid down by the … Health Protection Agency’. The Health Protection Agency, now known as Public Health England, directs prescribing and safety of prescription and over-the-counter medications for the general population, not specifically soldiers or the military.
A subterfuge was also presented as the letter. It stated that a group action brought against the MoD in 2000 by servicemen serving in Sierra Leone had been ‘unsuccessful’ as the MoD was able to show that it had followed ‘expert advice’….. ‘in a logical and rigorous way’. It was not, however, made clear that this group action had not been around adverse events from mefloquine but rather by individuals who had contracted malaria despite taking mefloquine for malarial prophylaxis. The clear intention was to discourage ‘Mrs Quinn’ from pursuing legal action. The letter finally stated that the Procurator Fiscal’s questions had also been passed on to an unnamed ‘Defence Consultant in Communicable Disease Control’ for their comment.
In the light of this elusive response, Dr Quinn wrote in November 2006 to the Chief of General Staff General Sir Richard Dannatt KCB CBE MC ADC, to request an investigation into the continued use of mefloquine in the British Army. General Dannatt replied in person and deferred to the ongoing correspondence with the Medical Directorate as being the experts in this area. Wing Commander Andrew Green MB, BS, FRCPath, FFPH. FFTravMed, RCPS (Glasg) DTM&H RAF, the Defence Consultant in Communicable Disease Control finally responded in November 2006 after receiving a copy of Dr Quinn’s letter to the CGS.
Wing Commander Green was an entirely suitable person to address questions around mefloquine use in the military. He had been a serving member of the Advisory Committee for Malaria Prevention (ACMP) since 1993, this being the committee that advises PHE on anti-malaria policy. In his response to Dr Quinn, Wing Commdr Green stated that the ‘ACMP is the authoritative source of guidance in the United Kingdom. There has been a military representative on this Committee since 1993’ and that ‘Disease policy in the Armed Forces follows national guidance unless there are compelling reasons to differ’. In other words, military prescribing policy is dictated by the same policies used for recreational travellers, and that he was the authority providing advice to this committee from within the military.
General Dannatt’s response to the information provided by Wing Commdr Green was to ‘reassure’ Dr Quinn that ‘the continued prescription of Lariam to soldiers will be kept under review and in line with national and international best practice’. It has become increasingly clear that this assurance was not being honoured as, even in 2006, significant numbers of prescriptions were not being administered using PHE guidlines, or the usual prescribing policies for general medical practitioners; adverse events were not being reported through the appropriate channels (the Medicines and Healthcare products Regulatory Authority Yellow Card system in the UK) and no major, independent, review of the use of mefloquine in the military had been carried out.
After this exchange in 2006, it was clear to Dr Quinn that the MoD was not likely to make any substantial changes to its policy on the prescribing of mefloquine, nor were the two key individuals who might be able to elicit change, namely Wing Commander Green as the military representative on the ACMP, or General Dannatt as CGS, inclined to act. Dr Quinn returned to the process of grieving for her husband and caring for her children who had lost their father.
Remarkably, General, now Lord, Dannatt, was to call for a review of use of Lariam in the British armed forces in response to a newspaper article published in the Independent on the 28 September 2013. A day later, he stated ‘The risks are too high’, some seven years after he had been in a position to carry out this investigation himself, and had chosen not to do so. The irony of this is not lost on the author.
A Team is Built
Dr Quinn was not the only individual to have been significantly affected by the use of mefloquine in the UK military. Lt Col Andrew Marriott was engaging in his own debate with Defence Health, asking and finally achieving acceptance in 2009 that the nightmare disorder that he had suffered since taking mefloquine for service in Sierra Leone in 2002-3 was causal to his condition. He was also engaging to try to have medical conditions associated with mefloquine exposure recognised in the British military. He had also met with a wall of silence, avoidance or obfuscation. Interestingly, Lt Col Marriott’s is the only case, to the author’s knowledge, for which mefloquine has been accepted as causal to an ongoing medical complaint by the UK Department of Defence.
The catalyst point came in 2009 when a recent army divorcee, Ms Bea Coldwell, brought this group of likeminded, and deeply affected individuals together. Ms Coldwell had also suffered trauma at the hands of mefloquine, her ex-husband, a newly-promoted Lt-Colonel in the British infantry, having left her and their two children to cohabit with a Sierra Leonean nightclub worker he had met when on deployment in Africa. He had taken mefloquine for this deployment, during which his behaviour had changed radically,, culminating in his being returned to the UK for in-patient neurological treatment. Despite her protestations, his behaviour was dismissed or accepted and mefloquine was not recognised as being linked to his change in personality. Somehow, Ms Coldwell located Dr Quinn, who was now living on the opposite side of the globe in rural Australia, having been prompted that there was another army wife somewhere who had suffered the after-effects of exposure to mefloquine. She also found Lt Col Marriott in the wilds of Yorkshire, and the team started to work together to raise awareness of the effects of mefloquine toxicity in military personnel. Where previously three individuals had fought in isolation to no avail, the team now had strength and peer support and a new era of activities began.
