Declaration of Helsinki 12 Basic principles
Sound science Ethics Lecture 2 SH: Scientific Judged by an independent committee Misconduct Researcher’s qualifications & responsibilities Benefit > Risk Individual interests > science & society Autonomy & privacy
Declaration of Helsinki 12 Basic principles (cont’d) Scientific misconduct
Predictable hazards Research without integrity Publication – accuracy & integrity Research fraud Information & consent ( incl. Research dishonesty withdrawal) Purposefully misleading the public Free from duress (dependent relationships) Consider competence to consent (physical or mental incapacity, children) Statement of compliance Is there a link btw MMR and autism?
Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children A J Wakefield, et al. THE LANCET • Vol 351 • February 28, 1998 637 Early report Background: We investigated a consecutive series of children with chronic enterocolitis and regressive developmental disorder. Methods 12 children (mean age 6 years [range 3–10], 11 boys) were referred The five-page paper’s claims received huge media to a paediatric gastroenterology unit with a history of normal development attention, and were followed by a sustained attack followed by loss of acquired skills, including language, diarrhoea and abdominal pain. on the vaccine. This included further publications Findings Onset of behavioural symptoms was associated, by the parents, by Wakefield, criticising MMR, and led to an with measles, mumps, and rubella vaccination in eight of the 12 children. unprecedented collapse in public confidence in the Behavioural disorders included autism (nine), disintegrative psychosis (one), shot, which, since the late 1980s in the UK and and possible the early 1970s in the US, has been given almost postviral or vaccinal encephalitis (two). Interpretation We identified associated gastrointestinal disease and universally to children, soon after they are one developmental regression in a group of previously normal children, which year old, almost eradicating measles and rubella. was generally associated in time with possible environmental triggers. Lancet 1998; 351: 637–41 The prime cause of the alarm was "It's a moral issue for me," Dr findings in the paper claiming that the Wakefield said at the 1998 press parents of two thirds of the 12 conference, where he called for a children blamed MMR for the sudden boycott of the triple MMR, in favour of onset of what was described as a breaking it up into single shots, to be combination of both an inflammatory given at intervals. bowel disease and "regressive autism", in which language and basic skills are lost. Most disturbingly, the first behavioural symptoms were said to have appeared within only 14 days of the shot.
Then, a journalist published and expose As the doctor campaigned, UK vaccination rates slumped: below the level needed to keep measles at bay. Meanwhile, in America, a ferocious anti-vaccine movement took off, after Wakefield appeared on the CBS network's 60 Minutes programme in November 2000, speaking of an "epidemic of autism". REVEALED: MMR RESEARCH SCANDAL The Sunday Times (London) February 22 2004 Brian Deer
FULL details are disclosed today of the four-month Sunday Times investigation that has uncovered a medical scandal at the heart of the worldwide scare over MMR. Andrew Wakefield, the doctor who champions the alleged link between measles, mumps and rubella vaccine and autism in young children, stands discredited for misleading his medical colleagues and The Lancet. 22/2/2004
Brian Deer, an investigative journalist, The investigation discovered that, discovered that, that Wakefield had while Wakefield held himself out to be been pay rolled to create evidence a dispassionate scientist, two years against the shot, and, while planning before the Lancet paper was published extraordinary business schemes, he had been hired by a lawyer, meant to profit from the scare, he had Richard Barr: a solicitor, who hoped to changed and misreported data on the raise a speculative class action lawsuit anonymous children, published in the against drug companies which prestigious journal (Lancet). manufactured MMR. Unlike expert witnesses, who give In June 1997 - nearly nine months professional advice and opinions, before the press conference at which Wakefield had negotiated a lucrative Wakefield called for single vaccines - contract with Barr, then 48, to conduct he had filed a patent on products, clinical and scientific research. The including his own supposedly "safer" goal was to find evidence of what the single measles vaccine, two men called "a new syndrome", This only stood any prospect of intended to be the centrepiece of success if confidence in MMR was (later failed) litigation on behalf of an damaged. eventual 1,600 families, mostly recruited through media stories.
