Nº 216
The New Zealand “unfortunate experiment” 40 years back: ethical lessons for the younger generations
Quote this article as:
RW Jones (November 2022). The New Zealand “unfortunate experiment” 40 years back: ethical lessons for the younger generations. www.HPVWorld.com, 216
Dr Jones, what was in brief the “unfortunate experiment” that was revealed by you and your colleagues in New Zealand?
The ‘unfortunate experiment’1 was a poorly designed observational study of the natural history of a known cervical cancer precursor, carcinoma in situ (CIS, now known as CIN3). It was performed by Associate Professor Herbert Green at the National Women’s Hospital in Auckland, New Zealand starting in 1966.
As a young gynaecologist Green accepted the conventional view that CIS was a cancer precursor. He also supported PAP screening.
Over time his views evolved, ultimately believing CIS was a relatively benign condition, and screening cytology of little value. He was familiar with the literature on the subject and the ‘local expert’ in New Zealand.
The study involved withholding definitive treatment in a group of women presenting with abnormal PAP smears and biopsy evidence of CIS. Patients were followed assiduously with clinical examinations and PAP smears. Biopsies were repeated if there was concern. Colposcopy and biopsy were initially included in the protocol. However, Dr Bill McIndoe, the hospital cytologist/colposcopist who had earlier expressed concerns about the study, found he was unable to continue working with Green and soon withdrew his services. Consent was not sought.
When cases of cancer began to appear, McIndoe was joined by the hospital pathologist Dr Jock McLean and both men expressed written concerns to the medical authorities about the experiment. A committee of Green’s colleagues (later referred to as ‘the whitewash committee’) appointed to investigate the issues failed to stop the experiment.
What was your implication in the events that followed this project?
Almost a decade later I joined the senior medical staff as a young ‘outside’ appointment unburdened by loyalties to old teachers and staff. By this time Green’s experiment had been truly falsified and he had without approval begun a similar study of observing and not treating women with vulval CIS (now VIN 3) and with similar results.
Frustrated by the failure of the medical authorities’ to stop the experiment, McIndoe, McLean and I published our analysis of Green’s experiment in OBSTETRICS and GYNECOLOGY in 1984.2 A little over 1,000 women with histologically diagnosed CIS managed in the hospital and followed for at least five years were reviewed. Irrespective of their original management, women with continuing abnormal cytology were 25 times more likely to develop invasive cancer than women with normal cytology follow up. Prepublication copies of our paper were distributed to all senior staff members but there was no response.
What was the social reaction to this news? Did your work inspire the creation of international review panels and review methodologies in New Zealand? Worldwide?
When the results of Green’s study were made public by a women’s health group there was a furore which led to a Commission of Inquiry led by Judge Silvia Cartwright in 1988. The Inquiry Report and its Recommendations have changed New Zealand medicine forever: these include ethics, medical education, patient rights and code of rights, treating patients with dignity, informed consent, consent in clinical trials, peer review, research protocols, the introduction of an organised national cervical screening programme and more.
In clinical research with public health implications (i.e. introducing population screening programs) there is a debatable grey zone below which further research is still needed and above which intervention is required. In this case, research needed to unveil that if CIN lesions were left untreated the risk of cervical cancer increased dramatically. In your opinion, was the evidence in the early 80’s already above the intervention line?
The study should never have taken place because there was already sufficient evidence that the proposed study was unnecessary. Almost a century earlier, pathology research had clearly demonstrated the relationship between cervical cancer and a precursor lesion. Mid-20th century retrospective clinical studies confirmed the malignant potential of CIS and a prospective study of untreated CIS was stopped when cases of cancer occurred. Boyes et al reporting results from the British Columbia population screening programme noted that removal of precursor lesions by treatment led to a reduction in the incidence of cervical cancer. Green was familiar with these studies. He made no secret of his study, publishing and lecturing widely, though his findings were not generally accepted.
At the time, was the New Zealand observational project subjected to local research ethical committees?
