Machlojki swiatka nauki

W British Medical Journal w 2007 ukazal sie artykul dot. etyki w badaniach klinicznych. Ciagle aktualny.

Dr Julio Cruz, Brazylyjczyk, który równiez pracowal w U.S.A, sprawdzil skutecznosci dzialania wysokich dawek mannitolu u chorych w glebokiej spiaczce. Wyszlo Mu, ze wysokie dawki sa znacznie skuteczniejsze niz dotychczas stosowane gdyz smiertelnosc jest mniejsza. Wykazal rowniez, ze ubytki neurologiczne sa znacznie mniejsze u chorych ktorzy otrzymali wysokie dawki w prownaniu z tymi ktorzy otrzymali dawki standardowe. Zachecajace. Neurolodzy przyjeli wyniki z entuzjazmem. Badania opublikowano w dwoch renomowanych pismach medycznych – Neurosurgery i Journal of Neurosurgery.

Doktor Cruz mial 3 wspolautorow. Jeden z Japonii i dwoch medykow z Wloch. Niestety, doctor Cruz cierpial na depresje i w 2008 roku popelnil samobojstwo dlatego nic wiecej juz nam nie powie. Pozostaja nam jedynie Jego zagadkowe badania.

Na pewnym zjezdzie lekarzy w Ameryce Poludniowej, kilku neurochirurgow poddalo w watpliwosc rzetelnosc zebranych danych poniewaz doktor Cruz kiedy przeniosl sie do Brazylii nie mial wlasnych chorych. Badania pokazuja,ze chorych rekrutowa w U.S.A i w Brazylii. Mamy problem. Zaczyna sie dochodzenie.Doktor Cruz nic wiecej nam nie powie bowiem popelnil samobojstwo w 2008 na skutek ciezkiej depresji. Mamy jednak do dyspozycji 3 wspolautorow.

Kontakty z nimi owocowaly w bardzo ciekawa korespondencje ktora znajdziecie tu http://www.crash2.lshtm.ac.uk/Mannitol.htm

Co sie okazuje. Wszyscy znali doktora Cruza, ale nikt CZYNNEGO udzialu w badaniach nie bral. Byli tzw. Gift authors. Jeden z nich dyskutowal z nim telefonicznie i mial wrazenie,ze rowniez chorzyh na wysokich dawkach mannitolu maja mniej ubytkow neurologicznych i,ze czesc z nich wychodzi ze spiaczki.

Panowie z Wloch tez mieli swoj udzial w badanch. Jeden z nich przeczytal i zrecenzowal wyniki. Drugi mial role “ filozoficzna” tak jak sam to okresla.

Glowny autor zmarl. Badania nie sa wiarygodne poniewaz nie wiadomo gdzie rekrutowano chorych. Dr Cruz nigdy nie pracowal w miejscu podanym jako instytucji badawczej. Wspolautprzy niewiele wiedza bo zostali dopisani bo to kumple. Prof. Z Japonii nie wiedzial,ze doktor Cruz Go dopisal do momentu ukazania sie artykulow.

Nie posiadajac zadnej wiedzy o rzetelnosci przeprowadzonych badan staneli jednak w obronie zmarlego kolegi i uwazali,ze byl On uczciwym lekarzem i nigdy nie sfabrykowalby wynikow badan. Nie mogli tez wycofac prac bo uwazali,ze nie maja do tego prawa.

Dla zainteresowanych wklejam caly artykul z dochodzenia ( nie moglam podac linka bo trzeba byc zarejestrowanym w BMJ). Podejrzewam,ze to kropla w morzu. Z badniami roznie bywa.

Mnie – poza oczywiscie rzetelnoscia badan – interesuje tzw gift authors. Dopisywanie swoich kolegow ktorzy nie mieli czynnego udzialu w badaniu. W polskich klinikach jest to norma. Ktos cos napisze, napracuje sie a potem jest proszony ( grzecznie zmuszany bo przeciez nie odmowi :)), przez szefa kliniki zeby dopisal kolege X i kolezanke Z. Moze tez pania doktor radiolog ktora opisala zdjecia i doktora Y , ktory przeciez byl obecny w trakcie omawiania chorego albo Grzesia bo robi doktorat na ten temat i bedzie mial wiecej publikacji.

Praca moze byc skromna, ale autorow z 10 :). Wyglada to moim zdaniem bardzo zle bo podwaza autorytet wszystkich “autorow”. Musimy sie wspierac i sobie pomagac w swiecie nauki, ale czy dopisywanie kolegow i kolezanek jest w porzadku? Potem mamy 33 letniego doktora z 60 pracami. Czy jest to wiarygodne?

Co o tym sadzicie? Moze przesadzam i jest to calkiem normalne i powszechnie akceptowane.

