Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients (14 page)

Rosiglitazone was first marketed in 1999, and from the outset it was a magnet for disappointing behaviour. In that first year, Dr John Buse from the University of North Carolina discussed an increased risk of heart problems at a pair of academic meetings. The drug’s manufacturer, GSK, made direct contact in an attempt to silence him, then moved on to his head of department. Buse felt pressured to sign various legal documents. To cut a long story short, after wading through documents for several months, in 2007 the US Senate Committee on Finance released a report describing the treatment of Dr Buse as ‘intimidation’.

But we are more concerned with the safety and efficacy data. In 2003 the Uppsala Drug Monitoring Group of the World Health Organization contacted GSK about an unusually large number of spontaneous reports associating rosiglitazone with heart problems. GSK conducted two internal meta-analyses of its own data on this, in 2005 and 2006. These showed that the risk was real, but although both GSK and the FDA had these results, neither made any public statement about them, and they were not published until 2008.

During this delay, vast numbers of patients were exposed to the drug, but doctors and patients only learned about this serious problem in 2007, when cardiologist Professor Steve Nissen and colleagues published a landmark meta-analysis. This showed a 43 per cent increase in the risk of heart problems in patients on rosiglitazone. Since people with diabetes are already at increased risk of heart problems, and the whole point of treating diabetes is to reduce this risk, that finding was big potatoes. His findings were confirmed in later work, and in 2010 the drug was either taken off the market or restricted, all around the world.

Now, my argument is not that this drug should have been banned sooner, because as perverse as it sounds, doctors do often need inferior drugs for use as a last resort. For example, a patient may develop idiosyncratic side effects on the most effective pills, and be unable to take them any longer. Once this has happened, it may be worth trying a less effective drug, if it is at least better than nothing.

The concern is that these discussions happened with the data locked behind closed doors, visible only to regulators. In fact, Nissen’s analysis could only be done at all because of a very unusual court judgement. In 2004, when GSK was caught out withholding data showing evidence of serious side effects from paroxetine in children, the UK conducted an unprecedented four-year-long investigation, as we saw earlier. But in the US, the same bad behaviour resulted in a court case over allegations of fraud, the settlement of which, alongside a significant payout, required GSK to commit to posting clinical trial results on a public website.

Professor Nissen used the rosiglitazone data, when it became available, found worrying signs of harm, and published this to doctors, which is something that the regulators had never done, despite having the information years earlier. (Though before doctors got to read it, Nissen by chance caught GSK discussing a copy of his unpublished paper, which it had obtained improperly.
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If this information had all been freely available from the start, regulators might have felt a little more anxious about their decisions, but crucially, doctors and patients could have disagreed with them, and made informed choices. This is why we need wider access to full CSRs, and all trial reports, for all medicines, and this is why it is perverse that Roche should be able even to contemplate deciding which favoured researchers should be allowed to read the documents on Tamiflu.

Astonishingly, a piece published in April 2012 by regulators from the UK and Europe suggests that they might agree to more data sharing, to a limited extent, within limits, for some studies, with caveats, at the appropriate juncture, and in the fullness of time.
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Before feeling any sense of enthusiasm, we should remember that this is a cautious utterance, wrung out after the dismal fights I have already described; that it has not been implemented; that it must be set against a background of broken promises from all players across the whole field of missing data; and that in any case, regulators do not have all the trial data anyway. But it is an interesting start.

Their two main objections – if we accept their goodwill at face value – are interesting, because they lead us to the final problem in the way we tolerate harm to patients from missing trial data. Firstly, they raise the concern that some academics and journalists might use study reports to conduct histrionic or poorly conducted reviews of the data: to this, again, I say, ‘Let them,’ because these foolish analyses should be conducted, and then rubbished, in public.

