Q145

[Chair] “Good morning everybody. Welcome to the final public session of our inquiry entitled “An acceptable risk? The use of Lariam for military personnel”. First, may I ask our four witnesses briefly to introduce themselves for the record?”

[Brigadier Hodgetts] “Good morning, Sir. My name is Brigadier Tim Hodgetts. I am the medical director for the Defence Medical Services.”

[Mark Lancaster] “I am Mark Lancaster, Minister for Defence Personnel.”

[Surgeon Vice Admiral Walker] “I am Surgeon Vice Admiral Alasdair Walker. I am the new Surgeon General.”

[Surgeon Captain Sharpley] “I am Surgeon Captain John Sharpley, and I am the Surgeon General’s defence consultant adviser on mental health and healthcare.”

Comment. [AC] As the Chair clearly states at the outset of the oral evidence session, this Parliamentary inquiry is about the use of Lariam, and other antimalaria drugs, to prevent malaria in military personnel. However [please see Annex A to this joint scientific response]:

• Brigadier Hodgetts was registered with the General Medical Council (GMC) in 1996 as an accident and emergency physician.
• Mr Lancaster has a degree, and a higher degree, in business studies; he has no medical training.
• Surgeon Vice Admiral Walker was registered with the GMC in 1996 as a general surgeon.
• Surgeon Captain Sharpley was registered with the GMC in 2001 as a general psychiatrist.

None of the three doctors who are medical witnesses for the Ministry of Defence has any recent experience of prescribing Lariam or other antimalaria drugs to prevent malaria, nor any special competence or special knowledge or special training in tropical medicine. To the best of my knowledge, none of these three doctors has designed or conducted any research into malaria or its prevention, or into the effects of antimalaria drugs. In its current guidance to doctors, Good Medical Practice, the GMC states: “You must always be honest about your experience [and] qualifications... You must make clear the limits of your competence and knowledge when giving evidence or acting as a witness.”[1] [Please see Annex B to this joint scientific response]. When giving evidence to the Defence Committee on 12th January 2016 the three medical witnesses did not comply with the GMC’s guidance, as set out in Good Medical Practice.1 The three doctors did not make clear to the Defence Committee, at the start of their oral evidence on 12th January 2016, that their competence and knowledge in respect of malaria was severely limited. It would appear therefore that on 12th January 2016 the medical witnesses for the MoD did not fulfil their duties as set out in the GMC’s 2013 guidance document, Good Medical Practice.1

Comment. [RN] Although I myself am licensed as a physician in the United States, I have some familiarity with the British medical system. I concur with Dr Croft, in his observations regarding the three medical witnesses who on 12th January 2016 gave evidence in this inquiry, on behalf of the UK Ministry of Defence.         

Q146

[Chair] “I understand that the Minister wants to make a brief statement to open… I invite the Minister to say what he wishes to put forward.”

[Mark Lancaster] “Thank you, Dr Lewis. I can only apologise, given your earlier comments… In 2013 the Defence Primary Healthcare Organisation was formed… Prior to 2013, the single services were responsible for the provision of primary care and the procedures for prescribing anti- malarials.”

Comment [AC] In my oral evidence to the Committee, given on 8th December 2015, I referred at Q138 to the Army Primary Healthcare Service, which was in existence from, approximately, 2000 onwards.  On 8th December 2015 I advised the Committee that “Army primary care has been organised since 2000—it used not to be—into a district-wide service. In each district there is a Regional Clinical Director who is a senior RAMC officer, but usually they are not doctors but medical administrators—occasionally a nurse or maybe a pharmacist, but not doctors. They have never prescribed; they do not really understand this issue, because it is complex.” I would hope that the Defence Primary Care Organisation to which the Minister refers, and which has replaced the Army Primary Healthcare Service, is now managed by doctors, and not (as the APHCS was, in many instances) by medical administrators without the requisite level of senior medical knowledge and experience.

Comment [RN] A reassurance from Mr Lancaster would be helpful, on this point.

Q152

[Mrs Moon] “There are a number of anti-malarials on the market. Given the increased concerns about Lariam, why does the MoD continue to prescribe it to military personnel?

[Mark Lancaster] “…there is no single anti-malarial that is effective for all the various and different strains, and nor is there a single anti-malarial that is 100% effective or does not have any side effects.”

Comment. [RN] There is no strain of malaria for which mefloquine is considered more effective than either of the two safer and better tolerated antimalarials — doxycycline or atovaquone-proguanil (Malarone). In the U.S. and Australian militaries, although mefloquine continues to be prescribed to military personnel, it is retained for such use only as a “drug of last resort”, for use exclusively by those rare service members who cannot tolerate these two safer and equally effective alternatives.

Comment. [AC] I concur. Furthermore, Mr Lancaster is here making a scientific statement in response to Mrs Moon’s question, but without having any training or qualifications in medical science. Mr Lancaster holds qualifications in business studies.

Q153

[Mrs Moon] “Surgeon General, would you like to add anything?”

[Surgeon Vice Admiral Alasdair Walker] “… We need to maintain a portfolio of drugs that are effective against malaria, especially if people are allergic to some of the other drugs or there is resistance to them… Lariam or Mefloquine is but one drug… To take it away, however, would denude our ability to manage our forces.”