The investigation has found that when The Sunday Times has now he warned parents to avoid MMR, and established that four, probably five, of published research claiming a link with these children were covered by the autism, he did not disclose he was legal aid study. And Wakefield himself being funded through solicitors had been awarded up to £55,000 to seeking evidence to use against assist their case by finding scientific vaccine manufacturers. evidence of the link. The Lancet said yesterday that The Wakefield did not tell his colleagues or Sunday Times' evidence meant that medical authorities of this conflict of the finding linking MMR and autism interest either during or after the was "entirely flawed" and should never research.The children were subjected have been published. to a battery of invasive procedures, John Reid, the health secretary, called including colonoscopies and lumbar for an inquiry by the General Medical punctures. Council (GMC) "as a matter of urgency". Had already questioned GMC enquiry found recruitement The research paper published in The Lancet contained no scientific evidence of a link with MMR, only the In March 1998, as public alarm took "association" made by parents. off over the safety of MMR, a meeting of the Medical Research Council asked Wakefield about the source of the children he had analysed. Wakefield failed to take the opportunity to reveal his interest. Six weeks later he was faced with a letter in The Lancet raising the question of litigation. All children, Wakefield claimed, came through "formal channels" and that "no conflict of interest exists".
GMC findings Cont. In January 2010, a panel of the UK's General Medical Council vindicated Brian Deer's investigation. Among four Wakefield had repeatedly changed and counts of proven dishonesty, the panel misreported diagnoses, histories and found that Wakefield had dishonestly descriptions of the children, which misled The Lancet and its readers over made it appear that the syndrome had both the nature of the research and been discovered to give the how children came to be included in impression of a link between MMR, the paper. It also found that the bowel disease and the sudden onset of ethical statement in the paper was regressive autism, when otherwise false, that there was no ethical none was evident. approval for the research, and that Wakefield was "callous". Lancet retraction
The hospital's pathology service had February 2010: In a statement from repeatedly declared bowel biopsies the Lancet medical journal, the claims from the children to be normal, and made by Andrew Wakefield and his not one of the 12 cases was free of associates, linking the MMR vaccine critical mismatches between the paper with autism were fully retracted. which launched the vaccine crisis and the kids' contemporaneous clinical records. Some children showed signs of autism before vaccination. Some were deemed normal months afterwards. Some did not have autism at all.
Lancet retraction
This decision - finally capitulating to ‘It has become clear that several Brian Deer's multi-part investigation elements of the 1998 paper by for The Sunday Times - came just five Wakefield et al are incorrect, contrary days after Wakefield was found to be to the findings of an earlier "dishonest", "unethical", investigation. In particular, the claims "irresponsible" and "callous" by a in the original paper that children were disciplinary panel of the UK General 'consecutively referred' and that Medical Council (GMC), following up on investigations were 'approved' by the Deer's reports. local ethics committee have been proven to be false. Therefore we fully retract this paper from the published record." “The Unfortunate Experiment” Consequences:
Cervical Cancer Cervical cancer: Cancer that forms in tissues of the cervix The Experiment (organ connecting the uterus and vagina). It is usually a Conducted at National Women’s Hospital, Auckland, New slow-growing cancer that may not have symptoms, but Zealand, Headed by Dr. Herbert Green, OB/GYN at can be found with regular Pap smears (procedure in which NWH, professor cells are scraped from the cervix and looked at under a microscope). 948 patients with carcinoma in situ (CIS) of the cervix