Ethics committees were not in use in New Zealand when in 1966 Green gained informal approval from his colleagues for his study. Green recognised he needed the support of his colleagues, all of whom treated CIS, if he was to carry out his experiment. Two separate committees of colleagues considered his request and the brief minutes of the meeting record ‘there was much discussion’ and approval for a study ‘to attempt to prove CIS was not a premalignant lesion.’ No other consent was obtained. Elsewhere in the hospital women with CIS were treated conventionally with cone biopsy or when indicated hysterectomy. Ethics committees, including lay membership were formally introduced in the Auckland region in the mid-1970s. A further study by us using the same clinical and pathological material was reported in LANCET ONCOLOGY (McCredie et al. 2008).3 Here, analysis by assessment of the adequacy of treatment again demonstrated that women with untreated CIS had a high risk of developing cancer compared with women who received conventional treatment.
Is it possible that similar cases occurred elsewhere and remain undescribed? Was there an effect on the personality of hospital leaders?
It is likely that similar unreported studies have taken place elsewhere. Green’s published results were not widely accepted. Green was a large framed somewhat intimidating man with strongly held opinions. He believed his histological expertise was equivalent to that of his pathologist, McLean.
While the study was primarily his responsibility, the reason it was not stopped sooner was the failure of his colleagues to acknowledge the risks to which his patients were being exposed. An example of ‘good men doing nothing’. It is a story of misplaced loyalty by Green’s colleagues, some of whom were close friends.
Did the experience drive the creation of the ethics evaluation in clinical research?
The ‘unfortunate experiment’ has received widespread international recognition and the lessons learned have undoubtedly been of benefit to the research community.
References
1. Jones RW. Doctors in denial. The forgotten women in the “unfortunate experiment”. Otago University press, 2017. Dunedin, New Zealand. Available from: https://www.otago.ac.nz/press/books/otago635233.html
2.. McIndoe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in situ of the cervix. Obstet Gynecol. 1984 Oct;64(4):451-8. Abstract available at: https://pubmed.ncbi.nlm.nih.gov/6483293/
3. McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008 May;9(5):425-34. Available at: https://doi.org/10.1016/s1470-2045(08)70103-7
RW Jones (November 2022). The New Zealand “unfortunate experiment” 40 years back: ethical lessons for the younger generations. www.HPVWorld.com, 216
Dr Jones, what was in brief the “unfortunate experiment” that was revealed by you and your colleagues in New Zealand?
The ‘unfortunate experiment’1 was a poorly designed observational study of the natural history of a known cervical cancer precursor, carcinoma in situ (CIS, now known as CIN3). It was performed by Associate Professor Herbert Green at the National Women’s Hospital in Auckland, New Zealand starting in 1966.
As a young gynaecologist Green accepted the conventional view that CIS was a cancer precursor. He also supported PAP screening.
Over time his views evolved, ultimately believing CIS was a relatively benign condition, and screening cytology of little value. He was familiar with the literature on the subject and the ‘local expert’ in New Zealand.
The study involved withholding definitive treatment in a group of women presenting with abnormal PAP smears and biopsy evidence of CIS. Patients were followed assiduously with clinical examinations and PAP smears. Biopsies were repeated if there was concern. Colposcopy and biopsy were initially included in the protocol. However, Dr Bill McIndoe, the hospital cytologist/colposcopist who had earlier expressed concerns about the study, found he was unable to continue working with Green and soon withdrew his services. Consent was not sought.
When cases of cancer began to appear, McIndoe was joined by the hospital pathologist Dr Jock McLean and both men expressed written concerns to the medical authorities about the experiment. A committee of Green’s colleagues (later referred to as ‘the whitewash committee’) appointed to investigate the issues failed to stop the experiment.
What was your implication in the events that followed this project?
Almost a decade later I joined the senior medical staff as a young ‘outside’ appointment unburdened by loyalties to old teachers and staff. By this time Green’s experiment had been truly falsified and he had without approval begun a similar study of observing and not treating women with vulval CIS (now VIN 3) and with similar results.