When UK hospital mortality statistics first became easily accessible to the public, doctors were terrified that they would be unfairly judged: the crude figures can be misinterpreted, after all, because one hospital may have worse figures simply because it is a centre of excellence, and takes in more challenging patients than its neighbours; and there is random variation to be expected in mortality rates anyway, so some hospitals might look unusually good, or bad, simply through the play of chance. Initially, to an extent, these fears were realised: there were a few shrill, unfair stories, and people overinterpreted the results. Now, for the most part, things have settled down, and many lay people are quite able to recognise that crude analyses of such figures are misleading. For drug data, where there is so much danger from withheld information, and so many academics desperate to conduct meaningful analyses, and so many other academics happy to criticise them, releasing the data is the only healthy option.

But secondly, the EMA raises the spectre of patient confidentiality, and hidden in this concern is one final prize.

So far I have been talking about access to trial reports, summaries of patients’ outcomes in trials. There is no good reason to believe that this poses any threat to patient confidentiality, and where there are specific narratives that might make a patient identifiable – a lengthy medical description of one person’s idiosyncratic adverse event in a trial, perhaps – these can easily be removed, since they appear in a separate part of the document. These CSRs should undoubtedly, without question, be publicly available documents, and this should be enforced retrospectively, going back decades, to the dawn of trials.

But all trials are ultimately run on individual patients, and the results of those individual patients are all stored and used for the summary analysis at the end of the study. While I would never suggest that these should be posted up on a public website – it would be easy for patients to be identifiable, from many small features of their histories – it is surprising that patient-level data is almost never shared with academics.

Sharing data of individual patients’ outcomes in clinical trials, rather than just the final summary result, has several significant advantages. Firstly, it’s a safeguard against dubious analytic practices. In the VIGOR trial on the painkiller Vioxx, for example, a bizarre reporting decision was made.
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The aim of the study was to compare Vioxx against an older, cheaper painkiller, to see if it was any less likely to cause stomach problems (this was the hope for Vioxx), and also if it caused more heart attacks (this was the fear). But the date cut-off for measuring heart attacks was much earlier than that for measuring stomach problems. This had the result of making the risks look less significant, relative to the benefits, but it was not declared clearly in the paper, resulting in a giant scandal when it was eventually noticed. If the raw data on patients was shared, games like these would be far easier to spot, and people might be less likely to play them in the first place.

Occasionally – with vanishing rarity – researchers are able to obtain raw data, and reanalyse studies that have already been conducted and published. Daniel Coyne, Professor of Medicine at Washington University, was lucky enough to get the data on a key trial for epoetin, a drug given to patients on kidney dialysis, after a four-year-long fight.
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The original academic publication on this study, ten years earlier, had switched the primary outcomes described in the protocol (we will see later how this exaggerates the benefits of treatments), and changed the main statistical analysis strategy (again, a huge source of bias). Coyne was able to analyse the study as the researchers had initially stated they were planning to in their protocol; and when he did, he found that they had dramatically overstated the benefits of the drug. It was a peculiar outcome, as he himself acknowledges: ‘As strange as it seems, I am now the sole author of the publication on the predefined primary and secondary results of the largest outcomes trial of epoetin in dialysis patients, and I didn’t even participate in the trial.’ There is room, in my view, for a small army of people doing the very same thing, reanalysing all the trials that were incorrectly analysed, in ways that deviated misleadingly from their original protocols.

Data sharing would also confer other benefits. It allows people to conduct more exploratory analyses of data, and to better investigate – for example – whether a drug is associated with a particular unexpected side effect. It would also allow cautious ‘subgroup analyses’, to see if a drug is particularly useful, or particularly useless, in particular types of patients.

The biggest immediate benefit from data sharing is that combining individual patient data into a meta-analysis gives more accurate results than working with the crude summary results at the end of a paper. Let’s imagine that one paper reports survival at three years as the main outcome for a cancer drug, and another reports survival at seven years. To combine these two in a meta-analysis, you’d have a problem. But if you were doing the meta-analysis with access to individual patient data, with treatment details and death dates for all of them, you could do a clean combined calculation for three-year survival.

This is exactly the kind of work being done in the area of breast cancer research, where a small number of charismatic and forceful scientists just happen to have driven a pioneering culture of easier collaboration. The summaries they are publishing represent real collaboration, between vast numbers of people, and on vast numbers of patients, producing highly reliable guidance for doctors and patients.

