- Email: [email protected]
Double dealing with your data
784
intimidation by the security forces. This has particularly affected the provision of preventive health care, such as childhood immunisation and antenatal care. Although no official statistics are maintained, it is said that there has been a resurgence of diphtheria. Last November, 15 children in the village of Bemina contracted the disease, and 10 died. Increasing numbers of cases of whooping cough and polio are also claimed. The Children’s Hospital in Srinagar has reported a sharp fall in the number of admissions. This is thought to be due to travel difficulties and curfews. Delays in admission to the hospital are said to have increased the mortality from conditions such as pneumonia and meningitis. According to a local paediatrician, half the children admitted with meningococcal meningitis have died. The supply of essential drugs such as antibiotics and vaccines has been erratic because of the disruption of communication and business life. At present, however, essential supplies seem to be adequate, and the drop in the vaccination rate for children appears to have more to do with parental fear of travelling than shortage of vaccine. Visits to various hospitals showed that the workload has increased because of casualties from the unrest, but the budget has remained the same. Staff have been harassed within hospitals and in some instances have been detained. In addition, many Hindu doctors and nurses have left the region for their own safety. The remaining staff have had to cope with intermittent shortages of supplies and routine power cuts, and morale is consequently very low. A number of senior medical staff have been detained for questioning. The delegation met Professor Guru, who had just been released from detention. He was arrested on Sept 11 at Delhi airport on his return from a pilgrimage to Saudi Arabia. He said that he had been accused of collecting money for victims of the Iranian earthquake last year and for channelling funds to Kashmiris who had suffered as a result of the unrest. He had been detained for three months in conditions that he described as "appalling". Other doctors described incidents of personal harassment, house searches, and frequent questioning, which were often related to their medical work. For example, one senior doctor who lived in the centre of Srinagar said that his house had been raided and he had been questioned at length about his reasons for keeping supplies of drugs in his house. He was accused of keeping these in order to treat militants. Local human-rights groups were gravely concerned about the ways in which detainees are being treated. During the various waves of unrest, a large number of people have been arrested and detained. The Bar Association alleged that many of them are being held without trial and has provided the delegation with names of people in this category. From information provided it appears that there are over 3000 petitions for habeas corpus pending before the Kashmir wing of the Jammu & Kashmir High Court. It is also alleged that many detainees are being held in distant states such as Rajasthan, Nagaland, and Tamil Nadu, which makes visits by lawyers almost impossible. The violence in Kashmir and the abuses of human rights are not one-sided. The militants are said to have been responsible for the kidnapping and murder of a number of people, including Prof Mushirul Haque, vice-chancellor of Kashmir University, and it is estimated that nearly 65 000 Hindus have fled Kashmir for fear of their lives. Peter Kandela
Conference Double
dealing with your data
The Lancet publishes about ten articles and forty letters each week--over 2500 contributions per year in all. Despite the best efforts of editorial staff and peer review, how much of this information can we expect our readers to believe? Can an individual who is deeply involved in bringing clinical trial data into the public domain-sponsor, investigator, or even journal editor-ever be objective? Should a single trial aim to be the final arbiter of a specific scientific question, or should the quest for truth be left to that burgeoning band of
interlopers-the meta-analysts? Clinical pharmacologists occupy the special position of "mediator" between an industry often intent on commercial advantage and a public hungry for straightforward answers to their questions. Last week, at a Forum on Clinical Pharmacology held at the Royal Society of Medicine for this "diplomatic service" of the profession, the question of who should take responsibility for clinical trial results was put, and the participants attempted to furnish some answers. In 1987, Hampton and Julian expressed their concerns about the relation between the drug industry and clinical investigators.1 The often large financial contributions made by companies make them less likely to cede complete control to trialists. Hampton and Julian argued that the preservation of confidentiality must be ensured during collection of data relevant to the main end-points of the trial. They suggested that an independent Data and Safety Monitoring Committee was one answer to this potential difficulty. Despite some tetchy replies from the pharmaceutical industry,2,3 their recommendations are now standard practice for most large multicentre studies. The process by which ethical approval of a trial protocol is given also remains open to criticism. To what extent do local hospital ethics committees have the ability to judge the merits of a study? These committees often have insufficient time to discuss the subtleties of the ethical questions posed by each application. Who audits the work of ethics committees? Should data monitoring committees review the ethical conduct of the trial? A meeting about clinical trials without the presence of statisticians is now unthinkable. Those present at last week’s meeting remorselessly exposed the mathematical obfuscations that investigators introduce to portray their results in the most appealing light. A speaker ruefully pointed to the surprising fact that the Committee on Safety of Medicines does not employ an independent