Change did not come overnight. Over the next 2 years, Lt Col Marriott, a champion in the art of letter writing, penned correspondence to multiple MPs and finally the Rt Hon. William Hague MP. Having received no response to correspondence sent to the MoD in August of 2009, he received a reply from Mr Hague in January 2010, stating that the Surgeon General and Secretary of State for Defence had not yet responded to his (Mr Hague’s) queries. It was apparent that the MoD did not feel that they were required to respond to anyone, in the House or outside it, on this matter. When they finally did respond in July 2010, some 11 months after Lt Col Marriott’s original letter, their response was to state the same dogma: their deferral to the ACMP and PHE when defining protocols for mefloquine use in a military setting: exactly the same response that Dr Quinn had received some four years earlier.
This dismissal did not deter the group, but confirmed that things definitely needed to change. More correspondence followed, and years passed. Surgeon Generals and Ministers changed offices and governments came and went but the group kept writing and talking, finding more and more people who had been affected in similar ways as they went. After three years of little movement, they took the radical step of contacting the British press. Working through the official channels had met with an increasing level of institutional avoidance and an alternative approach was required.
Although this avenue was deeply painful to all three, the change of pace was immediate. In 2013, when media coverage of the situation was beginning to grow, Lt Col Marriott initiated an interesting correspondence between to Rt Hon William Hague MP and the Rt Hon Philip Hammond (Secretary of State forDefence). In this correspondence, Rt Hon Philip Hammond again stated the familiar response regarding accepting advice from the ACMP saying that ‘mefloquine is one of a number of anti-malarials that can be used’ and that ‘If this advice changes as a result of new evidence, the MOD will, of course, review its position’. Some seven years after General Dannatt had stated exactly the same position, and despite growing evidence of adverse events to mefloquine, it seems remarkable that this advice continued to be the same.
It was clear and apparent that nothing was changing the position of the MoD, or its advisors, despite the fact that side effects of mefloquine were being increasingly reported and the Centre for Disease Control in the USA had requested that mefloquine be required to carry a ‘black box’ warning, the highest level of notification around patient safety in that jurisdiction. What was important was that the public, and its ministers, was beginning to see that too.
A Lack of Duty of Care
One of the key concerns of the group was that it had become increasingly apparent that the majority of those prescribed mefloquine in the British military had received their drugs en masse. Although commissioned officers or those undertaking an individual deployment might have their medications issued by a qualified Medical Officer, generally the rank and file received their medications together in large groups. Sometimes this occurred when troops were issued their kit for deployment, or in the canteen at meal breaks, or at the drop zone on deployment or exit. In only a very few cases were they given any sort of information about the drugs they were receiving, or advised of the kinds of side effects they might experience, nor what to do about them. In addition to this blanket dosing, it has now been acknowledged by the MoD that individual patient assessments were only routinely introduced in 2013, some eleven years after the manufacturer alerted general practitioners that this was required .
This lack of appropriate prescribing was increasingly recognised by the team as a significant lack of duty of care. Neither did the general soldiers’ experience of the method of their mefloquine drug administration correlate with the Rt Hon Philip Hammond’s knowledge of the situation in 2013, when he was then Secretary of State for Defence: in his letter to William Hague he described that antimalarials were prescribed by ‘individual prescription, Patients Specific Direction (PSD) or Patient Group Direction (PGD), and that ‘Individual prescription and PSD require individual risk assessments and while PGD does not, I am advised that there would be few, if any, recorded incidents to suggest that mefloquine had been prescribed in this way. One would perhaps suggest his statement, therefore, to be lacking in evidence when one considers the anecdotal evidence of blanket prescription to troops operating in West Africa and Kenya often being administered by sergeants or corporals when troops were in the field, to ensure that everyone complied with the dosing regimen. Together, what was occurring on paper, or in policies letters and leaflets, and what occurred in practice were two very different things.
Colloquially, the days that mefloquine was administered to soldiers in the field becoming known as ‘lariam days’: days when all manner of odd events and behaviours would impact the operational effectiveness of the troops taking it. Oddly, if these effects were recognised by those in command, they were never acknowledged or practices changed to limit the impact. In an addendum to his letter to the Rt Hon William Hague MP,, Rt Hon Philip Hammond wrote ‘the way we prescribe this drug for military personnel is quite different from the way the US does so, justifying the difference in approach’. Quite what the UK ‘approach’ is, or was, other than being fundamentally unsafe, is far from clear.
Calls for an Inquiry
In the light of continued obfuscation by the MoD around the issue of mefloquine use in the military, their endless delay tactics and misinformation in response for requests for specific data, whether questioned directly or through secondary channels (including via Government ministers), the group decided to write to the Defence Select Committee directly asking for their involvement to address the issue of the continued use mefloquine in the UK military. This seemed to be the only way to see if an answer could be prised from the MoD, when they were required to respond to a formal Governmental inquiry.