Frustrated by the failure of the medical authorities’ to stop the experiment, McIndoe, McLean and I published our analysis of Green’s experiment in OBSTETRICS and GYNECOLOGY in 1984.2 A little over 1,000 women with histologically diagnosed CIS managed in the hospital and followed for at least five years were reviewed. Irrespective of their original management, women with continuing abnormal cytology were 25 times more likely to develop invasive cancer than women with normal cytology follow up. Prepublication copies of our paper were distributed to all senior staff members but there was no response.
What was the social reaction to this news? Did your work inspire the creation of international review panels and review methodologies in New Zealand? Worldwide?
When the results of Green’s study were made public by a women’s health group there was a furore which led to a Commission of Inquiry led by Judge Silvia Cartwright in 1988. The Inquiry Report and its Recommendations have changed New Zealand medicine forever: these include ethics, medical education, patient rights and code of rights, treating patients with dignity, informed consent, consent in clinical trials, peer review, research protocols, the introduction of an organised national cervical screening programme and more.
In clinical research with public health implications (i.e. introducing population screening programs) there is a debatable grey zone below which further research is still needed and above which intervention is required. In this case, research needed to unveil that if CIN lesions were left untreated the risk of cervical cancer increased dramatically. In your opinion, was the evidence in the early 80’s already above the intervention line?
The study should never have taken place because there was already sufficient evidence that the proposed study was unnecessary. Almost a century earlier, pathology research had clearly demonstrated the relationship between cervical cancer and a precursor lesion. Mid-20th century retrospective clinical studies confirmed the malignant potential of CIS and a prospective study of untreated CIS was stopped when cases of cancer occurred. Boyes et al reporting results from the British Columbia population screening programme noted that removal of precursor lesions by treatment led to a reduction in the incidence of cervical cancer. Green was familiar with these studies. He made no secret of his study, publishing and lecturing widely, though his findings were not generally accepted.
At the time, was the New Zealand observational project subjected to local research ethical committees?
Ethics committees were not in use in New Zealand when in 1966 Green gained informal approval from his colleagues for his study. Green recognised he needed the support of his colleagues, all of whom treated CIS, if he was to carry out his experiment. Two separate committees of colleagues considered his request and the brief minutes of the meeting record ‘there was much discussion’ and approval for a study ‘to attempt to prove CIS was not a premalignant lesion.’ No other consent was obtained. Elsewhere in the hospital women with CIS were treated conventionally with cone biopsy or when indicated hysterectomy. Ethics committees, including lay membership were formally introduced in the Auckland region in the mid-1970s. A further study by us using the same clinical and pathological material was reported in LANCET ONCOLOGY (McCredie et al. 2008).3 Here, analysis by assessment of the adequacy of treatment again demonstrated that women with untreated CIS had a high risk of developing cancer compared with women who received conventional treatment.
Is it possible that similar cases occurred elsewhere and remain undescribed? Was there an effect on the personality of hospital leaders?
It is likely that similar unreported studies have taken place elsewhere. Green’s published results were not widely accepted. Green was a large framed somewhat intimidating man with strongly held opinions. He believed his histological expertise was equivalent to that of his pathologist, McLean.
While the study was primarily his responsibility, the reason it was not stopped sooner was the failure of his colleagues to acknowledge the risks to which his patients were being exposed. An example of ‘good men doing nothing’. It is a story of misplaced loyalty by Green’s colleagues, some of whom were close friends.
Did the experience drive the creation of the ethics evaluation in clinical research?
The ‘unfortunate experiment’ has received widespread international recognition and the lessons learned have undoubtedly been of benefit to the research community.
References
1. Jones RW. Doctors in denial. The forgotten women in the “unfortunate experiment”. Otago University press, 2017. Dunedin, New Zealand. Available from: https://www.otago.ac.nz/press/books/otago635233.html
2.. McIndoe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in situ of the cervix. Obstet Gynecol. 1984 Oct;64(4):451-8. Abstract available at: https://pubmed.ncbi.nlm.nih.gov/6483293/
3. McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008 May;9(5):425-34. Available at: https://doi.org/10.1016/s1470-2045(08)70103-7