Stage 0: The cancer is found only in the top layer of cells Women followed from 1955 to 1976; study officially in the tissue that lines the cervix. Stage 0 is also called began in 1966 carcinoma in situ. Properly treated, tumor control of in situ cervical carcinoma should be nearly 100%. To prove that CIS never develops into invasive cervical cancer, is not a premalignant condition Punch biopsy: a sharp, hollow device is used to remove sample of cervical tissue. To reduce number of major/invasive procedures to treat CIS, such as hysterectomy Cone biopsy: removes a cone-shaped sample of tissue. The Methodology The Results 1.5% of group A and 22% of group B developed invasive NWH patients recruited with cervical CIS who were cancer under 35 yo, there were to be no signs of invasive carcinoma Women with continuing abnormal cytology 24.8 times more likely to develop invasive carcinoma Followed from 5 to 28 years In group A (normal follow-up), 3.2 times more likely to Split into groups by normal (A) or abnormal (B) cytology develop cancer than women who never had CIS at follow up Some women later died Received cone biopsies and other diagnostic procedures – not complete cancer removal Green reclassified some of those who developed invasive cancer as having been missed initially
The Controversy The Inquiry, continued In 1987, women’s health activists published an article, Early attempts at questioning the cytologist and pathologist “An Unfortunate Experiment,” in the Metro magazine program went nowhere – Superintendent-in-Chief of the outlining the study. This article focused on one patient, Auckland Medical Board did not consider the matter “urgent” “Ruth,” who was followed from 1964 to 1979, and finally diagnosed with cervical cancer in 1985. Other clinicians did not want to interfere with Dr. Green’s “clinical freedom” Public outcry occurred, and judicial inquiry ordered by the Ministry of Health Cases of invasive cancer were identified in 1969, but trial continued Cartwright inquiry – officially, “Committee of Inquiry into Allegations Concerning the Treatment of Cervical Enrollment protocol not followed – women over 35 were Cancer at National Women’s Hospital and into Other included fairly regularly, invasive signs ignored, despite Related Matters,” headed by District Court Judge Silvia numerous recommendations for improvement: patient advocates, Cartwright Women’s Statements Historical Context
“I can’t explain the shock that I felt when I found out by Declaration of Helsinki written in 1964; Nuremburg Code accident that I had a cone biopsy.” also in existence at time of study
“…I was never actually told that I had carcinoma in situ.” According to the Cartwright report: “By the early 1960s most experts in Europe, the United States of America and “After I had the cone biopsy I was told that they had got it Australia considered that CIS was a precursor of invasive all. I have since learnt that this was not the case. I was cervical cancer.” told that the chance of getting any form of cancer again were the same as any other woman.” Indirect and direct evidence was in existence when study began that CIS could in fact lead to invasive cancer “For instance, if I had known that my biopsy in 1975 showed that I had microinvasion, I would never have Less invasive management techniques were already ceased to go to follow-up clinics.” gaining favor before 1966
The Inquiry Findings The Aftermath Determined that the study was unethical: women not ~130 patients identified and contacted for follow-up. This informed they were in a study; not informed of other was not perfect, as follow-up sometimes occurred in the treatment options; inadequately addressed risks to patients; course of routine clinical care, without women being symptoms of invasive disease downplayed or overlooked; provided with full details of their past enrollment into Dr. some women never even told they had CIS Green’s study
Dr. Green maintained it was not in the women’s interests to Bureaucracy and resistance slows action on Cartwright tell them what he was doing report recommendations. Some physicians call informed consent procedures too burdensome. Other revelations: medical students were doing vaginal exams on anaesthetized women without their knowledge or Cartwright Inquiry challenged, attacked as a “feminist consent; >2,000 newborn females received cervical witch hunt,” but later vindicated. Some physicians smears; women later enrolled in R Series trial of differing investigated and fined. Dr. Green not punished due to treatments of invasive cancer without their knowledge poor health. Several women sue and receive damages. Summary Resources Study based on personal beliefs rather than established Campbell AV. A report from New Zealand: an ‘unfortunate facts; Questionable handling of adverse events experiment.’ Bioethics. 1989 Jan;3(1):59-66.