statistical advisor to review product licence applications. A special difficulty is the small clinical trial that does not have the power to overcome a type II (false-positive) error. The probability of finding a single positive result from twenty small trials is high, whereas the statistical power of a larger trial may make such chance effects unlikely. These small trials will undoubtedly continue to be sponsored and published and the incentive for the pharmaceutical industry to sponsor large studies remains poor. To combat this disagreeable trend, some individuals have argued vigorously in favour of meta-analyses or overviews. This form of objective assessment of both published and (more importantly) unpublished trials is intended to kill off the review that is based on the experience of a reflective specialist. Although critics have unkindly labelled this approach as "garbage-processing", a compromise view may be that meta-analyses offer a quantitative review rather than
785
decisive arbitration. Their observational nature, despite valiant efforts to include all studies known to have been
completed, inevitably leads to a risk of bias. An experiment should remain the unit of scientific activity. A wider question that was only briefly touched on at this conference, but which is at the heart of the subject of responsible conduct by those concerned with the execution of clinical trials, is the way investigators release data to the media, sometimes before adequate peer review and publication. For instance, the release of part of the data from the third International Study of Infarct Survival (ISIS-3), at a recent meeting of the American College of Cardiology in Atlanta, was followed by a stream of press releases from pharmaceutical companies that had an interest in the trial. There was extensive newspaper coverage and discussion in economics journals. A fuller discussion of both thrombolytic efficacy and adverse events, together with subgroup analyses, drug company responses, and editorial comment on how clinical practice will be affected by the results has now appeared in Scrip 4 Yet these results had not been delivered to the medical community in such a way as to allow a thoughtful response by those with the responsibility of treating patients. That there are many other examples of this disturbing tendency perhaps reflects both the pressure on investigators from sponsors and the need for publicity to encourage funding bodies to continue their support. Each individual involved in whatever capacity with publishing clinical trial results has different aims and responsibilities that seem impossible to resolve. While mechanisms can be built into the conduct of trials either to avoid inappropriate disclosure of information or to prevent unwanted commercial pressure from outside agencies, the entire clinical trial machinery demands a large measure of good faith from all concerned. So, how much of The Lancet can you trust? Perhaps we need a trial to find out. Richard Horton Hampton JR, Julian DG. Role of the pharmaceutical industry in major clinical trials. Lancet 1987; ii: 1258-59. 2. Smith RN. Role of the pharmaceutical industry in major clinical trials. Lancet 1987; ii: 1464. 3. Burley D, Parr G. Role of the pharmaceutical industry in major clinical 1.
trials. Lancet 1987; ii: 1464-65. 4. Hughes S. ISIS-3: Streptokinase the thrombolytic of choice. March 8: 22-23.
Scrip 1991;
Medicine and the Law Diethylstilboestrol: third-generation injury claims On Feb 19,1991, the New York Court of Appeals rejected the right to claim for a third-generation injury resulting from ingestion of diethylstilboestrol (DES) during pregnancy. The plaintiff was a 9-year-old girl with cerebral
palsy. Her grandmother had taken DES during pregnancy in 1959, and her mother (born in 1960) had deformities in her reproductive system which, it was claimed, led to premature birth and neurological injuries in the third generation. DES was marketed for about 30 years in the belief that it reduced the risk of miscarriage. Over two hundred firms manufactured it, and it was widely prescribed in the Netherlands and USA. In 1971 it was banned by the US Food and Drug Administration (FDA) because of evidence of an abnormal incidence of vaginal and cervical cancer in the daughters of women who had taken DES during pregnancy. There were also adverse effects in male children.
There are now thousands of claims afoot against manufacturers in the USA. These second-generation claims have faced difficulties because of the long time lapse between ingestion of DES and discovery of injury: the ill-effects of DES were not identified until the daughters reached puberty at the earliest. Another problem has been to identify which manufacturer produced the brand of DES that each woman took. Furthermore, records have been destroyed or lost, manufacturers have closed down, prescribers have retired or died, and memories have faded. Early claims named the FDA as co-defendants but all claims against the Administration were dismissed. One approach was the "concerted action petition", which aimed to identify all distributors who participated in the "common purpose" of supplying DES to a particular area in which the plaintiffs mother had lived at the time of ingestion. This ploy was seldom successful, but in Michigan and New York courts ruled that the manufacturer’s marketing strategy showed evidence of conscious parallel strategies, and two cases did succeed. An attempt to shift the burden of proof on to a defendant, so that a manufacturer would have to establish his innocence, failed. The courts ruled that it would be unjust to find a firm guilty of dispensing an unsafe product when that individual manufacturer was merely one of a group whose identity was doubted. In California in 1980 plaintiffs were allowed to sue, on the basis of market share, all DES manufacturers who had supplied the drug to a particular area. This approach, though much criticised, has been the model for the later cases in which the plaintiff has been able to prove the manufacturer’s failure to test the safety of the drug or to warn the users of potential harm.
