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.

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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. Efficacy was not

14 The Belmont Report 1979, USA, established three basic ethical principles: Respect for persons, Beneficence, Justice. Research on vulnerable groups very strictly controlled (prisoners, mentally infirm). 15 Nuremberg Code (1947) – 10 principles: (1) voluntary consent, (2) the experiment should bring fruitful result for the good of mankind… (3) the experiment should be so designed and based on results of animal experimentation and a knowledge of the natural history of the disease or other problem…to justify the performance of the experiment, (4) conducted to avoid all unnecessary physical or mental suffering and injury, (5) no experiment to be performed where the priori reason is death or disability will ensue… (6) degree of risk should never exceed the problem to be solved, (7) proper preparation and adequate facilities, (8) should be conducted by scientifically qualified persons, (9) the volunteer is able to withdraw from the experiment at any time, (10) the scientist must be prepared to terminate the trial at any time if he has probable course to believe that continuation of the experiment is likely to cause death, disability or injury. 16 ICH GCP E6 1996. 17 Ledmerer, supra, at139. 18 Ledmerer, id at 37. 19 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149409/#ref1 20 Declaration of Helsinki, 1964,

4 Helen Fovargue considered. In the UK, there was little regulation and few controls to support experimental drugs and their use on children. In the USA, Frances Kelsey, working for the FDA, is attributed with keeping thalidomide out of the USA. She refused marketing authorisation of thalidomide in the USA because there was insufficient characterisation of fundamental mechanisms of action, in particular pre-clinical toxicology. Over the past 40–50 years the major regulatory authorities around the world have introduced virtually all the principles of ‘regulatory science’ foreseen by Frances Kelsey. These principles have now evolved into the common features of the regulatory framework for the evaluation of benefit–risk that is practised worldwide. Paternalism meets the fundamental rights of the patient to choose In the twentieth century medicine and health care became increasingly more available to the general public through direct access via doctors or health authorities.21 Before the late 1970s medicine and treatments were generally paternalistic in nature and the public unquestioningly followed the advice of the health professional.22 Today, vastly increased access to medical information has changed the focus from paternalism to patient rights, and the patient is more willing to question the act of medical advice, and the medical fraternity are increasingly made accountable for their actions.23 This shift in approach has added a further layer of complexity in the approach to clinical trials and medicines, to the benefit of the patient. Consent The cornerstone of any clinical trial is the patient/volunteers consent. In 1935, in the USA, the courts acknowledged the fact that if surgery and medicine is to progress there must be a certain amount of experimentation and “any such experiments must be done with the knowledge and consent of the patient or those responsible for him”.24 In the late 1940s to early 1950s, an African-American lady, Henrietta Lacks,25 was being treated for cancer of the cervix. She received vast doses of radiation in the quest to rid her of the cancerous tumour. It was during this treatment that cancerous cells were taken from Henrietta – no permission was sought – and used to culture her cells to conduct experiments. These experiments have proven to be tremendously important in biomedical research – the birth of HeLa26. Henrietta’s cells are used worldwide yet Henrietta never gave consent for her body to be used in this way. Today we are outraged by this, we demand the ability to freely decide and consent, but the 21st century is a very different society to the 1950s, an era primarily driven by medical paternalism. Today, the right of a person to decide, to consent, still has its caveats. In the USA, in Moore v. Regents of the University of California (1999). “...a person's discarded tissue and cells are not their property and can be commercialized”. In Washington University v. Catalona (2007), patients who donated biological material for research no longer retained either property rights in it or the right to authorise transfer. In Greenberg v. Miami Children’s Hospital Research Institute (2003), a research product developed from human tissue is factually and legally distinct from the original tissue and as such becomes the property of the researcher while the donor retains no rights.

21 Emergence of public health – US Food and Drug Administration, UK Department of Health, etc. 22 Example the treatment of Henrietta Lacks. 23 Regulation of doctors for example General Medical Council in the UK as to how a doctor must practise medicine, and the Patient’s Charter in the NHS. 24 Foriner v. Koch (1935) Michigan appellate opinion. 25 Henrietta Lacks – the birth of HeLa 1951. 26 1951.