Comment. [RN] Unlike mefloquine — for which 10% or more of users are contraindicated the drug prior to prescribing — true allergies or contraindications to doxycycline or atovaquone-proguanil (Malarone) are rare. Although intolerance to doxycycline is not uncommon, Malarone is exceptionally well tolerated, with blinded trials reporting a rate of discontinuation due to adverse events of only 1% to 2% during prophylactic use. Under military policies that retain mefloquine for use only as a “drug of last resort”, the drug should therefore be expected to be prescribed to fewer than 1-2% of deploying service members.[2] Consistent with these figures, the Australian Defence Force (ADF) estimates fewer than 1% of its antimalarial users are prescribed mefloquine,[3] and in the U.S. military, since 2013, fewer than 1% of its antimalarial users have been prescribed mefloquine.[4]

Comment. [AC] I concur with Dr Nevin. I must also point out that Surgeon Vice Admiral Walker’s competence and knowledge in respect of malaria is severely limited. Surgeon Vice Admiral Walker did not make these limitations clear to the Committee in his introduction [at Q145], or at any point during the evidence session. It would appear therefore that in giving oral evidence to the Committee, Surgeon Vice Admiral Walker has not fulfilled his duties as set out in the GMC’s 2013 guidance document, Good Medical Practice.[5] [Please see Annex B to this joint response.]

Q155

[Mrs Moon] “Our witnesses in December said that there were no geographical areas where Lariam was the most appropriate drug. Do you agree with that?”

[Surgeon Vice Admiral Alasdair Walker] “I think the assessment of which drug to prescribe is based on a variety of things, such as the person’s ability to take the drug and their geographical location.”

Comment. [RN] There are no geographic areas where there is resistance to either of the two safer, better tolerated, and equally effective antimalarials, doxycycline and atovaquone-proguanil (Malarone). Under the policies of the U.S. and Australian militaries, which retain mefloquine for use only as a “drug of last resort”, mefloquine is never prescribed on the basis of geographic considerations, and is permitted only in those rare instances of a service member’s documented intolerance or contraindication to both of the safer preferred drugs. Although the UK has not yet declared Lariam a “drug of last resort”, the MoD has assured the committee that mefloquine is not a first line drug, even for certain geographic areas, and that it is used primarily in cases where other drugs would not be effective or appropriate for that person. However, MoD statistics reveal that in 2014 alone, 1,892 UK Regular Armed Forces personnel were prescribed Lariam, and in the 7 years prior, from 2007 through 2013, another 14,581 — over 2,000 a year — were prescribed Lariam.[6] These data are not consistent with a claim that mefloquine is prescribed only on an individualized basis, and suggest instead that the drug’s use remains routine, particularly for deployments to certain geographical areas.

Comment. [AC] I concur with Dr Nevin’s scientific clarification. It incidentally demonstrates the limitations that Surgeon Vice Admiral Walker is under (but which he doesn’t declare to the Committee), in providing useful, science-based evidence during this oral session.

Q.156

[Mrs Moon] “So in which geographic areas do you feel it is essential that Lariam is used?”

[Surgeon Vice Admiral Alasdair Walker] “The opportunity to have Lariam in the west of Africa is important. I am not saying that it is the prime drug, but having that in the armamentarium is important, for those who cannot take other drugs.”

Comment. [RN] West Africa, as is much of sub-Saharan Africa, is an area highly endemic for malaria. According to recent U.S. Africa Command medical guidance,[7] in “high malaria transmission areas… Atovaquone-Proguanil (Malarone) is the recommended drug of choice for the prevention of malaria. For individuals unable to receive Atovaquone-Proguanil due to intolerance or contraindication, Doxycycline will be the preferred second-line therapy. Use of Mefloquine prophylaxis is a third-line recommendation and should be restricted to individuals unable to receive either of the other regimens.” In apparent contradiction to the witness’s statement that Lariam is not “the prime drug”, in a paper recently published by UK military authors in the Journal of Travel Medicine,[8] it is acknowledged that Lariam “is currently the default choice for antimalarial prophylaxis for British military personnel on exercise in Kenya.”

Comment. [AC] I concur with Dr Nevin’s scientific clarification. This inadequate response from a witness again demonstrates the limitations that the witness is under (but which he himself doesn’t acknowledge), in providing useful, science-based evidence to the Committee.

Q158

[Mrs Moon] “According to the Secretary of State, Lariam makes up only 1% of the MoD’s anti-malarial stocks. What other anti-malarials are you using?”

[Surgeon Vice Admiral Alasdair Walker] “The antibiotic Doxycycline is one of our main anti-malarials, and Malarone, a combination drug, is another.”

Comment. [RN] As mefloquine is dosed once-weekly, and doxycycline and the combination drug atovaquone-proguanil (Malarone) are dosed once-daily, comparing only the number of tablets in stock may be misleading, as a 1% stock of mefloquine is equivalent to a 7% stock of these safer antimalarials. Expressed in terms of dosages sufficient for a six month deployment, as of August 2015, 16.2% of MoD stocks were in doxycycline, 14.0% in mefloquine, and only 3.0% in Malarone,[9] the drug preferred by the U.S. military for deployments to sub-Saharan Africa.

Comment. [AC] I concur with Dr Nevin that the Secretary of State’s data, and the comments on those data by Surgeon Vice Admiral Walker, do not reflect the true position regarding stocks of mefloquine (i.e. Lariam).

Q160

[Jim Shannon] “…Why is there so much emphasis on Lariam, rather than on usage of the other ones?”