A ponizej artykul omwiajacy cala sprawe

BMJ 2007;334:392-394 (24 February), doi:10.1136/bmj.39118.480023.BE

Feature

Research ethics

Doubts over head injury studies

Ian Roberts, clinical coordinator CRASH-2 trial, Richard Smith, visiting professor, Stephen Evans, professor of pharmacoepidemiology

London School of Hygiene and Tropical Medicine, London WC1E 7HT

Correspondence to: I Roberts Ian.Roberts@Lshtm.ac.uk

Patients are receiving treatment that may be unsound as investigationsby Ian Roberts and colleagues raise questions about whetherinfluential trials of high dose mannitol ever took place

Each year, worldwide, many thousands of people are treated inemergency departments for head injuries. Mannitol is an osmoticdiuretic that is believed to reduce intracranial pressure afterhead injury and may improve patient outcome. Between 2001 and2004, a Brazilian neurosurgeon JulioCruz and colleagues publishedthree clinical trials comparing high dose and conventional dosemannitol in the treatment of head injury (table

).¹²³ No othertrials had examined this question.

The results showed that high dose mannitol greatly reduced deathand disability six months after the head injury. A Cochranesystematic review that included these trials concluded: "highdose mannitol seems to be preferable to conventional dose mannitolin the acute management of comatose patients with severe headinjury."⁴ However, one of the trials was accompanied by an editorialthat questioned the reliability and validity of the results,calling for further multicentre studies.⁵ A subsequent investigationby the Cochrane Collaboration was unable to confirm that thestudies took place.

View this table:
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Details of trials of high dose mannitol

Doubts over the data

In May 2006, Dr Jorge Mejia, the Colombian national coordinatorof the CRASH-2 (clinical randomisation of an antifibrinolyticin significant haemorrhage; www.crash2.Lshtm.ac.uk) trial, wroteto IR (who is editor of the Cochrane Injuries Group) after attendinga meeting of the Latin American Brain Injury Consortium in Brazil.He was concerned about the inclusion of the Cruz trials in theCochrane review:

"During the discussion some Brazilian physicians expressed somesurprise with the inclusion of JulioCruz' paper in the meta-analysis(Cruz 2004; J Neurosurgery, 100:376) ... Cruz had no patientsat his arrival to Brasil, back from USA where he had developedhis research career."

Dr Mejia was clearly shocked by this revelation: "I do not knowwhat to do, but I feel betrayed. I guess that someone shouldcontact the others authors and ask them. I feel that I can notstay passive, but I have no evidence."

Dr Cruz, the lead author, had killed himself in 2005. However,the reports had coauthors from Italy and Japan, and we contactedthem for further information.

Dr Minoja wrote on 15 May 2006:

"It was a pleasure for me to be included along the authorsof the papers written by JulioCruzon the use of high dosesof mannitol in head trauma emergencies. My Unit and I did notprovide to Dr. Cruza personal series of randomized patients,but my contribution was discussing with him and sharing hisassumption, because occasionally, in emergency situations, Ihave used and I still use with success aggressive high-dosemannitol approach."

In a second message, he wrote: "I think that patients were enrolledin USA and more recently in Brazil, but I honestly don't knowthe period and in what Institution."

Dr Okuchi responded:

"Since I did not conduct any study related to the results ofDr Cruz's high-dose mannitol trials in Japan, I have no datato present you. I did not know any part of the paper beforehe called me about the acceptance in the journal every time"(18 May 2006).

Dr Facco wrote:

"The paper I am co-author, springs from the clinical experienceI shared with JulioCruzabout the potential effectiveness ofhigh doses of mannitol in selected very critical patients. Idiscussed with him (mainly by phone) about my anecdotal experienceI never had the opportunity to check in a prospective study,and he also had the same clinical impression of its effectiveness.... Following our discussion, he decided to test high mannitoldoses in the emergency setting and involved me as co-author,but my role was "philosophical" rather than clinical: to myknowledge, the study was conducted personally by Julio, probablyin Brazil, and I only helped him with discussion and text revision"(22 May 2006).

Since none of the authors could provide any reassurance aboutthe integrity of data, the Cochrane systematic review was withdrawnin 2006 while an investigation was made.

The Cruz papers were published in Neurosurgery and the Journalof Neurosurgery and we wrote to the editors about the concerns.In July 2006, John Jane, the editor of the Journal of Neurosurgerywrote:

"I have tried unsuccessfully to contact you by phone with regardto the Cruzpapers. As you can tell by Dr. Marshall's editorial,we all doubted the data. But to doubt is different from concludingthat Dr. Cruzfabricated the data. I thought he did, but hopedas stated in the editorial that publication would encouragerepetition of the studies. My Editorial Board thought Dr. Cruz'work should be published. I wouldn't trust the data."

The editorial by Dr Marshall which accompanied the Journal ofNeurosurgery report stated:

"These results are clearly of substantial interest, but alsoraise questions about how reliable and valid are clinical studiesthat show very dramatic improvements in outcome when they areperformed at only one institution. This does not demean thework of Dr Cruzand his colleagues; rather it indicates thatmulticentre studies, such as those being conducted at presentfor novel pharmacological therapies, need to be applied to alternativedosing regimens for more traditional methodologies."⁵

We asked Dr Marshall if he had any concerns about the integrityof the data. He would not respond in writing but he left a phonemessage saying that he had "serious concerns" about the paper(8 August 2006).