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In the UK (and EU), in 2001, the retention of organs at the Alder Hey Children's Hospital in Liverpool scandal came to light. This was the unauthorised removal, retention and disposal of human tissue, which included children's organs, during the period 1988 to 1995. Organs were retained in more than 2,000 pots containing body parts from around 850 infants. This scandal was the main precursor which led to the legislation in the UK the ‘Human Tissue Act 2004’, which lays down the foundation and the principles as to how, when and where tissues may be taken, transferred and retained. In the EU, following on the heels of the organ scandal, came the EU Tissue and Cells Directive (EUTCD) via the Human Tissue (Quality and Safety for Human Application) Regulations 2007.27 In the twentieth century, consent to procedures, or to test on discarded tissue, or to protect a person’s identity, has created a plethora of laws globally (data protection and privacy28, ECHR) and regulation and guidance in the clinical trial industry (ICH GCP 1995), primarily to protect people and also to enable people to choose and decide themselves. Also, springing out of these protections has come a secondary layer of protective laws to tackle abuse on these fundamental rights (issues of cybersecurity, lack of safe harbour in the transfer of data from the EU to the USA29). The Rise of Contract Research Organisations (CROs) There are many factors that have led to the outsourcing of clinical trials, First, government and private sector cost containment and marketplace globalisation pressures on drug prices. Second, pipeline management may pose a problem when the number of new compounds approaching market approval is large. Third, industry consolidation may also be a CRO stimulus, as merged companies seek to manage costs by reducing jobs, centralised R&D, and outsourcing to reduce fixed costs. Fourth, biotechnology firms, with great scientific competence, often lack the internal resources and experience (capital, equipment, and staff) to conduct preclinical and clinical research, and many have chosen to outsource rather than to create these capabilities de novo. Fifth, as the market for new drugs has become increasingly global, the concurrent harmonisation of US, European, and Japanese drug evaluation procedures has created the opportunity for drug firms to seek regulatory approval in various national markets simultaneously rather than sequentially. “Coupled with an increase in multinational trials, international CROs often are better able than a drug firm’s central regulatory affairs unit is to provide expertise about the regulatory requirements of a specific country and can help to tailor clinical trials accordingly. Finally, as clinical trials have become more complex in response to chronic disorders and life threatening conditions, CROs with particular therapeutic expertise become attractive to drug firms with promising research but limited experience in a given therapeutic area…”30 “In the United States, HIV/AIDS activists were leaders in challenging the research status quo. During the 1980s, as gay men sought to cope with a growing epidemic, they looked to medicine for assistance. Because physicians and scientists could tell them little about the new disease, the need for research was obvious, and the path to expanded access essential, and yet faced with a lethal epidemic and no effective treatments, they embarked on their urgent mission, however, they collided with a drug development system that was slow, inflexible, and highly risk-averse. People with no time to spare were shocked to

27 The EUTCD is made up of three Directives, the parent Directive (2004/23/EC) which provides the framework legislation and two technical directives (2006/17/EC and 2006/86/EC), which provide the detailed requirements of the EUTCD. 28 Data Protection Act 1998 (UK), HIPPAA 1996 (USA). 29 ECJ Judgment in Case C-362/14, Maximillian Schrems v. Data Protection Commissioner, Oct 6, 2015. 30 ‘The Industrialization of Clinical Research’, Richard A. Rettig, 19 Health Affairs 129, 134-35, 137-38 (2000).