[Surgeon Vice Admiral Alasdair Walker] “It is not unique to Lariam, but, because of the type of side effects, it has become more prominent in the public psyche. It has become very prominent because of the other discussions among other people.  However, studies show that Doxycycline has a greater side-effect profile in terms of the number of people affected. Some of them can be quite significant—for example, gastrointestinal side effects and skin side effects.”

Comment. [RN] Of the three available drugs commonly used in the prevention of chloroquine-resistant malaria, mefloquine is the most poorly tolerated and is the least safe. Of the UK Summary of Product Characteristics (SPC) for the three drugs, only the SPC for Lariam warns of a risk of life-threatening mental health effects including suicide, and the potential for “irreversible” neurological adverse effects. Reactions from Lariam described as “very common” (>10%) include nightmares, abnormal dreaming, and insomnia, and reactions described as “common” (1-10%) include anxiety and depression. The Lariam SPC emphasizes that certain of these reactions “have to be regarded as prodromal for a more serious event”, and require the medication’s immediate discontinuation. In contrast, no reactions from doxycycline are described as “very common”, and the only “common” reaction is abdominal pain. Although the SPC for Malarone notes “very common” reactions including headache, nausea, vomiting, stomach pain, and diarrhoea, and “common” reactions including dizziness, insomnia, abnormal dreams, and depression, unlike as is the case for Lariam, none of these are considered “prodromal for a more serious event”, and these consequently do not require discontinuation of the medication. In actual practice, atovaquone-proguanil (Malarone) is exceptionally well tolerated, with blinded trials reporting a rate of discontinuation due to adverse events of only 1% to 2% during prophylactic use.

Comment. [AC] I concur with Dr Nevin, with the additional rider that I have expressed in my comment at Q155, above. In his reply to Mr Shannon, Surgeon Vice Admiral Walker alludes vaguely to “the type of side effects” associated with Lariam, but he does not concede that these adverse effects of Lariam include very severe, and sometimes irreversible, neuropsychiatric adverse effects. Surgeon Vice Admiral Walker refers to “the other discussions among the other people”. What does he mean by this? Surgeon Vice Admiral Walker is not qualified to give evidence to this important inquiry.

Q164

[Jim Shannon] “The difference, as the Chair says, is between the Lariam being dispensed and prescribed; when dispensed it goes to a group of soldiers, and when prescribed it goes to individuals.”

[Brigadier Hodgetts] “Let me just add some further clarity, please. There are two methods of actually prescribing Mefloquine. One is by individual face-to-face consultation, and that is what we deem to be a prescription. We also have authorised a patient-specific directive, where the individual clinician still has to conduct the risk assessment. That risk assessment will be done from the patient’s notes.”

Comment. [AC] What does Brigadier Hodgetts mean by “a patient-specific directive”? And who exactly (Brigadier Hodgetts refers to “we”, without explaining who “we” is) has authorised this? On what date, exactly, was this authorised? In UK clinical practice, general practitioners are permitted to delegate to practice nurses, and to other healthcare workers, the supply of some prescription-only medicines (POMs). They do this through using a Patient Group Direction (PGD). Is this what Brigadier Hodgetts is referring to? In August 2013, NICE published good practice recommendations for organisations involved with PGDs.[10] In this published guidance, NICE stipulated that “supplying and/or administering medicines under PGDs should be reserved for situations in which this offers an advantage for patient care, without compromising patient safety.”10 Lariam, which is known to be a potentially unsafe drug, and which in fact is the least safe of the currently-available antimalaria drugs, could not reasonably be prescribed to Armed Forces personnel under a PGD, without endangering their safety. It could never be prescribed safely to Armed Forces reservists, through a PGD. In oral evidence to the Committee on 10th November 2015 Dr Frances Nichol, Head of Drug Safety Quality, Roche Products Limited, confirmed [at Q10 and Q25] that prescribers of Lariam should in every case perform an “individual risk assessment”. The Committee may wish to ask Roche Products whether a risk assessment “done from the patient’s notes” (which Brigadier Hodgetts states is what happens) and under an “authorised” (authorised by whom, exactly?) “patient-specific directive” satisfies the manufacturer’s requirement for an individual risk assessment, to be carried out by a physician.

Comment. [RN] In my view an individual risk assessment clearly implies a lengthy, face-to-face consultation between a patient, and the patient’s prescribing physician. Simply checking the patient’s notes does not constitute an individual risk assessment. I would be interested to see what Roche Products have to say about this.

Q165

[Jim Shannon] “Is it your belief that there is no difference in the risks attached to Lariam use by civilians and by the military?”

[Brigadier Hodgetts] “There is no body of evidence to suggest that a non-immune UK civilian traveller is any different to a non-immune UK military traveller in terms of how they will react to individual drugs. There is an issue in relation to the overall risk that soldiers are potentially put at, etc.”

Comment. [AC] Brigadier Hodgetts is inferring that military travellers will react to antimalaria drugs, such as Lariam, in the same way as civilian travellers. If this is what Brigadier Hodgetts believes, then he is wrong. There are fundamental differences between civilian travellers and military travellers which make it likely that the military will in fact react to these drugs differently.[11] It is imperative therefore that antimalaria policies for travelling military populations are unique to the military, and do not slavishly follow civilian guidelines. This principle of good medical practice is recognised by the CDC in the United States, and is recognised in other advanced countries also. [Please see Annex C to this joint scientific response.]

Comment. [RN] I concur with Dr Croft.

Q169

[Johnny Mercer] “Is it your view that an individual risk assessment has been carried out on individuals since 2004?”