The claims for third-generation injuries by about 100 "DES granddaughters" marks a new stage in the battle for compensation. They allege that maternal uterine hypoplasia, cervical stenosis, and/or endometriosis caused by their mothers’ exposure to DES ingestion while in utero are responsible for their own congenital deformities. They also claim for large sums to compensate for anxiety over the increased risk of clear-cell adenocarcinomas. In most cases, thirty years or more have elapsed since the original DES ingestion, and such cases would normally be well outside time limits for bringing a suit. Even under the Consumer Protection Act 1987, which is not retrospective and which came into force in Britain on March 1, 1988, there is a maximum time limit of ten years in which claims may be brought. Beyond that, the plaintiff must pursue a claim in negligence in the normal way, if not time barred. By a majority of 6 to 1, the New York Court of Appeals rejected in principle the right to pursue a third-generation DES injury claim. Giving the judgment of the majority, Chief Judge Sol Wachtler said: "For all we know, the rippling effects of DES exposure may extend for generations. It is our duty to confine liability within manageable limits. Limiting liability to those who ingested the drug or who were exposed to it in utero serves this purpose." Judge Stewart F. Hancock Jr, dissenting, argued that the girl "should have the same right to sue the drug makers for her injuries as her mother... [she] is one of a class of thousands of persons who have allegedly suffered devastating abnormalities and injuries resulting from Is there any basis in the defendants’ marketing of DES law or social policy or any principled reason in justice and fairness for holding that she-unlike other members of the class--should not be permitted to prove her case?" The New York decision is likely to be persuasive in other states, though it is not binding outside New York, and with so much at stake the large numbers of would-be plaintiffs are unlikely to give up the struggle just yet. ...
Enright v Eli Lilly & Co, no 19. New York Court of Appeals, Feb 19,1991. Diana Brahams
intimidation by the security forces. This has particularly affected the provision of preventive health care, such as childhood immunisation and antenatal care. Although no official statistics are maintained, it is said that there has been a resurgence of diphtheria. Last November, 15 children in the village of Bemina contracted the disease, and 10 died. Increasing numbers of cases of whooping cough and polio are also claimed. The Children’s Hospital in Srinagar has reported a sharp fall in the number of admissions. This is thought to be due to travel difficulties and curfews. Delays in admission to the hospital are said to have increased the mortality from conditions such as pneumonia and meningitis. According to a local paediatrician, half the children admitted with meningococcal meningitis have died. The supply of essential drugs such as antibiotics and vaccines has been erratic because of the disruption of communication and business life. At present, however, essential supplies seem to be adequate, and the drop in the vaccination rate for children appears to have more to do with parental fear of travelling than shortage of vaccine. Visits to various hospitals showed that the workload has increased because of casualties from the unrest, but the budget has remained the same. Staff have been harassed within hospitals and in some instances have been detained. In addition, many Hindu doctors and nurses have left the region for their own safety. The remaining staff have had to cope with intermittent shortages of supplies and routine power cuts, and morale is consequently very low. A number of senior medical staff have been detained for questioning. The delegation met Professor Guru, who had just been released from detention. He was arrested on Sept 11 at Delhi airport on his return from a pilgrimage to Saudi Arabia. He said that he had been accused of collecting money for victims of the Iranian earthquake last year and for channelling funds to Kashmiris who had suffered as a result of the unrest. He had been detained for three months in conditions that he described as "appalling". Other doctors described incidents of personal harassment, house searches, and frequent questioning, which were often related to their medical work. For example, one senior doctor who lived in the centre of Srinagar said that his house had been raided and he had been questioned at length about his reasons for keeping supplies of drugs in his house. He was accused of keeping these in order to treat militants. Local human-rights groups were gravely concerned about the ways in which detainees are being treated. During the various waves of unrest, a large number of people have been arrested and detained. The Bar Association alleged that many of them are being held without trial and has provided the delegation with names of people in this category. From information provided it appears that there are over 3000 petitions for habeas corpus pending before the Kashmir wing of the Jammu & Kashmir High Court. It is also alleged that many detainees are being held in distant states such as Rajasthan, Nagaland, and Tamil Nadu, which makes visits by lawyers almost impossible. The violence in Kashmir and the abuses of human rights are not one-sided. The militants are said to have been responsible for the kidnapping and murder of a number of people, including Prof Mushirul Haque, vice-chancellor of Kashmir University, and it is estimated that nearly 65 000 Hindus have fled Kashmir for fear of their lives. Peter Kandela
Conference Double
dealing with your data