6 Helen Fovargue learn that it took about ten years for new drugs and other medical products to undergo the human testing that was a prerequisite to approval for clinical use.”31 “Activists were enthusiastic partners in the campaign to publicise clinical trial availability and increase insurance coverage for trial participants…”32 The rigours of clinical trial testing to satisfy regulation meant that any potentially effective new drugs were too slow coming to market. HIV/AIDs helped the emergence of outsourcing to CROs to off-set the protracted clinical trial and to reduce the exorbitant and escalating cost of trials by invoking efficiencies. Today, out of every 10,000 compounds tested only one makes it through the rigorous testing to market, and for that one compound it costs approximately $1 billion dollars to get it to market. Each compound has a patent life and it is during the patent life that the pharmaceutical companies seek to get their investment back and make a profit to be able to have funds to develop the next successful drug/product. In addition, in 2000, it was estimated that drug companies lose $1.3million each day that there is a delay in obtaining FDA approval.33 The quest to off-set these escalating costs has seen the emergence of CROs, the development of biosimilars, and evergreening, but there is still the need to find other efficiencies. The emergence of Anti-corruption and Anti-bribery practice – and its overarching effects on the pharma and biotechnology industry The desire to reap financial rewards from products introduced to the market to cover the escalating costs of clinical trials and produce a successful drug (treatment) has led industry to push the boundaries of common business practice, resulting in legislative backlash to curb the practices. “Until a decade ago, giving bribes to win business or speed up transactions was widely seen as a necessary evil, especially in emerging markets. In parts of Europe, companies were even allowed to deduct kickbacks they had paid against tax. But anti-bribery enforcement has been transformed since the early 2000s, when Non-Government Organisations started to raise a stink and America stepped up use of its Foreign Corrupt Practices Act (FCPA).”34 Bio-Rad, which self-reported its misconduct and extensively cooperated during the investigation, agreed to pay $55 million to settle the SEC’s charges … the U.S. Department of Justice said: “This enforcement action, which reflects credit for Bio-Rad’s cooperation in our investigation, reiterates the importance of all companies ensuring they have the proper internal controls to prevent FCPA violations.”35 These are just a few examples of FCPA actions against the pharma and biotech industry and related industry. Though America remains the toughest enforcer, in the past few years other countries have started to flex their muscles … China’s anti-corruption drive under Xi Jinping has ensnared GSK, a British drug maker. It was found guilty last year (2014) of using travel agencies to create bribery slush funds and fined $490m—though local managers got away with suspended sentences because the company showed remorse.”36 Britain, which consolidated and improved upon a hotchpotch of previous legislation with its Bribery Act of 2010.

31 When science offers salvation, Rebecca Dresser, 23-25, 48-49, 51 (2001), 32 When science offers salvation, Rebecca Dresser, 23-25, 48-49, 51 (2001). 33 ‘The Movement of Research from Academic Health Centers to Private Physicians’ Offices and the Rise of Contract Research Organizations’, ‘The Ethics and Regulation of Research with Human Subjects’ Carl H. Coleman et al., 2005, pp88, quotes New England Journal of Medicine, written 2000, see Thomas Bodenheimer, ‘Uneasy Alliance – Clinical Investigators and the Pharmaceutical Industry’, 342, New Eng. J. Med. 1539 (2000). 34 as amended, 15 U.S.C. §§ 78dd-1, et seq. (FCPA). 35 ‘SEC Charges California-Based Bio-Rad Laboratories With FCPA Violations’, U.S. Securities and Exchange Commission, Washington D.C., Nov. 3, 2014. 36 The Economist, ‘The Anti-Bribery Business – As the enforcement of laws against corporate bribery increases, there are risks that it may go too far’, 9th May, 2015.