[Mark Lancaster] “Providing the policy has been followed, a risk assessment will have been carried out, yes. That is what the policy states.”

Comment. [RN] With regards to contraindications and risk assessments, since at least 1991, the Lariam UK product documentation has warned that “… patients with a history of psychiatric disturbances” should not be prescribed the drug. The MoD admits that only since 2013 — or well over two decades after these warnings first appeared — has compliance with this aspect of the product documentation warning received central scrutiny. Prior to this, including since 2004, MoD policies appeared to have relied on individual clinician discretion to comply with the product documentation. However, since at least 2010, published evidence had demonstrated that such a strategy is inadequate to prevent the drug’s inappropriate prescribing. Despite a U.S. policy memorandum dating to 2002 requiring clinicians to be “familiar with the proper use, contraindications, warning and precautions for prescribing mefloquine”, in 2007, mefloquine was still being inappropriately prescribed to 1 in 7 deploying U.S. service members with documented contraindications.[12] These findings contributed to a series of successively restrictive U.S. military policies, beginning in 2009, which significantly curtailed overall use of the drug, and which led in 2013 to Lariam being declared “a drug of last resort”. However, despite successive restrictions on the use of Lariam in the U.S. military, rates of its inappropriate prescribing continued to rise and have risen at least 4 fold since this 2007 analysis — demonstrating that even as use of the drug is curtailed and its prescribing comes under greater scrutiny, it is now more likely that these few remaining prescriptions are issued contrary to policy and product documentation.

Comment. [AC] I concur with Dr Nevin. As noted at Q164 above, I would question whether conducting a Lariam risk assessment “from the patient’s notes”, which is what the Committee has been told is the current practice in the UK military (although without any confirmatory evidence that this practice does in fact occur, ever), in fact meets Roche Product’s published guidance that every doctor prescribing Lariam to a patient should carry out an individual risk assessment, on that particular patient. The evidence of Dr Frances Nichol at Q15 was that “because of the legal classification of [Lariam] as being a prescription-only medication, the prescribing decision sits with the physician.” Hence, the expectation would be that a physician personally sees every individual to whom he or she prescribes a drug that has the same legal classification as does Lariam. The Committee may wish to seek confirmation from Roche Products, on this important point.

Q178

[Johnny Mercer] “…that’s the gripe of people who have suffered as a result of this, because they were prescribed the drug without an individual risk assessment when the company had said, ‘Don’t prescribe without an individual risk assessment’.”

[Mark Lancaster] “It is difficult, but you will appreciate that I—“

[Mark Lancaster] “I can only really—I mean, I have been the Minister since May. Under my tenure, I am confident that policy is being followed.”

[Mark Lancaster] “This policy has evolved over many years. There have been many updates. And I am very sorry, but I have to apologise to the Committee: I simply don’t know what advice was given to Ministers in 1984, or indeed under the last Government, or the Government before that. The Surgeon General seems keen to come in.”

[Surgeon Vice Admiral Walker] “I have tried to go back through my predecessors’ policy letters over nearly the last 20 years. The first letter that I can actually document is from 1997 and it talks about Mefloquine specifically, along with other anti-malarial measures, bite avoidance measures and all the other measures, etc.”

Comment. [AC] Mefloquine (i.e. Lariam) was made mandatory for all British soldiers deploying to sub-Saharan Africa, in 1993.[13] The policy instruction was issued from the office of the then Surgeon General. Why does the present Surgeon General appear to hold no policy letters issued by his predecessors in respect of mefloquine, prior to 1997? What has happened to the Surgeon General’s files on mefloquine, for the years 1993–1997? The Surgeon General’s Department should hold all policy directives for malaria prevention, and file copies of all associated correspondence and records of meetings etc, dating back to 1993, or earlier. It is inconceivable that these documents have not been retained. To assist in its final deliberations in this matter, the Committee may wish to ask for disclosure of all historic documents on malaria prevention, emanating from the Surgeon General’s Department since, say, 1990.

Comment [RN] I agree that this is a matter that should greatly concern the Committee. It is especially worrisome that government files are missing, or apparently missing, in view of the fact that a number of individuals formerly or currently in the UK military are contemplating legal action against the MoD. These claimants will expect, and are entitled to, full disclosure of all MoD policy documents relating to mefloquine (Lariam).

Q.193

[Douglas Chapman] “I have another question. Some of the evidence that we received from Dr Nevin and others suggested that, even when the individual risk assessments are undertaken, military personnel tend to hide previous episodes of reactions in the fear that they might be undermined or disadvantaged in some way.”

[Surgeon Captain Sharpley] “You cannot stop someone from hiding something if they feel that the risk of revealing this outweighs the risk of hiding it, but that is an individual responsibility. If they hide a mental health symptom or history that we do not know about, that is a risk that has to be tolerated really.”

Comment. [RN] The U.S. military experience has demonstrated that service members remain strongly motivated to underreport potentially disqualifying mental health conditions, including those that may be formally undiagnosed or undocumented. As mefloquine is contraindicated in patients with mental health conditions, the continued availability of mefloquine in military settings where such underreporting is known to occur obligates commanders and policy makers to accept responsibility for the predictable risk of misprescribing and for the consequent harms that may arise as a result. In the U.S. military, growing recognition that owing to such underreporting, mefloquine may not always be prescribed safely and in accordance with the product documentation, and that the risks of any such misprescribing exceed any benefits of its widespread use, have contributed to mefloquine being declared a “drug of last resort”, or its use being prohibited altogether by certain military units.