The Lancet publishes about ten articles and forty letters each week--over 2500 contributions per year in all. Despite the best efforts of editorial staff and peer review, how much of this information can we expect our readers to believe? Can an individual who is deeply involved in bringing clinical trial data into the public domain-sponsor, investigator, or even journal editor-ever be objective? Should a single trial aim to be the final arbiter of a specific scientific question, or should the quest for truth be left to that burgeoning band of
interlopers-the meta-analysts? Clinical pharmacologists occupy the special position of "mediator" between an industry often intent on commercial advantage and a public hungry for straightforward answers to their questions. Last week, at a Forum on Clinical Pharmacology held at the Royal Society of Medicine for this "diplomatic service" of the profession, the question of who should take responsibility for clinical trial results was put, and the participants attempted to furnish some answers. In 1987, Hampton and Julian expressed their concerns about the relation between the drug industry and clinical investigators.1 The often large financial contributions made by companies make them less likely to cede complete control to trialists. Hampton and Julian argued that the preservation of confidentiality must be ensured during collection of data relevant to the main end-points of the trial. They suggested that an independent Data and Safety Monitoring Committee was one answer to this potential difficulty. Despite some tetchy replies from the pharmaceutical industry,2,3 their recommendations are now standard practice for most large multicentre studies. The process by which ethical approval of a trial protocol is given also remains open to criticism. To what extent do local hospital ethics committees have the ability to judge the merits of a study? These committees often have insufficient time to discuss the subtleties of the ethical questions posed by each application. Who audits the work of ethics committees? Should data monitoring committees review the ethical conduct of the trial? A meeting about clinical trials without the presence of statisticians is now unthinkable. Those present at last week’s meeting remorselessly exposed the mathematical obfuscations that investigators introduce to portray their results in the most appealing light. A speaker ruefully pointed to the surprising fact that the Committee on Safety of Medicines does not employ an independent statistical advisor to review product licence applications. A special difficulty is the small clinical trial that does not have the power to overcome a type II (false-positive) error. The probability of finding a single positive result from twenty small trials is high, whereas the statistical power of a larger trial may make such chance effects unlikely. These small trials will undoubtedly continue to be sponsored and published and the incentive for the pharmaceutical industry to sponsor large studies remains poor. To combat this disagreeable trend, some individuals have argued vigorously in favour of meta-analyses or overviews. This form of objective assessment of both published and (more importantly) unpublished trials is intended to kill off the review that is based on the experience of a reflective specialist. Although critics have unkindly labelled this approach as "garbage-processing", a compromise view may be that meta-analyses offer a quantitative review rather than
785
decisive arbitration. Their observational nature, despite valiant efforts to include all studies known to have been
completed, inevitably leads to a risk of bias. An experiment should remain the unit of scientific activity. A wider question that was only briefly touched on at this conference, but which is at the heart of the subject of responsible conduct by those concerned with the execution of clinical trials, is the way investigators release data to the media, sometimes before adequate peer review and publication. For instance, the release of part of the data from the third International Study of Infarct Survival (ISIS-3), at a recent meeting of the American College of Cardiology in Atlanta, was followed by a stream of press releases from pharmaceutical companies that had an interest in the trial. There was extensive newspaper coverage and discussion in economics journals. A fuller discussion of both thrombolytic efficacy and adverse events, together with subgroup analyses, drug company responses, and editorial comment on how clinical practice will be affected by the results has now appeared in Scrip 4 Yet these results had not been delivered to the medical community in such a way as to allow a thoughtful response by those with the responsibility of treating patients. That there are many other examples of this disturbing tendency perhaps reflects both the pressure on investigators from sponsors and the need for publicity to encourage funding bodies to continue their support. Each individual involved in whatever capacity with publishing clinical trial results has different aims and responsibilities that seem impossible to resolve. While mechanisms can be built into the conduct of trials either to avoid inappropriate disclosure of information or to prevent unwanted commercial pressure from outside agencies, the entire clinical trial machinery demands a large measure of good faith from all concerned. So, how much of The Lancet can you trust? Perhaps we need a trial to find out. Richard Horton Hampton JR, Julian DG. Role of the pharmaceutical industry in major clinical trials. Lancet 1987; ii: 1258-59. 2. Smith RN. Role of the pharmaceutical industry in major clinical trials. Lancet 1987; ii: 1464. 3. Burley D, Parr G. Role of the pharmaceutical industry in major clinical 1.
trials. Lancet 1987; ii: 1464-65. 4. Hughes S. ISIS-3: Streptokinase the thrombolytic of choice. March 8: 22-23.