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The extra-territorial reach of the Bribery and FCPA Acts means that many international companies and their associates will fall within the scope of both Acts. The Serious Fraud Office (the guardian of the Bribery Act) has stated the focus is on the “controlling mind” of the company,37 including the circumstances, centres, size, potential risks exposed to the company, uniformity, and procedures to demonstrate form of culture. The industry and the legal profession have actively dealt with the issues of corruption and bribery is a prime example of the successful unification of the lawyer(s) and the business leaders partnering together as they strive forward to address the challenges of the ever changing landscape of business. The Present and the Future Lawyers need to assess risk and liability for the company as well as partner with the industry to move forward with the industry as it forges ahead in new science for the future and benefit of the global community. Clinical Trials Today and in the Future… Big Data and the future of Clinical Trials (and CROs) Big Data describes a holistic information management strategy that includes and integrates many new types of data and data management alongside traditional data. Big Data has been defined by the four Vs: Volume (the amount of data), Velocity (the fast rate at which data is received and perhaps acted upon), Variety (new unstructured data types), Value (data has intrinsic value – but it must be discovered). Big Data is opening up a whole new landscape for the performance of clinical trials including quantitative and investigative techniques to derive value from data,38 and predictive analytics can also be used to model and predict the behaviour of biomolecules, and are increasingly being used in the search for new chemical entities to fill the drug discovery pipelines of the pharmaceutical and biotechnology industries.39 Predictive Models for: patient/subject discovery; performance and operational analytics (determining the productivity, utilisation and profitability of clinical research initiatives); risk monitoring (for sponsors to assess investigator risk and allocate monitoring resources where they are needed most); financial modelling and cost effectiveness (to benchmark cost and visualise data in that context to help sponsors forecast, budget and negotiate the cost for outsourcing clinical trials); and manufacturing outcomes (used for process improvement analysis to improve scheduling and throughput). The possibilities are endless, as is the future potential of clinical trials to maximise efficiency and reliability. CROs are one of the keys to the success of Big Data and clinical trials, as CROs have the international footprint and expertise to successfully conduct such trials. Electronic Informed Consent Electronic Informed Consent enables efficient method to document and capture the informed consent of subjects on clinical trials. There is definitely a strong push from innovative pharmaceutical companies to adopt this new Electronic Informed Consent process concept in the conventional clinical trial setting and the implementation is fairly straightforward. In the virtual trial space there are still a few hurdles to overcome as there is a lack of defined regulatory requirements and a number of country-specific laws and regulations on the acceptability of electronic signatures, witnesses to the consent, the

37 Vivian Robinson QC, head of the SFO and the pioneer of the Bribery Act 2011, October 2011, The Law Society, England and Wales. 38 White paper: ‘Enterprise Architect's Guide to Big Data – Reference Architecture Overview’, Oracle, May 2015. 39 White paper: ‘Enterprise Architect’s Guide to Big Data—Reference Architecture Overview’, Oracle, May 2015.

8 Helen Fovargue need for video documentation and the use of telemedicine, which require a case-by-case assessment. “In fact there are readily available flexible platforms that allow adoption of country, and site-specific requirements, waiting to make this innovation happen in the global clinical trial environment. Clearly the technology adoption has already started and is likely to accelerate.”40 In the USA, the FDA has provided draft guidance on electronic informed consents,41 which could make it easier for companies to conduct clinical trials by explaining how federal regulators will permit companies to use electronic media like interactive websites to help facilitate the informed consent process. In addition, sponsors will need to ensure that data captured in the electronic informed consent process cannot be altered, and that a patient's privacy is adequately protected.42 In England, the first eConsent for Clinical Trial43 was approved in 2015. Electronic Informed Consent is the future of clinical trials which underpins and ensures the ethicacy of any trials.

Epidemics… of the global community… Societal demand to urgently find a cure Ebola epidemic of 2014–2015. Ebola virus disease is a severe, often fatal illness in humans.44 Worldwide to date there have been 28,639 cases of Ebola virus disease and 11,316 deaths.45 A clinical trial was rapidly arranged and the results of the clinical trials for the Ebola virus disease involving 4,000 people are remarkable because of the unprecedented speed with which the development of the vaccine and the testing were carried out, and scientists, doctors, donors and drug companies collaborated to race the vaccine through a process that usually takes more than a decade in just 12 months.46 The partnering of the CRO and pharma industry was the key to this success of this trial and speed to find a vaccine. The Zika virus, the mosquito-borne infection that has been linked to birth defects, outbreak in Latin America has an “explosive pandemic potential”47. The Zika virus has now been detected in 23 countries. It is a silent infection in a group of highly vulnerable individuals – pregnant women – that is associated with a horrible outcome for their babies.”48 There is no vaccine or specific drug for this virus49 and the notional vaccine- testing on pregnant women is a ‘practical and ethical nightmare’.50 The urgent need to find a cure has led President Obama to seek $1.8 billion in emergency funding from Congress in the USA to combat the Zika virus.51 In Europe, with no currently approved vaccines or medicines and none even undergoing clinical studies, the European Medicines Agency is ensuring Zika development work proceeds as rapidly as possible and is encouraging medicines developers to contact the agency if they have any promising projects in this area. The agency will also proactively reach out to companies already planning to work on investigational vaccines and offer scientific and regulatory advice. But scientists know relatively little about Zika and the road to developing a preventative vaccine against the mosquito-borne disease is strewn with hurdles.52

40 ‘Electronic Informed Consent: Considerations For Implementation In Clinical Trials’, Miguel Orri, InnovatOrri Pharma Consulting Ltd, February 23, 2015. 41 FDA, ‘Use of Electronic Consents in Clinical Trials Draft Guidance – not for implementation’, March 2015. 42 See more at: http://www.raps.org/Regulatory-Focus/News/2015/03/09/21673/FDA-Says-its-OK-With-Modernizing-the- Clinical-Trial-Informed-Consent-Process/#sthash.xrdSEU1J.dpuf 43 NHS approves electronic consent technology in clinical trials, Nov 27, 2015, Pharmafile, Joel Levy. 44 World Health Organization, ‘Ebola virus disease’, Fact sheet N°103, updated January 2016. 45 World Health Organization, Ebola rates http://www.who.int/csr/disease/ebola/en/ Statistics as of at 31 January 2016. 46 The Guardian, Sarah Boseley, Health editor, 31st July 2015. 47 Matthew Weaver and Sally Desmond, The Guardian, 28th January 2016, ‘Zika virus spreading explosively, says World Health Organisation’. ‘Addressing the global threat’, Lawrence Gostin, public health law expert from Georgetown University. 48 Jeremy Farrar, head of the Wellcome Trust. 49 WHO and Pan American Health Organization, 6 January 2016. 50 The Guardian, Robin McKie, 30th January 2016. Mike Turner, head of infection and immuno-biology at the Wellcome Trust. 51 8 February 2016, Dow Jones Institutional News, Copyright © 2016, Dow Jones & Company, Inc. 52 ‘EU drugs agency sets up Zika task force’, 8 February 2016, Channel News Asia, (c) 2016 MediaCorp News Pte Ltd. All Rights Reserved.

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Antibiotic resistant superbugs pose a global threat after breaking through the last line of defence. Each year these drug-resistant bacteria infect more than 2 million people nationwide and kill at least 23,000, according to the U.S. Centers for Disease Control and Prevention (CDC). Drug-resistant forms of tuberculosis, gonorrhoea, and staph infections are just a few of the dangers we now face.53 The epidemic/pandemic of the Zika and Ebola disease viruses and the increasing loss of effective traditional treatments, has led the industry and CROs to partner to ensure the safety of people whilst finding a cure. It is essential new drugs are discovered to combat disease without compromising the safety of the participant. However, clinical trials today are not without risk, even with high scrutiny of regulation, very occasionally unexpected and tragic events ensue – Te Genero (2008), Biotrial and Bial (January 2016), (a phase 1 trial, testing on healthy volunteers resulting in one man dead and five other volunteers also neurologically harmed).54 Conduct of the trials still need to strictly comply with regulation and the law to protect the vulnerable and disadvantaged, plus reduce the risk of harm. The Future… How will business meet the challenges of the future? How do businesses do things differently? To rethink how we do things The mapping of the genome sequence brings up a myriad of legal and/or ethical issues such as who has the right to decide and choose whether a foetus survives or is aborted and for what reason – societal, political and/or and personal belief. How society, medicine and the law decides these issues today may tomorrow be deemed abhorrent and not an ethical or moral decision. History has shown that any clinical trial which cuts the time and cost of getting an efficacious product to market may/will result in catastrophic failure to the detriment of mankind.55. But typically it costs $1 billion dollars per compound to get to market56, to ensure that a product is safe and efficacious. How does the pharma and biotech industry meet these challenges with increasingly reduced resources… the industry needs to find innovative ways to fund these trials whilst coping with competing forces of: (i) increased costs to meet the challenges of safety and efficacy, plus (ii) the increased urgent demand for answers and treatments, and finally (iii) the need to navigate the quagmire of the law. Medicine is going through a transformational era: (mapping of the genome sequence, stem cell curative treatment...) but there are still vast areas of medicine that are still in their infancy as to treatment availability and choice (pancreatic cancer, dementia, spinal cord complete fractures, organ transplantation) and there is great opportunity for growth and development. This growth and development requires increased focus and support in research and development (R&D) which needs ever increasing monetary resources. Profits made on a successful product need to be poured back into R&D to invent and create the next blockbuster product. The pharma and biotech industry needs to monetise its investment; traditionally this is monetised through IP-Patents. The Patent term provides a confined period of time during which the industry has the ability to monetise its investment. Efforts to off-set these escalating costs have seen the emergence of CROs, the development of biosimilars, and evergreening, but so far these have merely been a plaster on the issue.

53 Monthly newsletter from National Institutes of Health, part of U.S. Department of Health and Human Services, February 2014. 54 Agence France-Presse in Rennes, via The Guardian, 17th January 2016. 55 Tsuknee trial, thalidomide. 56 As of 2015.

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Faced with societal demand, market demand, the need for efficiency, the search for cures, increased costs, a patient rights driven society, with demand to consent to decide, the pharma and biotech industry must seek financially efficient ways to off-set these many demands. The CRO international industry has a global international footprint, knowledge, therapeutic expertise, integrations of science and technology to aid the fast route to find cures and/or treatment. The complexity of the law and clinical trials are riven with legal issues and the lawyers must support the business world to meet the challenges the industry faces in an ever moving (volatile) business. Conclusion The Hippocratic Oath remains the cornerstone and ethos of all medical care and treatment of a patient. The present trials are the trials of the future: Big Data, cloud-hosted services, stem cell research, reactive medicine (Zika virus, Ebola virus, antibiotic therapies) versus reducing the length of the trial time, and the need to maximise the monetary rewards to help study the next new drug. The clinical trials of the future need to be fit for purpose, to maximise financial and business efficiencies, without undermining the safety of the trial participant and the future user of the drug. How a clinical trial is conducted is also affected by cyber security, data protection and data privacy and evergreening, reclassification of medicines57, Intellectual Property (Patents, Copyright, Royalties) and the pressure to maximise financial compensation. Rapid advances in regulatory science such as adaptive licensing and personalised medicines make balancing objectives increasingly problematic. The ultimate goal of any successful treatment belies a history of divergent checks and balances to reach the pyramidal spike of success. The checks and balances historically have negative and/or positive endpoints but each successful end point creates a giant leap forward to the benefit of mankind. Lawyers need a fundamental understanding of the past to meet the challenges of the future, to partner with the industry to weave a safe path through the complexities of the potential impact for the industry whilst promoting efficiencies. Lawyers must partner and collaborate with the industry to enable the industry to move forward as it navigates its way through the quagmire of burgeoning laws and regulation to enable the industry to maximise its efficiency and profitability. History has proven that clinical trials are rife with wonderful successes but also countered with problems, and the past provides a rich tapestry of knowledge which the lawyer can make use of to help the industry move forward, whilst having the ability to sidestep or prevent future potential legal, ethical moral issues. Fundamentally it is up to lawyers to meet this challenge and partner with the industry, so that the industry is able to make efficient business decisions whilst mitigating the risks. *** Helen Fovargue is a Solicitor, England and Wales, Attorney-at-Law, New York. Worked in private practice in London and New York before moving in-house to specialise in the Life Science industry (biopharmaceutical product development and commercial outsourcing services) 9 years ago. Currently working in-house at Quintiles, for the past 7 years, Contract Research Organisation (CRO) - Global Legal Subject Matter Expert (SME) Early Clinical Development (phase1-2a), EMEA Legal SME central and bio-analytical laboratories, EMEA legal lead Vendor corporate enterprise agreements. Quintiles Transnational, INC, is a Fortune 500 company and the world’s largest provider of biopharmaceutical development and commercial outsourcing services with a network of more than 35,000 employees.

57 Blue Bio Pharms. ltd v. MHRA, No. [2014] EWHC 1679.