International In-house Counsel Journal Vol. 9, No. 35, Spring 2016, 1 “The Past, the Present, and the Future … Clinical Trials and the Contract Research Organisation (CRO)” HELEN LOUISE FOVARGUE Senior Legal Director, Quintiles In 2016, Clinical Trials globally are performed to ensure safe and efficacious treatment which meet ethical principles, but will these principles meet the challenges of the future? To understand how and why clinical trials are performed today and will be in the future it is essential to understand the past and the thorny path trodden in the performance of clinical trials. Overarching any clinical trial is a person’s right and ability to consent. The issues surrounding the urgent need for effective efficient treatments balanced by the risk/benefit analysis of the efficacy and efficient treatments is a universal global concern. The ultimate goal of any successful treatment belies a history of divergent checks and balances to reach the constant moving pyramidal spike of success and each end point creates a giant leap forward to the benefit of mankind. But the rapidly escalating cost of clinical trials has caused the pharmaceutical and biotech industry to seek new ways to off-set the burgeoning costs to reap financial reward and fund future trials of new innovative medicine, and the introduction of outsourcing through Contract Research Organisations (CROs). All of these factors in the past have created a plethora of legal and industry challenges. The law is always one step behind the advance of science, and ultimately the industry and the law must partner together to meet these challenges to strive forwards. The focus of this paper primarily pertains to events affecting the UK and USA. The Past … how the past shaped the future … Hippocratic Oath (fourth century BC) “I will use my power to help the sick to the best of my ability and judgement; I will abstain from harming or wrongdoing any man by it. I will not give a fatal draught [drugs] to anyone if I am asked, nor will I suggest any such thing.”1 The Hippocratic Oath remains the guiding principle of medicine today and underpins the ethos of medical doctors performing research2. It was essential that the physician observe and understand the individual patient and his or her symptoms in order to reach successful diagnosis and treatment, which is palpably the very genus of human research. Important landmarks in the evolution of clinical trials The earliest recorded clinical trial is evidenced in the Old Testament when King Nebuchadnezzar II of Babylon tested a meat and wine diet against a vegetables and water diet.3 In the sixteenth century the first clinical trial of a novel therapy was performed by Ambroise Paré,4 where he discovered a novel method to heal wounds. In 1747, James 1 Oath of Hippocrates, in Hippocratic Writings (translated by J. Chadwick and W.N. Mann, 1950). 3 King Nebuchadnezzar II ordered that his royal Jewish captives eat meat and drink wine. But Daniel requested that he and three other boys be allowed to eat only vegetables and drink water. After a trial period of ten days, Daniel and the other three were noticeably healthier than those on the meat and wine diet. 4 The first clinical trial of a “novel therapy” performed by Ambroise Paré, a French war surgeon in 1536. International In-house Counsel Journal ISSN 1754-0607 print/ISSN 1754-0607 online 2 Helen Fovargue Lind5 conducted the first controlled clinical trial on a group of sailors suffering from scurvy and he was able to prove that Vitamin C prevented scurvy.6 In 1863, Austin Flint7 performed the first trial to directly compare an active drug against a placebo. In the twentieth century the principles of informed consent coupled with monetary advantage and the concept of a binding contract were born.8 At the start of the century clinical experimentation was seen as merely deviation from accepted or standard medical practice during the course of therapeutic interventions.9 These important landmarks in the evolution of clinical trials are still relevant in the conduct of trials today. The path to success but at what cost… Ethical dilemmas Clinical trials are perceived at best as successful formulation of aspiration, but the path to such success is a thorny one, combining the desire to succeed, to prove, with socio- economic or political factors. Clinical Trials performed on the vulnerable and disadvantaged The Middle Ages marked the era of testing new drugs and initially physicians used themselves as subjects but this carried the risk that the physician could harm his own body diminishing his capacity to continue to provide healthcare.10 Thus, the use of the vulnerable and socially disadvantaged as experimental subjects commenced. Syphilis was the scourge of the nineteenth century and in the quest to understand this disease William Wallace11 set out to prove the transmission of syphilis between humans by the