The process sheds a stark light on the reality of data collaboration on such a large scale. Here, for example, is the author list on an academic paper from the
Lancet
in November 2011: it’s reporting an immense, definitive, and incredibly useful meta-analysis of breast cancer treatment outcomes, using individual patient data pooled from seventeen different trials. The author list is printed in four-point font size (though I suspect that might go wrong in the e-book edition…) because there are seven hundred individual researchers named in it. I typed each of them in by hand for you.

Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, Cutter D, Davies C, Ewertz M, Godwin J, Gray R, Pierce L, Whelan T, Wang Y, Peto R.Albain K, Anderson S, Arriagada R, Barlow W, Bergh J, Bliss J, Buyse M, Cameron D, Carrasco E, Clarke M, Correa C, Coates A, Collins R, Costantino J, Cutter D, Cuzick J, Darby S, Davidson N, Davies C, Davies K, Delmestri A, Di Leo A, Dowsett M, Elphinstone P, Evans V, Ewertz M, Gelber R, Gettins L, Geyer C, Goldhirsch A, Godwin J, Gray R, Gregory C, Hayes D, Hill C, Ingle J, Jakesz R, James S, Kaufmann M, Kerr A, MacKinnon E, McGale P, McHugh T, Norton L, Ohashi Y, Paik S, Pan HC, Perez E, Peto R, Piccart M, Pierce L, Pritchard K, Pruneri G, Raina V, Ravdin P, Robertson J, Rutgers E, Shao YF, Swain S, Taylor C, Valagussa P, Viale G, Whelan T, Winer E, Wang Y, Wood W, Abe O, Abe R, Enomoto K, Kikuchi K, Koyama H, Masuda H, Nomura Y, Ohashi Y, Sakai K, Sugimachi K, Toi M, Tominaga T, Uchino J, Yoshida M, Haybittle JL, Leonard CF, Calais G, Geraud P, Collett V, Davies C, Delmestri A, Sayer J, Harvey VJ, Holdaway IM, Kay RG, Mason BH, Forbes JF, Wilcken N, Bartsch R, Dubsky P, Fesl C, Fohler H, Gnant M, Greil R, Jakesz R, Lang A, Luschin-Ebengreuth G, Marth C, Mlineritsch B, Samonigg H, Singer CF, Steger GG, Stöger H, Canney P, Yosef HM, Focan C, Peek U, Oates GD, Powell J, Durand M, Mauriac L, Di Leo A, Dolci S, Larsimont D, Nogaret JM, Philippson C, Piccart MJ, Masood MB, Parker D, Price JJ, Lindsay MA, Mackey J, Martin M, Hupperets PS, Bates T, Blamey RW, Chetty U, Ellis IO, Mallon E, Morgan DA, Patnick J, Pinder S, Olivotto I, Ragaz J, Berry D, Broadwater G, Cirrincione C, Muss H, Norton L, Weiss RB, Abu-Zahra HT, Portnoj SM, Bowden S, Brookes C, Dunn J, Fernando I, Lee M, Poole C, Rea D, Spooner D, Barrett-Lee PJ, Mansel RE, Monypenny IJ, Gordon NH, Davis HL, Cuzick J, Lehingue Y, Romestaing P, Dubois JB, Delozier T, Griffon B, Mace Lesec'h J, Rambert P, Mustacchi G, Petruzelka, Pribylova O, Owen JR, Harbeck N, Jänicke F, Meisner C, Schmitt M, Thomssen C, Meier P, Shan Y, Shao YF, Wang X, Zhao DB, Chen ZM, Pan HC, Howell A, Swindell R, Burrett JA, Clarke M, Collins R, Correa C, Cutter D, Darby S, Davies C, Davies K, Delmestri A, Elphinstone P, Evans