Institutional safeguards broken/not followed Committee on Inquiry into Allegations Concerning the Treatment of Cervical Cancer at National Women’s Hospital and into Other Hypothesis disproved; trial continued Related Matters. Report of the Committee of Inquiry into Allegations Concerning the Treatment of Cervical Cancer at Informed consent – completely absent ; Lack of National Women’s Hospital and into Other Related Matters. understanding and voluntariness Auckland: The Committee, 1988.
Respect for persons – individuals not treated as Davis P. A fortunate inquest: the report of the cervical cancer autonomous agents inquiry. Community Health Stud. 1988;12(3):246-50.
Justice – subjects were chosen because they were Coney S, ed. Unfinished business: what happened to the available Cartwright Report?: writings on the aftermath of 'the unfortunate i'NilW'HilAkldW’
Resources - 2 Resources - 3
Flagler EA, Winkler ER. ‘An unfortunate experiment’: the New Rosier P. The speculum bites back: feminists spark an inquiry into Zealand study of cancer of the cervix. Ann R Coll Physicians Surg the treatment of carcinoma in situ at Auckland’s National Women’s Can. 1992 Apr;25(2):124-30. Hospital. Reprod Genet Eng. 1989;2(2):121-32.
Heslop B. ‘All about research’ – looking back at the 1987 Cervical Williams L. Looking back at the 1987 Cervical Cancer Inquiry. N Cancer Inquiry. N Z Med J. 2004 Aug 6;117(1199):U1000. Z Med J. 2004 Sep 24;117(1202):U1084; author reply U1084.
McIndoe WA, McLean MR, Jones RW, Mullins PR. The invasive Women’s Health Action Trust. Women’s Health Action [web potential of carcinoma in situ of the cervix. Obstet Gynecol. 1984 document]. Auckland: The Trust. [rev. 28 Dec 2005; cited 18 Apr Oct;64(4):451-8. 2006].
Munro K. The aftermath of the cervical caner inquiry in New Zealand: an antipodal aberration or universal struggle? Issues Reprod Genet Eng. 1991;4(1):31-9. An Australian case: Dr William McBride Twenty years later, Dr McBride became interested in another morning sickness drug, He had discovered the malforming Debendox, effects of a drug called thalidomide, that he suspected of also causing birth which malformed hundreds, if not deformities. He asked researchers at Foundation thousands, of children in the '50s and 41, Vardy and French to conduct some '60s, ‘so it was quite a...quite an experiments on rabbit embryos. honour to work for him.’ (former colleague)
Radio National expose: Radio National cont PHIL VARDY: Bill became interested in a drug called 'debendox' that was taken by pregnant women to prevent them One litter in six proves absolutely vomiting, and he came in one day and nothing. I certainly thought at the said, "Look, I want to test debendox in time that this was worthy of doing a rats and rabbits", and so we conducted a lot more work, but, ah, one litter in six series of experiments very rapidly. would be laughed out of any reputable Six female rabbits were dosed, one litter scientific journal. Unfortunately, that of offspring, foetuses from one particular work came to an end. I gave the rabbit was malformed. One litter in six results to Bill McBride and thought no proves absolutely nothing. more about it. Two years later we were horrified to Vardy and French confronted McBride discover our names as coauthors with but got nowhere. McBride on a paper published in the He used his spurious results to damn Australian Journal of Biological Debendox and its American Sciences. equivalent, Bendectin. In it, original data on the rabbit The drug was basically forced off the experiments had been altered and the market in 1983 – the drug company results had been changed. simply couldn’t afford more legal action.