The first attempt to initiate an inquiry was unsuccessful. In September 2014, Lt Col Marriot wrote to the then Chair of the Defence Committee, raising ongoing concerns with the use of mefloquine in the UK Armed Forces and the persistent refusal by the MoD to address questions surrounding this issue. Due to an impending election their response was to suggest that this ‘could be a subject to which a future Committee might be able to return’.
Increasing exposure in the media was also beginning to play its part. Lt Col Marriott, Ms Coldwell and Dr Quinn’s stories had appeared in an article in the Independent newspaper on 8 October 2013 and during 2013 and 2014 more articles were published around the topic, with evermore people talking about how they had been affected. The issue was not going away. In 2014, the excellent radio documentary ‘The Lariam Legacy’ was aired on Radio 4 as well as media reports on the British Forces Broadcasting Service (BFBS). In Britain, the story of how mefloquine had affected soldiers and their families, and the potential numbers involved, was beginning to get traction in the media, and from that some political leverage followed.
The extent of the problem.
The exact number of individuals potentially affected in the UK military is unknown, but significant.
An FOI release in response to Scottish filmmaker Cailean Watt’s enquiry in February 2015 (FOI 294060-25817167), proved another enormous turning-point. Defence Statistics provided information that, for the period 1 April 2007 – 30 December 2014, a total of 16,473 individuals in the UK regular Armed Forces had been prescribed mefloquine hydrochloride (Lariam™). Of this, a total of 994 individuals had a subsequent episode of care for a mental health disorder either provided by MoD health providers or another in-patient service provider. This equates to 6% of regular soldiers who have taken mefloquine presenting with a neuropsychiatric adverse event of sufficient severity to warrant hospitalisation. This figure does not include those who had left the services at the time of referral. Absolute numbers are not available prior to 2007 as the Defence Medical Capability Programme (DMICP) data management system did not exist prior to this date. As such figures for prescription from 1989-2007 are unknown but will make the overall figure much higher.
Despite these figures, only 28 adverse events were reported to the MHRA by military members, or their practitioners, between 2003 and 2010 (FOI 10-457/GENQ-00073673), despite 167 in-patient events linked to mefloquine exposure. Between 1996 and 2003, the total number of events reported was 28 (FOI 10-457/GENQ-00073673). These figures represent a clear failure to report adverse event data to the appropriate authorities by practitioners working within the MoD.
Why, given the increasing numbers of in-patients addmissions linked to mefloquine exposure, was the response by Ministry of Defence between 2006 and 2014 exactly the same?
The MoD appeared to be simply applying a wrote statement to all inquiries around use of mefloquine, regardless of the origin. An example can taken from a FOI in 2014 request, submitted by Mrs Trixie Foster, around the use of mefloquine for troops deploying to Sierra Leone (FOI2014/06237). The MoD response stated:
‘As you will appreciate, the life threatening risks of malaria are extremely serious and there are a number of effective antimalarial drugs used by the military in many parts of the world where the UK Armed Forces deploy. These drugs are licensed in the UK by the Medicines and Healthcare Products Regulatory Agency, based on the expert guidance of the Advisory Committee for Malaria Prevention of Public Health England. The MOD reviews its policy on the use of all antimalarial drugs in line with advice from the Advisory Committee. There has been a military representative on the Committee since 1993.
The exact choice of antimalarial drug prescribed to Service personnel depends on a number of factors, including the region the individual is deploying to, their health and any past history of side effects. Malarone is the first choice drug for those Service personnel deploying to Sierra Leone on Operation Gritrock. For those individuals unable to tolerate Malarone the second choice is Mefloquine (commercially known as Lariam). Doxycycline will be offered to those individuals who cannot tolerate Malorone (sic.) or Mefloquine.’ (Ministry of Defence, November 2014)
Given that significant new knowledge had been presented between 2006 and 2014 around the severity of adverse events associated with mefloquine exposure, the risk for female travellers, and the clear identification in medical literature and the manufacturer’s own product statement of the existence of long-term neuropsychiatric side effects, it seems remarkable that this ‘new evidence’ had failed to be assimilated into prescribing policy by the Ministry of Defence, the Surgeon General’s Department or the ACMP, but this was absolutely the case.
In August 2015, the MP for Plymouth Mr Johnny Mercer MP, member for a large Naval garrison town, called publicly for the Army to stop giving mefloquine to its troops. Mr Mercer raised questions in Parliament and, as a member of the Defence Select Committee, began to ask for questions to be raised at a higher level. In response to a request from the UK Defence Select Committee Secretariat, Lt Col Marriott and Dr Quinn, with assistance from a growing team in the UK which now included Mrs Ellen Duncan, the wife of the most senior member of the Armed Forces known to be affected by mefloquine exposure,Major-General Alistair Duncan, worked to produce a submission worthy of initiating an inquiry. This report was submitted to the Committee in July 2015.
On the basis of this evidence, a Defence Committee Inquiry was opened in October 2015. The findings of this inquiry: ‘An acceptable risk? Use of Lariam in military personnel’ will be published on 24 May 2016.
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