means of inoculation. He picked a group of three healthy young pre-pubescent boys and bound their cut flesh with bandages drenched in syphilitic dressing for a period of time. To his delight the children caught syphilis, thus proving the transmission of disease and its incubation period.12 He did not see that this trial was totally ethically immoral and abhorrent; for him the quest to prove transmission was greater than the welfare of the children. The twentieth century has seen the worst abuse of clinical testing on the vulnerable and/or disadvantaged, and in the aftermath of tragedy, mishap and evil, ethical practice has shaped the regulation of clinical trials. In 1937, untested formulation of Elixir Sulfanilamide13 led to laws in the USA requiring premarketing drug tests and the necessity to publish the findings of the results of trials. Sulfanilamide was used to treat streptococcal infections, and had been shown to have dramatic curative effects and had been used safely for some time in tablet and powder form. In 1937, S.E. Massengill Company's chief chemist and pharmacist experimented and found that sulfanilamide would dissolve in diethylene glycol. Because no pharmacological studies had been done on the new sulfanilamide preparation, he failed to note that diethylene glycol, a chemical normally used as an antifreeze, is a deadly poison. The drug was distributed and the resultant deaths led to the passage of the 1938 Federal 5 James Lind (1716–94), Treatise on Scurvy published in Edinburgh in 1753. Dodgson S.J. ‘The evolution of clinical trials’, The Journal of the European Medical Writers Association, 2006;15:20–21. 6 The first “controlled” clinical trial. 7 Austin Flint (1812–86) 8 Walter Reed, in 1900, offered $100 to be on the clinical trial; participants infected with yellow fever would get “the greatest care and most successful medical service”, and in the event they died of yellow fever would receive a further $100. 9 Carpenter v. Blake (1871) 10 The Ethics and Regulation of Research with Human Subjects, Carl H. Coleman et al, 2005, pp5. 11 1836. 12 R.S. Morton (1966). Dr William Wallace (1791–1837) of Dublin. Medical History, 10, pp 38-43 doi:10.1017/S0025727300010620 13 1937, Elixir Sulfanilamide crisis and the growth of the FDA. Contract Research Organisation 3 Food, Drug, and Cosmetic Act, which dramatically increased the FDA's authority to regulate drugs. The Tuskegee Syphilis Study in the USA was a longitudinal trial conducted on 600 African American males between 1933 and 1972. 400 of the subjects were diagnosed as infected with syphilis (but not told of their diagnosis). By the 1940s, penicillin was available and a cure for syphilis but the subjects were denied access to penicillin and many died. The result of the atrocities of this trial was the enactment of the National Research Act 1974, which required biomedical research to be conducted in accordance with basic ethical principles14, and research on vulnerable groups (prisoners, mentally infirm) is now very strictly controlled. Nazi Germany and the Nuremberg Code German physicians conducted pseudoscientific experiments on thousands of concentration camp prisoners without their consent. The majority of the victims were Jews who died or were permanently disabled as a result of the experiments. At the conclusion of World War II a variety of plans were drawn up to bring war criminals to justice. During the Nuremberg trials it became clear that while there are permissible medical experiments, certain principles must be adhered to in order to satisfy moral, ethical, and legal concepts (now known as the Nuremberg Code).15 The Nuremberg Code is the precursor to the ICH GCP16 which has shaped the principles to be adhered to in the performance of clinical trials globally today. In the USA, the result of World War II and its aftermath saw two phenomena that had an enormous impact on medical research: (1) “The ties formed between the federal government and academic medical centers during World War II irrevocably altered the scale of medical research in the United States.”17 (2) The development of biostatistics “help structure studies, eliminate investigator and participant bias, control for multiple interacting factors, and determine levels of statistical significance”.1819 The ethical principles set out in the Nuremberg Code have been further elaborated and clarified by the World Medical Association through the ‘Declaration of Helsinki’20. The Declaration of Helsinki provides the ethical foundation for ICH E6 (ICH GCP), the European Clinical Trial Directive (2001/20/EC) and GCP Directive (2005/28/EC) and national clinical research legislation. Thalidomide In 1960, drug regulation lacked three key areas: proof of safety and efficacy, test regulation; and accountability. In the USA, the FDA had sixty days to prove a new drug unsafe, based on the company tests; otherwise, approval was automatic.