Comment. [AC] I concur with Dr Nevin. Surgeon Captain Sharpley is a consultant psychiatrist. He is consequently well aware that Lariam can cause serious neuropsychiatric symptoms. These neuropsychiatric adverse effects of Lariam have been reported, very frequently, in users of the drug who did not have any previous “mental health symptom or history”. Surgeon Captain Sharpley however has turned his response to Mr Chapman’s question into a veiled criticism of Service personnel who “hide” an existing or historic mental illness. He has not acknowledged, as he should have done, that Lariam is an equally dangerous drug for people who have no such mental illness. Surgeon Captain Sharpley’s prime responsibility as a physician is towards the patients he represents, and not towards his employer. He should not appear to support the continued use of Lariam in the Armed Forces.

Q194

[Douglas Chapman] “Very quickly on one point in the evidence of Dr Nevin and others during that session about the link between Lariam and use of alcohol. I think some of their evidence suggested that the use of alcohol perhaps exacerbates some of the symptoms?”

[Surgeon Captain Sharpley] “I might be able to partially answer that, if the Brigadier can help me…”

[Brigadier Hodgetts] “I will follow up, Sir. Certainly I would concur with my colleague that the evidence is very poor—very weak—in terms of definitely attributing any additional effect or impact of alcohol on top of Mefloquine. Indeed, the only controlled study that is available, done by Vuurman and colleagues, looked at the impact of Mefloquine versus placebo on driving, and then adding alcohol in at day 30 of that particular study, etc.”

Comment. [AC] Why should Surgeon Captain Sharpley think that Brigadier Hodgetts could “help” him, in responding to Mr Chapman’s reasonable question? Brigadier Hodgetts is an accident and emergency physician. He is not a specialist in Lariam, or on the adverse effects of alcohol, either taken on its own or when combined with other drugs (such as Lariam, for example). The Vuurman study that Brigadier Hodgetts cites was sponsored by Roche, as is stated in small print on Page 481 of the published paper.[14] Its findings as explained to the Committee by Brigadier Hodgetts are questionable, and indeed the supposed findings of this study have been questioned previously by me and by my scientific co-investigator Dr Andrew Herxheimer, who is a senior and highly respected clinical pharmacologist.[15], [16]

Comment. [RN] I concur with Dr Croft. Industry-sponsored studies are liable to be affected by ‘commercial bias’. It was improper of Dr Hodgetts to quote this study to the Committee, without making it clear that the study was funded by Roche. 

Q194

cont’d

[Douglas Chapman]“What advice is given to serving soldiers when they are on operations, and indeed when they return and they may be still taking Lariam, about the use of alcohol?”

[Surgeon Captain Sharpley] “On return, of course, people go through decompression and then go on leave and will be exposed to alcohol. I am not aware of any specific guidance that is given to personnel about the use of alcohol and Mefloquine.”

Comment. [AC] Surgeon Captain Sharpley practises as a psychiatrist in the Royal Navy. He may be correct, as regards the absence of Royal Navy guidance in this area. As regards the British Army (and as I advised the Committee, at Q125 of my oral evidence given on 8th December 2015), an instruction was issued to all Army medical officers on 16th December 2005, from the personnel branch of Headquarters Land Forces, UK. The instruction cited the ‘hypothesis’ paper that I published in BMC Public Health in March 2002, based on a critical review of 516 published case reports of mefloquine toxicity.[17] My co-author in the hypothesis paper was Dr Andrew Herxheimer MD, a senior British clinical pharmacologist and researcher, with over 200 published scientific papers. The Headquarters Land Forces instruction of 16th December 2005 stated: “The mefloquine syndrome presents in a variety of ways including disorders of sleep, mood, memory and concentration, nervousness, fatigue, occasionally frank psychosis as well as gastrointestinal [symptoms] and headaches.  Previous liver or thyroid disease and concurrent insults to the liver from alcohol, dehydration, the oral contraceptive pill, recreational drugs and other liver-damaging drugs will predispose to severe and prolonged adverse reactions to mefloquine. The prescribing advice therefore is that patients with pre-existing liver or thyroid disease should not take mefloquine.  Mefloquine users should avoid alcohol.” As far as I am aware, the Headquarters Land Forces instruction of 16th December 2005 has not been rescinded. To the best of my knowledge, it is still in force.

Q198

[Ruth Smeeth] “Moving on to the use of Lariam by the military, Dr Nevin, from whom we took evidence and whom many of us have cited, argues that Lariam can ‘adversely alter patterns of dreaming and significantly reduce overall sleep duration … despite broad military acknowledgement of the importance of sleep hygiene’. Do you agree that such side effects are incompatible with deployed servicemen?”

[Surgeon Captain Sharpley] There is no doubt that Mefloquine has this effect on some people, that the side effects are there and sleep disturbance is one of them, but it is common. I think we have probably all experienced sleep disturbance. I certainly had it last night…. That is all right: it is part of the job, it is what we are paid for. Sleep disturbance is a serious risk factor for operational effectiveness… but the commonality of this effect and the difficulty of sorting out whether someone’s sleep disturbance was due to the noisy generators next door, the helicopters that were coming in, the Lariam… would be very difficult…. We also have to educate people that if they are suffering from particularly disabling symptoms, or sleep disturbance that puts their operational effectiveness at risk, they put their hand up and say to the doctor, or whoever, that they have this issue. If they believe it is to do with Lariam side effects, that will be addressed by the [medical officer], who will say, ‘Okay, we might have to consider putting you on a different anti-malarial’, or whatever”.