Scrip 1991;
Medicine and the Law Diethylstilboestrol: third-generation injury claims On Feb 19,1991, the New York Court of Appeals rejected the right to claim for a third-generation injury resulting from ingestion of diethylstilboestrol (DES) during pregnancy. The plaintiff was a 9-year-old girl with cerebral
palsy. Her grandmother had taken DES during pregnancy in 1959, and her mother (born in 1960) had deformities in her reproductive system which, it was claimed, led to premature birth and neurological injuries in the third generation. DES was marketed for about 30 years in the belief that it reduced the risk of miscarriage. Over two hundred firms manufactured it, and it was widely prescribed in the Netherlands and USA. In 1971 it was banned by the US Food and Drug Administration (FDA) because of evidence of an abnormal incidence of vaginal and cervical cancer in the daughters of women who had taken DES during pregnancy. There were also adverse effects in male children.
There are now thousands of claims afoot against manufacturers in the USA. These second-generation claims have faced difficulties because of the long time lapse between ingestion of DES and discovery of injury: the ill-effects of DES were not identified until the daughters reached puberty at the earliest. Another problem has been to identify which manufacturer produced the brand of DES that each woman took. Furthermore, records have been destroyed or lost, manufacturers have closed down, prescribers have retired or died, and memories have faded. Early claims named the FDA as co-defendants but all claims against the Administration were dismissed. One approach was the "concerted action petition", which aimed to identify all distributors who participated in the "common purpose" of supplying DES to a particular area in which the plaintiffs mother had lived at the time of ingestion. This ploy was seldom successful, but in Michigan and New York courts ruled that the manufacturer’s marketing strategy showed evidence of conscious parallel strategies, and two cases did succeed. An attempt to shift the burden of proof on to a defendant, so that a manufacturer would have to establish his innocence, failed. The courts ruled that it would be unjust to find a firm guilty of dispensing an unsafe product when that individual manufacturer was merely one of a group whose identity was doubted. In California in 1980 plaintiffs were allowed to sue, on the basis of market share, all DES manufacturers who had supplied the drug to a particular area. This approach, though much criticised, has been the model for the later cases in which the plaintiff has been able to prove the manufacturer’s failure to test the safety of the drug or to warn the users of potential harm.
The claims for third-generation injuries by about 100 "DES granddaughters" marks a new stage in the battle for compensation. They allege that maternal uterine hypoplasia, cervical stenosis, and/or endometriosis caused by their mothers’ exposure to DES ingestion while in utero are responsible for their own congenital deformities. They also claim for large sums to compensate for anxiety over the increased risk of clear-cell adenocarcinomas. In most cases, thirty years or more have elapsed since the original DES ingestion, and such cases would normally be well outside time limits for bringing a suit. Even under the Consumer Protection Act 1987, which is not retrospective and which came into force in Britain on March 1, 1988, there is a maximum time limit of ten years in which claims may be brought. Beyond that, the plaintiff must pursue a claim in negligence in the normal way, if not time barred. By a majority of 6 to 1, the New York Court of Appeals rejected in principle the right to pursue a third-generation DES injury claim. Giving the judgment of the majority, Chief Judge Sol Wachtler said: "For all we know, the rippling effects of DES exposure may extend for generations. It is our duty to confine liability within manageable limits. Limiting liability to those who ingested the drug or who were exposed to it in utero serves this purpose." Judge Stewart F. Hancock Jr, dissenting, argued that the girl "should have the same right to sue the drug makers for her injuries as her mother... [she] is one of a class of thousands of persons who have allegedly suffered devastating abnormalities and injuries resulting from Is there any basis in the defendants’ marketing of DES law or social policy or any principled reason in justice and fairness for holding that she-unlike other members of the class--should not be permitted to prove her case?" The New York decision is likely to be persuasive in other states, though it is not binding outside New York, and with so much at stake the large numbers of would-be plaintiffs are unlikely to give up the struggle just yet. ...
Enright v Eli Lilly & Co, no 19. New York Court of Appeals, Feb 19,1991. Diana Brahams