comment‘

The costs of inefficiencies are swallowed by the NHS. The sign might say “NHS pharmacy,” but it is ‘Pantone 300 blue lipstick on a corporate pig NO HOLDS BARRED Margaret McCartney Bring pharmacists into the NHS ommunity pharmacists to dealing with inquiries about out-of- should work directly stock drugs (a continual source of on-call for the NHS, mainly in time wasting). general practices, and not Teaming up with a pharmacist in private chemist stores. employed by and sited inside a private CThis intervention would be radical and company are the vested interests of the unusual, directing people back towards employer and disrupted communications the NHS rather than to private business. back to the NHS. I visited a local chemist’s shop Corporate pharmacy chains often recently. On the counter were some restrict which wholesalers they use, healing crystals and on the shelves a plethora creating work for the NHS. For example, this week of homeopathic preparations. Nearby a sign, a pharmacy phoned me to say that it had run out in official NHS Pantone 300 blue, offered NHS of lithium and asked whether I could prescribe services such as stop smoking and repeat an alternative. But a different pharmacy, with a prescription orders. different supplier, had no difficulty dispensing Most pharmacies now have little rooms to the drug. The costs of these inefficiencies are accommodate confidential conversations, but a lot transferred back to patients and swallowed by the of wares—from cough mixtures1 to topical agents NHS. The sign might say “NHS pharmacy,” but it is for insect bites2—do brisk trade without good Pantone 300 blue lipstick on a corporate pig. evidence of effectiveness. As GPs move to a contract with a lighter form of Pharmacists in the community have been the Quality and Outcomes Framework, ever closer plagued by corporate conflicts of interest in much to a salaried rather than a contractor model, we the same way as GPs have under the Quality and should reassess the situation. If remote general Outcomes Framework, pushed to meet targets practices can dispense, practices with a pharmacist for drug reviews even when inappropriate.3 working on the same team most certainly can. Many pharmacists working for large chains are The idea that private companies should do NHS demoralised, as happens to us all when judged by dispensing ignores the uncounted problems of standards that we know are not in patients’ best corporate firms. Could we at least consider testing interests. the idea of bringing high street pharmacists into The NHS 111 system directs many patients the NHS fold? to pharmacists. In some areas pharmacists are Margaret McCartney is a general practitioner, Glasgow already working in GP surgeries. Many things that [email protected] GPs do could be done by pharmacists, from helping ̻̻Follow Margaret on Twitter, @mgtmccartney with drug reviews and checking inhaler technique Cite this as: BMJ 2016;353:i3132 the bmj | 25 June 2016 525 BODY POLITIC Nigel Hawkes The travesty of expensive insulin A bad precedent for future drug pricing

lmost a century after It’s as if Bayer the federal health insurance system for its discovery insulin still owned people aged 65 or over, to negotiate remains out of reach the rights to prices directly with companies. Trump of millions of people, aspirin and claims this would save $300bn against the wishes of its charged us a (£210 bn) a year, but Medicare spends Adiscoverers. It’s simply too expensive only about $80bn a year on drugs. For fiver a pill a drug for a disease that makes the Republican candidate to suggest no distinctions of class, colour, or such a change, though, is interesting. birthplace. The issue is hot because two Many people agree that this is small companies recently imposed shameful.1 2 It also sets a terrible huge arbitrary price rises. Turing precedent for newer biological drugs Pharmaceuticals and Valeant and raises awkward questions about Pharmaceuticals International the patents system and drug market. were quickly disowned by the Many other drugs even a quarter Pharmaceutical Research and of insulin’s age are now available Manufacturers of America (PhRMA), as cheap generics. With insulin, but the price hikes drew attention to constant reinvention and marginal the large and widening gap between improvements, combined with barriers what the US and what most of the rest to market entry, have enabled a few of the world pays for drugs. “Break up companies to maintain their grip and the insulin racket,” a New York Times PhRMA said that the prices quoted generate huge profits. It’s as if Bayer still article by an endocrinologist, brought in the JAMA paper were misleading owned the rights to aspirin and charged the price of insulin into the mix.3 because they didn’t take account of us a fiver a pill. Many poor Americans with diabetes rebates. But if a market is so opaque, thebmj.com find it hard to pay for insulin. A recent why should we believe it? US election ̻̻Feature: Big JAMA study found that US prices had There is no doubt, however, about the The price of drugs has become a key profits for insulin tripled from 2002 to 2013, while other effect of insulin prices in poor countries. 4 issue in the US election. Donald Trump, manufacturers diabetes drugs had fallen in price. The life expectancy of a child with type 1 Hillary Clinton, and Bernie Sanders have (BMJ 2010;341: And even people with insurance or in diabetes in sub-Saharan Africa is just a called for a new law to allow Medicare, c7139) Medicare pay top-ups. year. True, insulin cannot be copied and