Comment. [RN] This is a critical point of misunderstanding by the witness. The current UK Lariam SPC is unequivocal in emphasizing that any changes to mental state that occur while taking the drug, including seemingly benign psychiatric symptoms such as abnormal dreams, require the drug’s immediate discontinuation, as such symptoms — according to the manufacturer’s guidance — “have to be regarded as prodromal for a more serious event”. Psychiatric symptoms described in the SPC as “very common” (>10%) include abnormal dreams and insomnia, and those described as “common” (1-10%) include anxiety and depression.  In a warning printed in boldface, the SPC emphasizes that “Patients on malaria chemoprophylaxis with mefloquine should be informed that if these reactions or changes to their mental state occur during mefloquine use, to stop taking mefloquine and seek medical advice immediately so that mefloquine can be replaced by alternative malaria prevention medication”. Given this emphasis, it would be clearly contrary to the manufacturer’s guidance for an individual service member, or a medical professional, to attempt to discriminate between possible causes of these symptoms, or to recommend discontinuing the medication only if “they believe it is to do with Lariam”. While compliance with the manufacturer’s guidance may risk some symptoms not due to mefloquine being incorrectly attributed to the drug, this is required to avoid the even greater risk of misattributing prodromal symptoms of drug toxicity to other causes, which risks “a more serious event”, including potentially life-threatening reactions from the drug. The high incidence of prodromal symptoms — such as abnormal dreams and insomnia — caused by the drug, and the high prevalence of potentially confounding conditions, in the context of the manufacturer’s guidance, contribute to the routine use of mefloquine being impractical in most military settings. In contrast, although similar symptoms may occur — albeit somewhat more rarely — with use of atovaquone-proguanil (Malarone), when these occur with this drug, these are not considered “prodromal to a more serious event”, and the drug does not need to be discontinued at their onset.

Comment. [AC] I concur with Dr Nevin. I must also point out that Surgeon Captain Sharpley’s competence and knowledge in respect of malaria is severely limited. It would appear therefore that in giving oral evidence to the Defence Committee, Surgeon Captain Sharpley has not fulfilled his duties as set out in the GMC’s 2013 guidance document, Good Medical Practice.1 [Please see Annex B to this joint response.]

Q212

[Chair] “I am… suggesting that a clear label, analogous to those we see on cigarette packets, could be affixed to this controversial drug’s packaging, simply saying, “This can cause serious side effects in some people. If you would rather be prescribed an alternative, please ask for it.” Is that a policy that you are prepared to consider implementing?”

[Surgeon Vice Admiral Walker] “I am happy to use that as part of the risk assessment with the patients, yes.”

Comment. [AC] The Chair’s suggestion is excellent. However the Surgeon General’s response is vague, insofar as he states that “I am happy to use that as part of the risk assessment with patients”. Is the Surgeon General agreeing that he will simply offer an alternative antimalaria drug to Lariam, if one is requested? The Surgeon General has failed to give a clearly-stated response, to the Chair’s excellent suggestion. A clearly-stated response from the Surgeon General might have been on the lines of, “Yes, we will look at labelling the Lariam packet with a warning that highlights its serious side effects.”

Comment. [RN] This is a low-cost, sensible suggestion by the Chair. If implemented by the MoD, it would enhance patient choice, and patient safety.

Q215

[Johnny Mercer] “Following the Chairman’s last point, this enquiry has been quite public, and no-one—not a single person—has complained to the Committee about any of the side effects associated with the alternatives to Lariam. It is definitely worth bearing that in mind.”

[Mark Lancaster] “Let me be absolutely clear. You are quite right to highlight the risks of malaria. In 2013 the World Health Organisation estimated that there were 198 million cases of malaria, of which 584,000 people died. There has not been a single death from malaria in Armed Forces personnel since 1992. As a broad base line, do I think that policy is working, on the basis that no service personnel have died of malaria? Yes. And it is a very real risk.”

Comment. [AC] Mefloquine (i.e. Lariam) was made obligatory for all British soldiers deploying on exercise to Kenya, in 1993.[18] However for a variety of reasons, the incidence of malaria in exercise troops in Kenya had been declining, for at least a decade before 1993.[19] Throughout the 1980s and the early 1990s, there were no malaria deaths at all, in the British Army.[20] There was no compelling reason for the MoD to have introduced mefloquine at all in 1993, still less to have introduced it on a mandatory basis.19 The death to which the Minister is alluding was of an RAF officer who was serving in Cambodia as a UN military observer, and who was not taking proper antimalaria precautions.20

Comment. [RN] It is misleading to compare the risk of malaria in military and non-military populations. They are quite different groups.

Q219

[Chair] “Dr Croft… has told us that both of his studies led him to the conclusion that Lariam was especially inappropriate for the military. Given that there seems to be some recognition in the MoD that Dr Croft is a man of some eminence and professional credibility on this matter, do you have any evidence to dispute Dr Croft’s comments on his own research?”