The editorial office of Neurosurgery wrote:

"With a serious charge, the possible fabrication of trials,a case must formally be presented with any and all possibleevidence that would indicate the cause for concern and the reviewersmust then address the issue. It is not possible or responsiblefor the Editor of a peer-reviewed journal to act hastily insuch a matter without the input of the reviewers who originallyaccepted the paper, nor would it be responsible to simply pullthe papers without presentation of the results of an investigationinto the matter. An unsubstantiated claim and verbal recitationof the inquiries made cannot suffice" (8 December 2006).

We have had no further correspondence.

Where did the patients come from?

None of the reports indicated where the patients came from.All of them stated that "institutional review board approvalwas obtained" but gave no further details. On each report, theDr Cruz's affiliation was the Comprehensive International Centrefor Neuroemergencies and Federal University of São Paulo."Reprint requests were to the centre at a postal box addressin São Paulo. We were unable to find any further informationabout the centre. In October 2006, the Federal University ofSão Paulo stated in response to our inquiry that it hadnever employed Dr Cruz.

We also wrote to the Brazilian national committee on ethicsin research, which began an investigation. The investigationfound that Dr Cruz had given an interview in which he said thatthe patients in one of the trials were from eight hospitalsin Brazil, Italy, and Japan. However, the authors from Italyand Japan had told us that they did not enrol any patients attheir hospitals. Dr Minoja had said that he thought that thepatients might have been recruited in the US (15 May 2006).We contacted the University of Pennsylvania, where Dr Cruz hadworked until March 1995. They searched their records but foundno indication that the research was conducted there (StevenFluharty, personal communication, 8 December 2006).

In September the Committee on Publication Ethics recommendedthat the living authors seek retraction of the reports on thebasis that they were gift authors and could not take responsibilityfor the results. We wrote to all three coauthors on 21 Septemberasking if they would be willing to seek retraction.

Dr Okuchi replied the next day: "I would like to retract thesepapers from the journals because I am not able to take responsibilityfor the content. Could you let me know how to act formally forthe purpose." A few days later (25 September) he wrote again,"On my last e-mail letter, I had mentioned withdrawal of thepapers, however I found that I had no right to retract the papersfrom the journals. I think it depends on whether Dr Cruz willdecide or not ... I will contact him in a few days."

IR wrote again to the coauthors on 10 October explaining thatDr Cruz was dead, stating that "it would be wrong of me notto follow up this matter and so unless you contact the journalsin question to seek retraction I will have to write to yourinstitutions to ask for their help. It is an unfortunate businessbut it will be better for everyone concerned that you take theappropriate steps to resolve this matter."

Later that month (27 October), Dr Facco wrote on behalf of DrMinoja and Dr Okuchi. He said that they did not believe thatthey were gift authors and declined to seek retraction. He arguedthat the papers were published in an international peer reviewedjournal, that the first author had taken responsibility fortheir content, and that they knew the first author well andbelieved that "he would never have been able to do somethingfalse."

Wider implications

We are left with serious doubt about important studies but withno way of determining with confidence whether the results arefabricated or real. The main author is dead. There is no institutionto investigate. The implications for patients are serious. Theyare being treated on the basis of potentially unreliable evidence.It is plausible that mannitol in high doses may increase ratherthan decrease brain swelling.⁶ Shortly after the withdrawalof the Cochrane review, the Cochrane Injuries Group was contactedby US researchers preparing guidelines for the management ofsevere traumatic brain injury and by BMJClinical Evidence askingabout the outcome of our investigation because the Cruz resultswere about to be incorporated into guidelines.

There are also implications for the broader scientific community.Earlier this year an investigation by Science of more than adozen fraud or suspected fraud cases showed "uneven and oftenchaotic efforts to correct the scientific literature."⁷ If itwants to retain the confidence of the public and politicians,the scientific community needs to do better. Only a minorityof countries have an effective national system for respondingto scientific misconduct. However, research is a global enterpriseand a strong case exists for an international body to respondto the problem of research misconduct.

Contributors and sources: IR conducted the investigation withadvice from RS and SE. All authors contributed to the writingof the manuscript. IR is guarantor.

Competing interests: RS has a longstanding interest in researchmisconduct and was a founder member of the Committee on PublicationEthics. The only way that he could benefit financially fromthis article is if more people were to buy his book, which includesa chapter on research misconduct. IR is coordinating editorof the Cochrane Injuries Group and is an author of the mannitolreview.

References

Cruz C, Minoja G, Okuchi K. Improving clinical outcomes from acute subdural hematomas with emergency preoperative administration of high doses of mannitol: a randomized trial. Neurosurgery 2001;49:864-71.[ISI][Medline]

Cruz C, Minoja G, Okuchi K. Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupilary widening. Neurosurgery 2002;51:628-38.[CrossRef][ISI][Medline]

Cruz J, Minoja G, Okuchi K, Facco E. Successful use of the new high-dose mannitol treatment in patients with Glasgow coma scores of 3 and bilateral abnormal pupillary widening: a randomized trial. J Neurosurg 2004;100:376-83.[ISI][Medline]