On 2 November 1988 William McBride was found guilty of research misconduct and resigned from his research post in Australia. Twenty fine years earlier Mcbride had been In Australia, it took six years before the hero of thalidomide. He published a Foundation 41 set up an independent landmark letter in The Lancet on December enquiry into McBride, 16th 1961 pointing out a curious coincidence he had noticed. He is credited with identifying and that only after the fraud was the dangers of the drug. made public. His later research was problematical. The 1988 report stated: "we are forced to conclude that Dr. McBride did publish statements which he either knew were untrue or which he did not genuinely believe to be true, and in that respect was guilty of scientific fraud". They also said: Dr W G McBride, was removed from the medical register after a four-year inquiry by Had Dr McBride used any of the many the Medical Tribunal of New South Wales. Of opportunities available to him to make an the 44 medical practice allegations made honest disclosure of his misdemeanour, his against him by the Department of Health only conduct would have been excused by the one minor one was found proved Tribunal. However, he persisted in denying but 24 of the medical research allegations his fraudulent conduct for several years,. were found proved. Of these latter, the most The Tribunal unanimously found Dr McBride serious was that in 1982 he published a not of good character in the context of scientific journal, spurious results relating to fitness to practice medicine. The decision to laboratory experiments on pregnant rabbits deregister was taken by a majority of 3 to 1. dosed with scopolamine. British survey
Stephen Lock, editor, BMJ 1988, informal survey
"GIFT" AUTHORSHIP
Often, however, authorship is non- legitimate, granted as a gift ….. it's a bit like claiming you wrote Hamlet because you lent Shakespeare a pencil. But the same is happening in Britain; a colleague of mine, hypnotised by the new Grateful Med program at the National Library of Medicine, Bethesda, idly tapped in the names of two British authors, in three years one had almost 200 papers bearing his name, the other almost 100 Woolley's independent study comes to Publication retractions roughly the same conclusion. 463 retractions in English-language Study 1: PubMed files to see how papers from 1978 to 2008 many papers had been retracted Those due to misconduct rose from between 1988 and 2008. – some 40% in the late 1980s to 60% 529, in a randomly selected set of the 2000s. 312, she judged that only 28% were ? inc awareness of misconduct, she due to "honest error". says, the rest, repeat publishing the same The rise corresponds to the results (18%), plagiarism (15%), establishment of the US Office of fabrication (5%) and falsification (4%) Scientific Integrity in 1989 (which of data. became the Office of Research the unethical reasons stacked up to Integrity in 1992), and fresh 43%. guidelines on ethical publication standards
What happens to retracted articles
Small study of 9 retracted CT journal Bigger study (Budd et al): articles Reviewed 235 biomedical articles All articles had a published retraction, which had been retracted, and they median interval 8 months, (4 to 25) found that the articles had been cited months. 2034 times after retraction notices PDFs were available for eight, but only were issued two were marked “retracted” across the first page. Analysis of the nine articles revealed 40 citations to date, these have already been cited 263 times. Scientific misconduct
The violation of the standard codes of scholarly conduct and ethical behavior in the violation of ethical standards regarding professional scientific research. human and animal experiments, such as the The main forms of scientific misconduct are: standard that a human subject of the fabrication--the publication of deliberately experiment must give informed consent to false or misleading research, often the experiment. subdivided in: In addition, some academics consider fabrication--the actual making up of research data suppression--the failure to publish and (the intent of) publishing them significant findings due to the results being falsification--manipulation of research data and adverse to the interests of the researcher or processes or omitting critical data or results his/her sponsor(s)--to be a form of plagiarism--the act of taking credit (or misconduct as well; attempting to take credit) for the work of another
Why
In some cases, scientific misconduct Career pressure – publish or perish may also constitute violations of the Science is still a very strongly career-driven law, but not always. discipline. "Knowing the right answer" "The ability to get away with it" Even on the rare occasions when scientists In most scientific fields, results are often do falsify data, they almost never do so difficult to reproduce accurately, being with the active intent to introduce false obscured by noise, artifacts and other information into the body of scientific extraneous data. That means that even if a knowledge. Rather, they intend to scientist does falsify data, they can expect introduce a fact that they believe is true, to get away with it - or at least claim without going to the trouble and difficulty innocence if their results conflict with of actually performing the experiments others in the same field. required.