[Brigadier Hodgetts] “I would… note that in his recent online publication in the Pharmaceutical Journal in November 2015, Dr Croft states emphatically that we should move away from Doxycycline Hyclate to Doxycycline Monohydrate. In other words, we should use a different salt of Doxycycline, because the salt that he was suggesting has a substantially lower risk of side effects. In fact, there is no body of evidence to support that. Indeed, a paper published by the US Centers for Disease Control and Prevention in 2011 looked at the various studies involving Doxycycline and says that, in most cases, it is not even stated which salt is used or which formulation is used, so you cannot make that conclusion.”

Comment. [AC] Brigadier Hodgetts rightly states that in my article in the Pharmaceutical Journal, published online on 4th November 2015, I advocated that doxycycline (in its monohydrate, not its hyclate form) should replace mefloquine, as first-line prophylaxis for UK soldiers in locations where chloroquine-resistant Plasmodium falciparum malaria is known to exist.[21] Brigadier Hodgetts is incorrect however in stating that there is “no body of evidence” to support my suggestion. In a multicentre randomised controlled trial published in the British Medical Journal in 2003, and in which 173 participants took doxycycline in its monohydrate form, no oesophageal ulceration was observed.[22] Brigadier Hodgetts’ citing of the CDC’s 2011 paper is irrelevant, and indicates a level of knowledge that is out-of-date. The CDC’s current travel medicine manual, ‘the Yellow Book’, in fact states, in respect of doxycycline hyclate, “Gastrointestinal side effects (nausea or vomiting) may be minimized by taking the drug with a meal or by specifically prescribing doxycycline monohydrate.”[23]

Comment. [RN] Brigadier Hodgetts has misled the Defence Committee, by purporting to be an expert on malaria, when he is not, and by then asserting as “fact” something that is demonstrably incorrect.

Q220

[Chair] “I do not want to prolong this unduly, so I would just like to ask, given that you seem to have an open-minded approach to these concerns, whether, if Dr Croft wished to engage directly with you and the MoD over his concerns, you would be willing to have that dialogue.”

[Brigadier Hodgetts] “Absolutely. As you identified in the previous Committee, we engaged with Roche immediately after the Committee.”

Comment. [AC] While I was serving as an Army uniformed medical officer (that is, until April 2013) the Defence Medical Services were aware of my serious concerns regarding Lariam. I remain concerned about the MoD’s continued use of Lariam as routine malaria prophylaxis, and about its historic practices, and I would be prepared to discuss these concerns with the MoD. The MoD have not approached me, however.[24] On the other hand it appears that the MoD have recently “engaged with” Roche Products. Brigadier Hodgetts presumably means by this phrase that a face-to-face meeting has taken place. At the evidence session on 10th November 2015 the Chair of the Committee asked Dr Frances Nichol [at Q90], in response to her assertion that Roche Products had recently “reached out” to the MoD, “Will you kindly keep us informed of what happens next?” It would be helpful if the transcript of this important meeting between Roche Products and the MoD could be made publicly available, on the Defence Committee’s website.

Comment. [RN] I concur entirely. 

Q221

[Ruth Smeeth] “Do you accept the fact that the CDC does not consider Lariam equally suitable for military personnel?

[Brigadier Hodgetts] “Doxycycline given as prophylaxis does not provide adequate protection, as it does not adequately clear the sleeping liver phase of two of the malaria parasites.”

Comment. [AC] Brigadier Hodgetts is an accident and emergency physician, not a malaria expert. As is evident from several of his previous responses, Brigadier Hodgetts’ competence and knowledge in respect of malaria is severely limited. By not making this clear to the Committee at the start of his oral evidence, it would appear that Brigadier Hodgetts is in breach of his duties as a doctor, as defined by his governing professional body, the GMC, in ‘Good Medical Practice’.[25] [Please see Annex B to this joint response.] There is a grain of truth in Brigadier Hodgetts’ response to Ms Smeeth, (and even though, because he is not a malaria expert, he in fact uses incorrect scientific terminology). The picture that Brigadier Hodgetts goes on to paint, of an insoluble clinical conundrum should doxycycline be used as prophylaxis, is contrived, and conjures up a dilemma which is in fact false. There are four malaria species that commonly affect humans: Plasmodium falciparum, P. vivax, P. ovale, and P. malariae.[26] Plasmodium falciparum is the most dangerous malaria species, and the commonest infecting species in the tropics. It is effectively prevented by doxycycline alone.[27] Two of the human malaria species, P. vivax and P. ovale, have a dormant liver stage; Brigadier Hodgetts refers, inaccurately, to two of the malaria “parasites” having a sleeping liver “phase”. Doxycycline may not adequately clear the dormant liver stages of these two species, under conditions where the user has been exposed to intense and prolonged exposure (e.g. for 6 months or more) to P. vivax and / or to P.ovale. In practice those circumstances rarely arise, in UK military deployments.[28] Under conditions where they do arise, or where they might arise in the future, the solution is to offer Malarone as malaria chemoprophylaxis. Malarone, although more expensive than doxycycline, prevents the development of ‘pre-liver’ forms of P. vivax and P. ovale.[29]

Comment. [RN] I concur with Dr Croft’s analysis. Brigadier Hodgetts’ response to Ms Smeeth’s question is evasive, and misleading.

Q222

[Ruth Smeeth] “So you are saying that they [the U.S. Special Forces] do not use it [Lariam] solely because they cannot guarantee the risk assessment, and therefore the policies and checks and balances are in place?”

[Brigadier Hodgetts] “That is one issue, but there is another confounding factor within the U.S. All US service personnel are issued with a drug called moxifloxacin, which is an antibiotic. We know that moxifloxacin directly interacts with Mefloquine, and can cause abnormal heart rhythms. We do not use that antibiotic, and we certainly do not give it to individual soldiers to take if they have sustained a wound on the battlefield.”