ACUTE PERSPECTIVE David Oliver The department of spin

Some say don’t shoot the messenger. me, check the @DeptHealthPress solutions have prompted considerable The professionals leading government tweets from April and May, when the academic debate, with authors and communications offices are simply junior doctors’ industrial dispute editors disputing the spin.3 politicians’ minions. I don’t believe was playing out and gaping holes Press officers also said that, by the that. were exposed in NHS workforce end of this parliament in 2020, the During the current crises in planning, funding, and deteriorating number of doctors trained by the NHS healthcare, ministers may be the performance. Media relations staff will have increased by 11 000 and that lightning rod for our anger. But we made a timeline of the junior doctors’ this government had already overseen need to stop letting the Department dispute, which failed to mention that an increase of more than 10 000 The messages 4 of Health’s press office off the hook, it was the department that (twice) had are often hospital nurses and doctors. They also challenge and expose its partial to be exhorted to the mediator, Acas, made big promises about increases truths. The messages it pumps out, and terminated January’s talks.1 The loaded in the GP workforce as part of April’s inconvenient facts omitted, seep into word “imposition” did not feature. against the Forward View.5 the media and public consciousness The press office claimed that services and Strangely, the press office omitted and are often loaded against the evidence for the weekend mortality professionals mention of parliamentary committees services and professionals it claims effect was “overwhelming”2—even it claims to flagging the disastrous failure of to support . If you don’t believe though its existence, causes, and support NHS workforce planning, with

526 25 June 2016 | the bmj disappeared in favour of human insulin created by recombinant DNA THEBMJ.COM BLOGS David Payne techniques, and human insulin is now being replaced by analogue insulin. Time to pause Scotland’s Each change brought improvements “named person” policy in performance whose importance is “They fuck you up, your mum and dad. They may not contested, as well as prolonging patent mean to, but they do.” Was Philip Larkin right, and, if protection and sustaining prices. The so, are state funded parenting classes the answer? Or extra cost of analogue insulin to the NHS should we be offering all children, regardless of their over 10 years has been estimated at background, access to a state guardian from birth to £625m.5 age 18 to help safeguard their wellbeing? Modern drugs are always costly, One apparent problem; two potential solutions. largely because the US market is so John Ashton, outgoing president of the UK Faculty of skewed in pharma’s favour. But they Public Health, told the Times that 10-15% of school usually leave behind a trail of affordable leavers are in trouble emotionally or mentally, with one generics that do the job very nearly as child in 10 having a mental health problem. well. That is a strong justification for the It’s not just parents from disadvantaged drug industry. With insulin, though, this backgrounds who struggle to raise children, he adds, hasn’t happened. saying, “There’s some terrible parenting among If we’re not careful, this story will wealthy people who neglect their children and spoil be repeated with today’s best new them in other ways.” drugs, many of which are biologicals. The industry has successfully sold Are state funded parenting classes the story that biologicals are costly to the answer? make (once true, now much less so) Ashton wants to see the public health role of

STEVE MCCRAKEN STEVE and that biosimilars, unlike generics, midwives strengthened and antenatal classes must be trialled to ensure equivalent extended. The prime minister, David Cameron, talked produced for pennies, but by now we performance (true, but the trials are of state run parenting classes and of them being seen might have hoped to do a lot better. simpler and less costly). Combine that as an “aspirational thing for families to attend.” with the arthritic performance of the The move, first mooted in January, is likely to enrage Evergreening? NHS in using a biosimilar version of 6 those who fear “a nanny state,” said much of the news It’s easy to point fingers. The three infliximab and you’re laughing if you’re coverage. In Scotland, where the government is due companies that dominate the market, an investor in the drug industry. If you’re to introduce a “named person” policy from 31 August, Novo Nordisk, Eli Lilly, and Sanofi, a patient, especially in a poor country, the rage has already erupted. have pursued a policy of product prospects are much less rosy. What does being a named person entail, and improvement that critics characterise Nigel Hawkes is a freelance journalist, London why does every child need one? It is, the Scottish as “evergreening”: animal insulin Cite this as: BMJ 2016;353:i2933 government website says, “a central point of contact if a child, young person or their parent(s) want information or advice, or if they want to talk ACUTE PERSPECTIVE David Oliver about any worries and seek support. They can also, when appropriate, reach out to different services The department of spin who can help.” 22 000 nursing and 4000 medical workforce—junior doctors—would What types of professionals are we talking about 6 7 11 vacancies. Silence reigned over gaps “deliver a seven day NHS.” Problem here? GPs are not mentioned. In the case of preschool in trainee recruitment to posts in key solved, then. children, health visitors are suggested. At school it medical specialties—including for In 2013 the head of the DH will be a teacher. But the types of teachers most talked 8 those overpromised new GP trainees. press office said, “We have to be about include head teachers, principal teachers, and The department’s public relations transparent and honest with the guidance teachers. It’s not clear how many children staff said that the NHS had received public. You can’t hide stuff and will be allocated to them, but health board and local 12 the sixth biggest funding increase hope that nobody notices.” For authorities will have a statutory duty to provide one 9 in its history. The chief economist the sake of open democracy and the until a child reaches 18. at the King’s Fund showed this to be future NHS, it’s vital to challenge But is the legislation yet more “ill conceived 10 nonsense. Soundbites can’t save the department at every turn. Its nannying,” designed to control the lives of ordinary a service already facing deficits and apolitical civil servants are supposed Scots who don’t need or want it? In a sense, the under further pressure to save money to work for us taxpayers—not for question has already been answered. A Survation despite rising demand, diminishing party headquarters. poll of 1024 adult Scots earlier this month found performance, and real terms cuts to David Oliver is a consultant in geriatrics that 64% thought it was an “unacceptable social care. and acute general medicine, Berkshire intrusion” into family life. The spinners claimed that agreeing [email protected] David Payne is digital editor, The BMJ a new contract with one depleted Cite this as: BMJ 2016;353:i3237

the bmj | 25 June 2016 527 ANALYSIS Drugs for rare diseases: bridging the evidence gap Post-approval studies seldom cover the deficit of knowledge about orphan drugs, findRoberta Joppi and colleagues GARY WATERS/GETTYIMAGES GARY

eveloping medicines for Licensing products using their name or MESH phase III trial anagrelide was worse rare diseases is difficult. of orphan term(s), and their authorised or than hydroxyurea in preventing Small target populations products designated indication(s). After arterial and venous thrombotic limit the potential to with no or a library search, two reviewers events, serious haemorrhage, and recover investments incomplete independently screened abstracts and death in 809 patients with essential Din research and development, and full texts, and separately extracted thrombocythaemia (odds ratio =1.57; proof of their even when medicines get to clinical efficacy may data. Discrepancies were solved by 95% confidence interval 1.04 to 2.37; trials, there may be too few patients consensus. We considered 10 years P=0.03).6 to support adequately sized trials. unduly harm sufficient time to answer the clinical Two further trials primarily Trials for these drugs often also have patients questions still open at the time of examined reduction in platelet count. other shortcomings—for example, the and waste approval. It is also the period covered However, one small trial also reported use of placebo as control, surrogate health service by patent and the special protection no thrombotic events with anagrelide endpoints instead of hard clinical resources reserved for licensed orphan and 11 with hydroxyurea.7 In one outcomes, or an inadequate length of products, and companies should non-inferiority trial anagrelide seemed follow-up. As a result, orphan drugs— still be interested in increasing the to be as effective as hydroxyurea in those intended for rare diseases evidence relating to their products. preventing thrombocythaemia related (box)1—are not only few but often have Here, we summarise the evidence clinical events, though the wide insufficient evidence of efficacy and available before and after approval for confidence intervals indicate that it safety at the time of approval.2 each of the drugs. could be much better or much worse Regulation introduced in Europe than placebo (hazard ratio=0.92; 95% in 2000 aimed to encourage research Anagrelide CI 0.57 to 1.46).8 and development into orphan drugs.1 Anagrelide was authorised How the evidence changed—At The regulation did not substantially for the treatment of essential the time of approval it was known improve the evidence underlying their thrombocythaemia on the basis of that anagrelide reduced platelet approval2‑4 but allowed regulators to two compassionate use programmes count but not what its effects were grant marketing authorisation trusting verifying platelet count reduction on thrombotic or haemorrhagic that post-marketing research would in 1176 patients overall. Three complications of essential bridge the gap of knowledge on their further studies (the intended thrombocythaemia or whether it was safety and effectiveness. To check phase II, single arm, pivotal study; better than other platelet reducing whether those expectations are being another uncontrolled study; and a agents. Post-marketing studies met and the missing data provided, randomised comparative trial against indicate that anagrelide is probably we examined the evidence generated hydroxyurea) were either stopped worse than hydroxyurea in reducing in the 10 years after marketing early or reported unreliable efficacy thrombocythaemia related vascular authorisation for orphan products and safety data according to good events but no regulatory action has approved in a single year. clinical practice inspectors.5 been taken. Of the eight post-marketing Pre- and post-marketing available studies,6‑13 three compared anagrelide Cladribine evidence and hydroxyurea. In the largest Cladribine was approved for patients We analysed all six orphan products with hairy cell leukaemia on the basis authorised by the European Medicines KEY MESSAGES of two single arm studies reporting Agency (EMA) in 2004 (table) and inconsistent overall response rates • Authorisation of drugs for rare diseases with conducted a literature search for unmet treatment needs relies on post-marketing (97% and 19%). No overall survival 14 studies of these drugs up to December research to cover incomplete information figures were collected. 2014. We systematically searched After marketing approval two • However, questions about safety and effectiveness 15 16 MedLine, Embase, and Cochrane are seldom settled in the post-marketing phase studies found no difference in databases for published randomised response rates and toxicity with • Ongoing uncertainty about these drugs may harm clinical trials, observational studies, patients and waste health system resources the daily and weekly schedules of and meta-analyses of the selected cladribine. Another phase II single

528 25 June 2016 | the bmj Definition of “orphan medicinal product” European regulation No 141/2000 says that a medicinal product shall be designated as an orphan medicinal product if its sponsor can establish: a) That it is intended for the diagnosis, prevention, or treatment of a life threatening or chronically debilitating condition that affects ≤5 in 10 000 persons in the EU when the application is made or for which marketing is unlikely to generate sufficient return on investment without incentives b) And that no satisfactory method of diagnosis, prevention, or treatment of the condition has been authorised in the EU or, if such method exists, that the medicinal product will be of significant benefit to those affected by the condition

neurological or cognitive impairments arm study17 assessed responses a dose-range study18 and a double than intravenous ibuprofen.26 and bone marrow minimal residual blind randomised trial of prophylactic Of the two meta-analyses, one disease in 36 patients given five daily ibuprofen versus placebo in neonates showed that oral ibuprofen gave cladribine doses followed one month with gestational age less than 28 a higher ductal closure rate than later by eight weekly rituximab doses. weeks.18 Of the 47 infants who reached intravenous ibuprofen but the Persistent disease was reported in 36 weeks of gestational age, none rate was similar to intravenous 12/27 evaluable patients (44%) given in the ibuprofen group and five in indomethacin.24 The second meta- cladribine, while none had persistent the placebo group required surgery. analysis concluded that ibuprofen disease after rituximab. Ibuprofen was not recommended for was as effective as indomethacin How the evidence changed—Post- prophylactic use because the possible and possibly there was less risk of marketing studies did not help clarify small advantage in avoiding surgery necrotising enterocolitis and transient clabribine’s relative efficacy and place was counterbalanced by higher risks renal insufficiency.25 in therapy with respect to rituximab of renal failure and pulmonary adverse How the evidence changed—At or the inconsistent findings on the events without a survival advantage. the time of approval ibuprofen response of the disease. The trial was stopped at 60% of was known to be no better than recruitment. indomethacin for patent ductus Ibuprofen After the marketing authorisation, arteriosus. Post-marketing data Ibuprofen solution (Pedea) was five small single centre trials,19‑23 showed its renal toxicity in newborns approved for patent ductus arteriosus two systematic reviews with meta- with gestational age less than 27 in preterm newborns on the basis of analyses,24 25 and one observational EU regulation weeks. Information about the long a meta-analysis of six randomised study26 were published. One of the stipulates term neurological and pulmonary controlled trials comparing it with trials found that continuous infusion that new safety of ibuprofen relies on one indomethacin.18 The meta-analysis, of ibuprofen was more effective medicines observational study. The news was which was conducted by the company and just as safe as the bolus dose; are approved that paracetamol was as effective as itself, concluded that ibuprofen in a second trial ibuprofen proved on the basis ibuprofen but less toxic, but this was and indomethacin were equivalent as effective as indomethacin, while of proved never taken into account. with regard to ductal closure (75% v in two trials paracetamol was as quality, Mitotane 73%, odds ratio=1.14, 95% CI 0.73 effective as ibuprofen but safer. In efficacy, and to 1.77), requirement for surgical the last trial ibuprofen caused more Mitotane was approved for advanced safety, but ligation (11.7% in both groups, renal impairments than placebo in adrenal cortical carcinoma on the odds ratio=1.00, 0.55 to 1.81), and neonates with gestational age less few licensed basis of 18 uncontrolled studies, perinatal mortality (10.1% v 9.1%, than 27 weeks and in low birthweight orphan mostly retrospective case series.27 hazard ratio=1.11, 0.55 to 2.24). infants. The observational study found products meet Only a few studies had evaluated the The regulatory dossier also included that oral ibuprofen caused no fewer these criteria efficacy of mitotane on survival with

Evidence available before and after marketing for six orphan drugs approved in 2004 Best available evidence Type of evidence (GRADE level) Orphan drug (disease) Before After Before After Anagrelide (essential thrombocythaemia) Platelet count reduction More vascular events than with adequate comparator* Case series (4) Superiority RCT (2b) Cladribine (hairy cell leukaemia) Inconsistent response rates (19-97%) 56% responses after cladribine became 100% after Case series (4) Case series (4) rituximab† Ibuprofen (patent ductus arteriosus (PDA)) As effective as indomethacin in As effective as indomethacin in closing PDA, but less Meta-analysis of Systematic review with closing PDA necrotising enterocolitis and transient renal insufficiency† RCT (1a) meta-analysis of RCT (1a) Mitotane (adrenal cortical carcinoma) Response rate 20-30% Response rate 48.6%† Case series (4) Case series (4) Porfimer sodium (Barrett’s oesophagus) More frequent ablation of dysplasia Reduced risk of adenocarcinoma as add-on to omeprazole‡ RCT (1b) RCT (1b) as add-on to omeprazole Zinc acetate (Wilson’s disease) Prevents progression of disease None† Case series (4) None Case series means uncontrolled studies. RCT=randomised controlled trial. GRADE rating of evidence ranges from 1 (highest) to 5. *Post-marketing trial shows worse efficacy. †Evidence unchanged. ‡Post-marketing studies show better efficacy but drug withdrawn for safety reasons. the bmj | 25 June 2016 529 respect to activity, and their results contributed slightly to defining its Whenever are still on the market. The US were contradictory. role in treatment relative to other the efficacy Food and Drug Administration also The post-marketing research options such as 5-aminolaevulinic or safety of an approved these drugs with no post- 28 included one randomised trial, two acid and argon plasma coagulation. orphan product marketing commitments, and all of single arm studies (one phase I29 and Unfortunately, porfimer was them are still on the US market. 30 is not clear, the one phase II ), and one observational withdrawn from the market in 2012 EMA should The present situation is concerning. study.31 The randomised trial28 because of reports suggesting it Licensing of orphan products with 32 require further showed no difference in overall caused deep vein thrombosis. no or incomplete proof of their survival in patients treated with clinical research efficacy and safety, sometimes even mitotane-etoposide-doxorubicin- Zinc acetate dehydrate relative to other available treatments, cisplatin or mitotane-streptozocin Zinc acetate dehydrate was approved may unduly harm patients and (14.8 months and 12.0 months, for Wilson’s disease, an autosomal waste health service resources.40 respectively; hazard ratio=0.79, 95% recessive defect in hepatic excretion EU regulation stipulates that new CI 0.61 to 1.02; P=0.07). The phase of copper, on the basis of long use in medicines are approved on the I, single arm trial of the combination clinical practice as a maintenance basis of proved quality, efficacy, of mitotane and cixutumumab was treatment. Other zinc salts had long and safety, but few licensed orphan terminated on account of toxicity.29 been used to reduce the intestinal products meet these criteria.41 The phase II uncontrolled study31 absorption of copper. The marketing Moreover, the regulation on orphan found complete response in only 5/72 authorisation was granted on the products allows market exclusivity patients. The observational study31 basis of data accumulated over more only for new products that are showed that only patients receiving than 40 years.38 Most came from shown to be “clinically superior” to early specialised care survived longer. a cohort of 148 patients treated competitors already on the market.1 How the evidence changed— None with zinc since the 1980s.39 The This is difficult to achieve without of the studies showed any survival evaluation was based on an overall comparative trials that have clinically benefit with mitotane. clinical impression of lack of disease meaningful outcomes. progression. These problems apply to any Porfimer sodium The dossier also included medicine approved on the basis Porfimer was approved for uncontrolled studies and one trial of insufficient evidence, not just photodynamic treatment of Barrett's using zinc sulphate (the two zinc salts orphan products.40 Moves to abridge oesophagus. Clinical data in the are pharmacologically comparable and simplify the evaluation of new regulatory dossier came from one and they are dealt with as such in the medicines, such as conditional randomised trial and two single European public assessment report).38 approvals and adaptive licensing, centre, uncontrolled studies.32 In the The one non-randomised trial of zinc should therefore be approached with controlled trial complete ablation sulphate versus penicillamine was in caution.42 Whenever the efficacy or of dysplasia was more common 67 newly diagnosed patients, 56 of safety of an orphan product is not with porfimer plus omeprazole than whom had symptoms.38 Improvement clear, the EMA should require further omeprazole alone (76.8% v 38.6% at was reported in 15 patients in the zinc clinical research—for example, to 24 months). group and 14 in the penicillamine prove real clinical benefit in the long Three randomised trials were group, and deterioration in, term instead of surrogate advantages published post-marketing,33‑35 respectively, two and three patients in a limited time frame. Evidence together with two dose escalation from the two groups. should be provided well before the 10 studies36 and one observational How the evidence changed—Post- year market protection expires. If the retrospective study published as marketing studies suggest that zinc company does not comply with the an abstract.37 In one trial porfimer has similar efficacy to penicillamine EMA’s requests, the agency should plus omeprazole reduced the risk in Wilson’s disease and lower toxicity withhold its marketing authorisation, of adenocarcinoma more than than other copper chelators. Despite engage an independent institution omeprazole alone (13% v 20%, this, no post-marketing head to head to complete the requested studies, P=0.006 at two years and 15% v 29%, trials have been done. and in the meantime ensure the P=0.004 at five years).33 The second drug is available to currently treated trial found argon plasma coagulation Need for change patients through an expanded access and porfimer sodium equally effective Our analysis shows that post- programme. 34 in eradicating Barrett’s mucosa. marketing clinical research did not Roberta Joppi, researcher The final trial35 found no difference in satisfactorily cover the deficit of [email protected] efficacy and safety of photodynamic knowledge about orphan products Chiara Gerardi, researcher treatment with 5-aminolaevulinic at the time of their licensing in 2004. Vittorio Bertele’, researcher Silvio Garattini, director, IRCCS-Istituto di acid or porfimer. Furthermore, manufacturers were not Ricerche Farmacologiche Mario Negri, Milan, How the evidence changed— obliged to carry out further studies. Italy; and Pharmaceutical Department, Local Post-marketing studies confirmed Despite lack of evidence, the original Health Unit of Verona, Italy the better efficacy of porfimer as regulatory decisions were not revised Cite this as: BMJ 2016;353:i2978 an add-on to omeprazole and and all the products except porfimer Find this at: http://dx.doi.org/10.1136/bmj.i2978

530 25 June 2016 | the bmj Noshir Hormusjee Wadia Pioneer in Indian neurology

Noshir Hormusjee Wadia (b 1925, show the scale of the challenges that q Grant Medical College, Mumbai, faced him. He strived to bring in new 1950; MRCP Lon), d 10 April 2016. technologies and best practices, which enabled the unit to build a formidable Noshir Hormusjee Wadia was born reputation. In 1973 he set up another to a Parsi family of modest means. neurology department at a private He eschewed the family’s timber hospital, Jaslok Hospital and Research business and became a doctor. In 1950 Centre, which is now recognised for he graduated from Mumbai’s Grant postgraduate studies. Medical College and Sir JJ Hospital with a degree in general medicine. Research and an Indian perspective Wadia is credited with having Neurology and independence identified two unique Indian As a graduate student, Wadia was diseases—a new variant of keenly interested in neurology, but the hereditary ataxia with slow eye scope for specialisation in the subject movements, and adult poliomyelitis Wadia is and girls” have gone on to hold did not exist in India at the time. So due to a new virus (enterovirus 70) credited pivotal positions as clinicians and when he travelled to England to sit associated with pandemic acute with having academicians around the world. He the examination for membership haemorrhagic conjunctivitis. His identified two would be generous with his time and of the Royal College of Physicians studies included neurological unique Indian advice whenever students approached (MRCP), Wadia was determined to complications of manganese diseases him. He helped students obtain make the most of it. In London he poisoning in Indian miners, the scholarships for further studies and signed up for a three month course on high prevalence of craniovertebral used his connections around the neurology. After obtaining his MRCP, anomalies in India, Wilson’s disease, world to help them undertake further Wadia decided to undergo further tuberculosis presenting primarily as training. Misra and Vijayaraghavan training. He joined the department spinal meningitis, and nutritional were among the many whom Wadia of neurosurgery at Newcastle disorders of the nervous system—all counselled and assisted by introducing General Hospital, after which he was of which he reported and published. them to faculty at institutes overseas. appointed regional medical officer Wadia’s former students V Peter One unfortunate incident in Wadia’s at the National Hospital for Nervous Misra and Shanti Vijayaraghavan life brought together doctors from Diseases in Maida Vale, London, in said that when he returned to India across the world. In 1961, as he was 1953. This gave him the opportunity he immediately noticed that the returning from a neurology event in to work with some of the finest prevalence of neurological diseases Buenos Aires, he was forcibly detained neurologists in the UK—including was different from the rates in the in Portugal as retaliation for India’s Russell Brain. Wadia demonstrated standard textbooks. So he researched, invasion of Goa. Dorothy Russell, a exemplary medical acumen there and planned, and edited a multiauthored renowned British neuropathologist, was soon appointed registrar to Brain. book, Neurological Practice: an wrote a letter to The BMJ, “In After four years in the UK, Wadia Indian Perspective. Wadia supported December 1961, Dr N H Wadia, an returned to India at the age of 32. In patients and their families. He was Indian neurologist well known to 1957 he joined his alma mater—as founder, trustee, or member of many in England after having worked honorary assistant neurologist at numerous societies, and the founder as registrar in two London teaching the JJ and lecturer in neurology at member of the Indian Epilepsy hospitals, was detained in Portugal for Grant Medical College. At a time Association. He also supported two months in the notorious Caxias when neurology was considered a societies for multiple sclerosis, prison as a reprisal for the Indian separate discipline at many leading muscular dystrophy, Parkinson’s annexation of Goa . . . Continued institutions around the world, Wadia disease, and motor neurone disease. pressure from medical bodies and was given the mandate to set up one Numerous honours—including eminent neurologists in this and of the first departments in India. the Padma Bhushan, India’s third other European countries, the A few months later, Gajendra Sinh highest civilian award bestowed on USA, and Chile helped to hasten Dr and Jimmy Sidhva joined the JJ, and him in 2012—recognised Wadia’s Wadia’s release.” together the three doctors built a many accomplishments. Wadia leaves his wife, Piroja; two formidable neurosciences unit. The stepsons; and four step-grandchildren. department grew from six to 45 beds Teaching career Jeetha D’Silva, Mumbai over 25 years. Wadia’s accounts of Wadia trained nearly 100 neurologists [email protected] the early years of the department over half a century. Many of his “boys Cite this as: BMJ 2016;353:i2613 the bmj | 25 June 2016 531 LETTERS Selected from rapid responses on thebmj.com. See www.bmj.com/rapid-responses

DPP-4 INHIBITORS But in the paper CKD and SLE LETTER OF THE WEEK don’t fall in the high risk category, Inclusion of EXAMINE study Heart safety of methylphenidate in adults as more than one risk factor is in DPP-4 meta-analysis needed. UK obstetricians will find The main criterion in Salvo and Shin and colleagues it difficult not to start aspirin in colleagues’ meta-analysis on showed an increased patients with CKD or SLE when increased risk of hypoglycaemia risk of arrhythmia from these are the only risk factors was that trials studied the methylphenidate in present. effect of adding one dipeptidyl children and young Secondly, the findings will peptidase-4 (DPP-4) inhibitor people with attention- generate debate in managing or placebo to sulphonylureas deficit/hyperactivity and investigating small for (Research, 7 May). disorder (ADHD) gestational age fetuses, as RCOG It is unclear why the EXAMINE (Research, 4 June). We guideline 31 recognises SLE and study was included—a were recently notified of CKD as a major (single) risk factor cardiovascular outcome study a spontaneous adverse drug reaction of ventricular extrasystoles in qualifying aspirin use before 16 comparing alogliptin with an adult patient who had taken only methylphenidate. Treatment weeks. placebo, plus standard care was stopped and cardiological evaluation seven months later gave Junaid Rafi ([email protected]) for type 2 diabetes. It did not normal results. The causality (imputation) score was deemed likely. Cite this as: BMJ 2016;353:i3403 compare adding alogliptin or To investigate this adverse drug reaction, we used VigiBase, placebo to sulphonylureas WHO’s global individual case safety report (ICSR) database. Among or assess specific drug the 9 573 704 reports between 1978 and 2016 in which both age Authors’ reply combinations. and sex were known, 18 329 concerned methylphenidate, 30 having WHO, NICE, and the USPSTF find Treatments and doses other been registered as ventricular extrasystoles. After medical review aspirin prophylaxis appropriate than alogliptin and placebo of these 30 reports, 27 were included. Most (22) cases occurred in in high risk women, listing could change during the study children and young people, but five were in adults. chronic kidney disease (CKD) and at the investigators’ discretion. These case reports from another international database are in systemic lupus erythematosus Moreover, standard care differs agreement with the work of Shin and colleagues. Thus we emphasise (SLE) as “high risk” factors for between countries. In Europe, the potential risk of cardiac arrhythmia in general and of ventricular pre-eclampsia. We estimated the 4 mg glibenclamide daily is extrasystoles in particular, not only in children and young people but absolute risk, aiming to quantify recommended; in the US, 8 mg also in adults, during exposure to methylphenidate. Although this it and compare it with a threshold glimepiride can be used. serious adverse drug reaction is rare as indicated by the number of that may warrant aspirin The EXAMINE results probably reports on VigiBase, it should be taken into account because of the prophylaxis. reflected patients’ baseline widespread exposure to methylphenidate. CKD and SLE were not among characteristics. A major follow-up François Montastruc ([email protected]), Guillaume Montastruc, the solitary risk factors to warrant bias makes it unsuitable for this Jean-Louis Montastruc, Alexis Revet this. At a 10% relative risk meta-analysis. And the authors Cite this as: BMJ 2016;353:i3418 reduction (RRR) the threshold state that results would be similar number needed to prevent (NNP) after excluding it, but it accounts patients’ clinical status (eg, Francesco Salvo for CKD is below 200, but its ([email protected]), for 35.8% of the pooled analysis. hypoglycaemia events). Nicholas Moore, Mickael Arnaud, upper 95% confidence interval Denis Boucaud-Maitre It was a “pragmatic trial” in Philip Robinson, Emanuel Raschi, crosses the NNP of 250. If aspirin ([email protected]) Fabrizio De Ponti, Bernard Bégaud, primary care in patients with Antoine Pariente conferred a 30% or 50% RRR Cite this as: BMJ 2016;353:i3186 type 2 diabetes, and it offered Cite this as: BMJ 2016;353:i3188 against pre-eclampsia, the NNP high quality information for our for CKD falls significantly below Authors’ reply meta-analysis. We asked the PRE-ECLAMPSIA RISK FACTORS 250—an adoptable solitary risk The methodological problem authors how many patients in the Pre-eclampsia paper raises factor. For SLE, however, it did Boucaud-Maitre raises was alogliptin and placebo groups not fall below the threshold at discussed in the selection used sulphonylureas at baseline aspirin dilemma any RRR, largely because of wide process, and we decided to and the corresponding number Bartsch and colleagues confidence intervals from the few include this trial for various of hypoglycaemia events. quantify risk factors for pre- studies on pregnancy outcomes. reasons. EXAMINE probably Consequently, we conducted an eclampsia (Research, 23 April), Some clinicians may still feel better reflects real life situations intention-to-treat analysis. We do but clinicians face a dilemma comfortable deeming CKD and than other studies because not believe that a different kind of following the recommendations. SLE important enough solitary no action on standard care analysis (eg, per protocol) would Firstly, NICE states that women risk factors to warrant aspirin was taken before the trial, and have greatly altered the EXAMINE with chronic kidney disease prophylaxis. the glucose lowering regimen result because most treatment (CKD) and systemic lupus Joel G Ray ([email protected]), could be modified in the changes would have occurred erythematosus (SLE) are high Emily Bartsch follow-up period according to after a hypoglycaemic event. risk, qualifying to start aspirin. Cite this as: BMJ 2016;353:i3402

532 25 June 2016 | the bmj