V, Gettins L, Godwin J, Gray R, Gregory C, Hermans D, Hicks C, James S, Kerr A, MacKinnon E, Lay M, McGale P, McHugh T, Sayer J, Taylor C, Wang Y, Albano J, de Oliveira CF, Gervásio H, Gordilho J, Johansen H, Mouridsen HT, Gelman RS, Harris JR, Hayes D, Henderson C, Shapiro CL, Winer E, Christiansen P, Ejlertsen B, Ewertz M, Jensen MB, Møller S, Mouridsen HT, Carstensen B, Palshof T, Trampisch HJ, Dalesio O, de Vries EG, Rodenhuis S, van Tinteren H, Comis RL, Davidson NE, Gray R, Robert N, Sledge G, Solin LJ, Sparano JA, Tormey DC, Wood W, Cameron D, Chetty U, Dixon JM, Forrest P, Jack W, Kunkler I, Rossbach J, Klijn JG, Treurniet-Donker AD, van Putten WL, Rotmensz N, Veronesi U, Viale G, Bartelink H, Bijker N, Bogaerts J, Cardoso F, Cufer T, Julien JP, Rutgers E, van de Velde CJ, Cunningham MP, Huovinen R, Joensuu H, Costa A, Tinterri C, Bonadonna G, Gianni L, Valagussa P, Goldstein LJ, Bonneterre J, Fargeot P, Fumoleau P, Kerbrat P, Luporsi E, Namer M, Eiermann W, Hilfrich J, Jonat W, Kaufmann M, Kreienberg R, Schumacher M, Bastert G, Rauschecker H, Sauer R, Sauerbrei W, Schauer A, Schumacher M, Blohmer JU, Costa SD, Eidtmann H, Gerber G, Jackisch C, Loibl S, von Minckwitz G, de Schryver A, Vakaet L, Belfiglio M, Nicolucci A, Pellegrini F, Pirozzoli MC, Sacco M, Valentini M, McArdle CS, Smith DC, Stallard S, Dent DM, Gudgeon CA, Hacking A, Murray E, Panieri E, Werner ID, Carrasco E, Martin M, Segui MA, Galligioni E, Lopez M, Erazo A, Medina JY, Horiguchi J, Takei H, Fentiman IS, Hayward JL, Rubens RD, Skilton D, Scheurlen H, Kaufmann M, Sohn HC, Untch M, Dafni U, Markopoulos C, Dafni D, Fountzilas G, Mavroudis D, Klefstrom P, Saarto T, Gallen M, Margreiter R, de Lafontan B, Mihura J, Roché H, Asselain B, Salmon RJ, Vilcoq JR, Arriagada R, Bourgier C, Hill C, Koscielny S, Laplanche A, Lê MG, Spielmann M, A'Hern R, Bliss J, Ellis P, Kilburn L, Yarnold JR, Benraadt J, Kooi M, van de Velde AO, van Dongen JA, Vermorken JB, Castiglione M, Coates A, Colleoni M, Collins J, Forbes J, Gelber RD, Goldhirsch A, Lindtner J, Price KN, Regan MM, Rudenstam CM, Senn HJ, Thuerlimann B, Bliss JM, Chilvers CE, Coombes RC, Hall E, Marty M, Buyse M, Possinger K, Schmid P, Untch M, Wallwiener D, Foster L, George WD, Stewart HJ, Stroner P, Borovik R, Hayat H, Inbar MJ, Robinson E, Bruzzi P, Del Mastro L, Pronzato P, Sertoli MR, Venturini M, Camerini T, De Palo G, Di Mauro MG, Formelli F, Valagussa P, Amadori D, Martoni A, Pannuti F, Camisa R, Cocconi G, Colozza A, Passalacqua R, Aogi K, Takashima S, Abe O, Ikeda T, Inokuchi K, Kikuchi K, Sawa K, Sonoo H, Korzeniowski S, Skolyszewski J, Ogawa M, Yamashita J, Bastiaannet E, van de Velde CJ, van de Water W, van Nes JG, Christiaens R, Neven P, Paridaens R, Van den Bogaert W, Braun S, Janni W, Martin P, Romain S, Janauer M, Seifert M, Sevelda P, Zielinski CC, Hakes T, Hudis CA, Norton L, Wittes R, Giokas G, Kondylis D, Lissaios B, de la Huerta R, Sainz MG, Altemus R, Camphausen K, Cowan K, Danforth D, Lichter A, Lippman M, O'Shaughnessy J, Pierce LJ, Steinberg S, Venzon D, Zujewski JA, D'Amico C, Lioce M, Paradiso A, Chapman JA, Gelmon K, Goss PE, Levine MN, Meyer R, Parulekar W, Pater JL, Pritchard KI, Shepherd LE, Tu D, Whelan T, Nomura Y, Ohno S, Anderson A, Bass G, Brown A, Bryant J, Costantino J, Dignam J, Fisher B, Geyer C, Mamounas EP, Paik S, Redmond C, Swain S, Wickerham L, Wolmark N, Baum M, Jackson IM, Palmer MK, Perez E, Ingle JN, Suman VJ, Bengtsson NO, Emdin S, Jonsson H, Del Mastro L, Venturini M, Lythgoe JP, Swindell R, Kissin M, Erikstein B, Hannisdal E, Jacobsen AB, Varhaug JE, Erikstein B, Gundersen S, Hauer-Jensen M, Høst H, Jacobsen AB, Nissen-Meyer R, Blamey RW, Mitchell AK, Morgan DA, Robertson JF, Ueo H, Di Palma M, Mathé G, Misset JL, Levine M, Pritchard KI, Whelan T, Morimoto K, Sawa K, Takatsuka Y, Crossley E, Harris A, Talbot D, Taylor M, Martin AL, Roché H, Cocconi G, di Blasio B, Ivanov V, Paltuev R, Semiglazov V, Brockschmidt J, Cooper MR, Falkson CI, A'Hern R, Ashley S, Dowsett M, Makris A, Powles TJ, Smith IE, Yarnold JR, Gazet JC, Browne L, Graham P, Corcoran N, Deshpande N, di Martino L, Douglas P, Hacking A, Høst H, Lindtner A, Notter G, Bryant AJ, Ewing GH, Firth LA, Krushen-Kosloski JL, Nissen-Meyer R, Anderson H, Killander F, Malmström P, Rydén L, Arnesson LG, Carstensen J, Dufmats M, Fohlin H, Nordenskjöld B, Söderberg M, Carpenter JT, Murray N, Royle GT, Simmonds PD, Albain K, Barlow W, Crowley J, Hayes D, Gralow J, Green S, Hortobagyi G, Livingston R, Martino S, Osborne CK, Adolfsson J, Bergh J, Bondesson T, Celebioglu F, Dahlberg K, Fornander T, Fredriksson I, Frisell J, Göransson E, Iiristo M, Johansson U, Lenner E, Löfgren L, Nikolaidis P, Perbeck L, Rotstein S, Sandelin K, Skoog L, Svane G, af Trampe E, Wadström C, Castiglione M, Goldhirsch A, Maibach R, Senn HJ, Thürlimann B, Hakama M, Holli K, Isola J, Rouhento K, Saaristo R, Brenner H, Hercbergs A, Martin AL, Roché H, Yoshimoto M, Paterson AH, Pritchard KI, Fyles A, Meakin JW, Panzarella T, Pritchard KI, Bahi J, Reid M, Spittle M, Bishop H, Bundred NJ, Cuzick J, Ellis IO, Fentiman IS, Forbes JF, Forsyth S, George WD, Pinder SE, Sestak I, Deutsch GP, Gray R, Kwong DL, Pai VR, Peto R, Senanayake F, Boccardo F, Rubagotti A, Baum M, Forsyth S, Hackshaw A, Houghton J, Ledermann J, Monson K, Tobias JS, Carlomagno C, De Laurentiis M, De Placido S, Williams L, Hayes D, Pierce LJ, Broglio K, Buzdar AU, Love RR, Ahlgren J, Garmo H, Holmberg L, Liljegren G, Lindman H, Wärnberg F, Asmar L, Jones SE, Gluz O, Harbeck N, Liedtke C, Nitz U, Litton A, Wallgren A, Karlsson P, Linderholm BK, Chlebowski RT, Caffier H.