Comment. [RN] The witness introduces a specious explanation for current U.S. military policy that is not supported by the scientific literature. Moxifloxacin is a popular fluoroquinolone antibiotic that is licensed and has been commonly used by healthcare providers in both the U.S. and the UK for many years. Neither the UK SPC nor the U.S. product insert for moxifloxacin list mefloquine as a contraindication to its use, nor list a specific mechanism for such a possible interaction. Similarly, neither the UK SPC nor the U.S. product insert for mefloquine list moxifloxacin as a contraindication to its use, nor list a specific mechanism for such a possible interaction. Moxifloxacin is a component of the U.S. Central Command formulary, providing for its availability at allied military healthcare facilities in Afghanistan, including surgical facilities, where it has been commonly used for treatment of soft tissue and other infections, undoubtedly for service members from both countries. If such an interaction as the witness describes had a basis in science, it would have by now undoubtedly affected many service members in both countries.

Comment. [AC] I concur with Dr Nevin. Brigadier Hodgetts’ evidence is highly misleading at this point, and in fact wrong.

Q226

[Ruth Smeeth] “I would like to expand on that, because we have also been told that the Defence Ministries in Germany, the Netherlands, Denmark and Canada have either banned the use of Lariam or use it as a last resort, which I assume is what is happening in France?”

[Surgeon Vice Admiral Walker] “That is not the case. I have had that discussion, especially with my Canadian colleagues, because they were surprised to see that this data was being bandied around. They were quite adamant, and my Irish colleague was equally adamant.  As I said, in many of these countries it is not the drug of initial choice, but they keep that drug within their armamentarium so that they have the option to use it should they need to.”

Comment. [AC] Surgeon Vice Admiral Walker’s response appears somewhat incoherent, but in fact he may be partly right, because of the way the question has been put to him. A more helpful answer might have been forthcoming if it had been put to the Surgeon General that “we have been told that the Defence Ministries in Germany, the Netherlands, Denmark and Canada have either banned the use of Lariam as malaria prophylaxis, or else use it as a last resort, for malaria prophylaxis.” Many national defence forces may still retain Lariam in their national pharmacopeias, for malaria treatment.  Arguably, this is a legitimate use of the drug.

Comment. [RN] I concur with Dr Croft. There are very few countries remaining (the UK is one of just a handful, and the number includes Ireland, as has always been recognized) which still use mefloquine as routine, first-line malaria prophylaxis. A number of national military forces do continue to hold stocks of mefloquine, for use primarily as malaria treatment, for which a different set of risk-benefit considerations apply.

Q228

[Douglas Chapman] “I was about to ask an interesting question, but I think you may have just answered it. It has repercussions. The question that we were going to ask was whether you think that the risks attached to Lariam are acceptable; and, if they are, why did the US army special operations command, which according to Dr Nevin has the most experience of using Lariam in the field, ban it altogether? I think the reply from the Brigadier was that they could not guarantee that the appropriate risk assessments would be carried out, but we have heard from the Minister this morning that you cannot guarantee that the appropriate risk assessments will be carried out, so doesn’t the same rule apply? Shouldn’t we be thinking about how we ban Lariam from the group of drugs available to serving personnel?”

[Brigadier Hodgetts]: “I reiterate what I said before. I agree, Mr Chapman, with your assessment that the reason why the Americans are not using it is principally an organisational issue, not a clinical issue. In parallel, the reason why the Australians have pushed it down the batting order is not a clinical issue but because they are concerned about the wider external media concern, so they have said that they will only use Mefloquine in people who have previously demonstrated a tolerance to the drug. It is not the body of clinical evidence driving the decisions; it is the external concern based on the theoretical side-effect profile.”

Comment. [RN] The witness mischaracterizes the positions of both the Australian Defence Forces (ADF) and the U.S. Army Special Operations Command (USASOC). The USASOC policy prohibiting use of mefloquine was motivated primarily on clinical grounds,[30] and was specifically intended to “decrease the risk of negative drug related side effects”. The policy was informed by a clinical statement in a publication of the U.S. Centers for Disease Control and Prevention (CDC) that the symptoms caused by mefloquine may confound the diagnosis of posttraumatic stress disorder and traumatic brain injury, and by the addition of the boxed warning to the approved U.S. drug label warning that side effects from the drug could be “permanent” or last “years after mefloquine use”. Similarly, the ADF has long deprioritized the use of mefloquine on the clinical basis of its known adverse neurological effects and has declared it a “third-line” drug, to be used only “when one of the other two medications is not appropriate”. So rare is the use of mefloquine in the ADF now that in “the past five years there has been an average of just 25 ADF members per year who demonstrated such intolerance to other anti-malarial medication as to warrant being prescribed mefloquine”. The Australian Department of Defence also “accepts that some people do continue to experience on-going issues” from use of mefloquine, and emphasizes that ADF members “who are diagnosed as suffering longer term or permanent side-effects from mefloquine use can also claim compensation”.

Comment. [AC] I concur with Dr Nevin, with the additional rider that I have expressed in my comment at Q222, above.

(Signed)

(Date)

           4th February 2016

(Signed)

(Date)

           4th February 2016

Brigadier Hodgetts: 

Surgeon Vice Admiral Walker:

Surgeon Captain Sharpley: