Clinical trials

5.3.1. Protocols and the three phases of clinical trials

A clinical trial is a controlled, scientific testing of the efficacy and safety of a treatment presumed to have the ability to cure, relieve or improve a certain medical condition. A clinical trial may involve a broad range of sampling and assessments, such as taking blood and tissue samples or blood pressure measurements. The main document describing a clinical trial and how it is designed is called a

‘protocol’, which contains descriptions of all elements of a trial, including the characteristics and number of the trial participants (who normally include both a test group and a control or placebo group), what tests and samples will be taken from these people and the details of taking these samples.

The protocol will thus describe whether, how often and when the samples are to be taken and in what sequence. The protocol also describes the criteria used in determining which participants will be allowed into the trial and who should be excluded.⁷⁶

The protocol further states what is the ‘primary endpoint’, which is essentially the main effect that the trial sets out to test and investigate. The definition of the primary endpoint is a crucial exercise, because if the drug shows itself to be effective and the trial is successful, the drug can only be sold and marketed with reference to the primary endpoint. Thus, although a drug may have unforeseen positive effects on some other disease or condition than the primary endpoint, the company can still only market the drug on what was defined as the primary endpoint in the trial protocol.

The protocol also describes the statistical considerations and methodology as well as how patient safety will be ensured and how any adverse events (side effects) will be reported.

Before a clinical trial on humans is conducted, the drug is tested in pre-clinical studies, most often on two species of mammals, in order to predict potential toxic effects of the drug. If the animal studies show no harm from a toxicology perspective, the drug candidate moves into the first phase of the clinical trials, known as ‘first-in-human’ studies.

According to international guidelines and legislation, to which I will return shortly, there are three phases of clinical trials on humans before a drug can be approved by the authorities. The purpose of the first phase is to test how the human body responds to the compound, to determine the dosage and to detect side effects. Phase one is often conducted among ‘healthy volunteers’, i.e. with humans who do

76 It is not uncommon to exclude participants with other severe conditions such as cancer or HIV, or people with substance abuse, since such conditions may interfere with the test results.

146 not suffer from the condition that the drug is intended to treat. These studies usually have very few patients, often less than 30.

In the following Phase two, the drug is tested for the first time on people who suffer from the condition that the drug is intended to treat. The trial is usually conducted with a couple of hundred patients. The purpose is to start testing the effectiveness of the drug.

If Phase two shows efficacy (according to the parameters for efficacy stated in the protocol), then the drug can move to Phase three, which is a large scale trial aimed at demonstrating effectiveness over a larger and statistically significant sample of patients. In order for the trial to be successful and

subsequently approved by the authorities, it generally needs to be demonstrated that the drug is at least as effective as existing drugs already on the market. Therefore, many trials are designed using a randomization process whereby a computerized algorithm randomly assigns some patients to receive the test drug and some to receive either the standard treatment already on the market or a placebo.

Usually, the studies are conducted as so called ‘double blind studies’ where neither the healthcare professional administering the drug to the patient nor the patient are told what drug they have been given. Phase three trials often involve several thousand people and are most often conducted across a range of hospitals in a range of countries in order to recruit the necessary volume of patients within a designated timeframe.

Besides the clinical trial officers and everyone involved with the trial within the pharmaceutical company, a few other actors in the clinical trial milieu must be mentioned. Firstly, pharmaceutical companies often collaborate with so called Contract Research Organizations (CROs) that provide specialized research services connected to clinical trials. Sometimes, CROs are in charge of a smaller part of the trial, such as testing specific bio-samples (blood, urine, tissue, etc.), while on other occasions they are contracted for the entire process of recruiting and managing the clinics and hospitals that are to participate in the trials.

Within the hospitals and clinics, ‘trial sites’ as they are called by clinical trials officers, a number of nurses and doctors are engaged to carry out the trial according to the specifications listed in the protocol. A Principal Investigator, known in the jargon as the PI, oversees the trial. The PI is often a high profile doctor within the therapeutic area of the drug under study, and engaging such doctors is

considered essential for well-run clinical trials. The assumption here is that having a high profile doctor in charge of a trial will make other doctors within other hospitals and countries more inclined to also participate in that trial. I will return to the logics of engaging such doctors in the following chapter and leave this very brief account of clinical research for now.

147 The pharmaceutical industry, I daresay, is governed by national and international legislation and

standards to a relatively larger extent than other industries. In order to get their products approved on different national markets, pharmaceutical companies must be able to demonstrate adherence to a number of regulatory frameworks as well as detailed registration of the entire process of developing the product. During my fieldwork within Ferring, as I will outline in this chapter, managers and staff often referred to these legislative structures – not only as rules to comply with but also as ethical frameworks to adhere to. And importantly for the present study, they were seen as ethical frameworks that took precedence over Ferring’s ethics program. Moreover, managers and staff working with clinical trials seem to share common reference points in historical events, and they mention these to

underscore the need for these legislative frameworks as well as the ‘common sense’ of Ferring’s ethics program that I shall return to later in this chapter. In the following, I will describe these historical events and regulatory frameworks and their presence in the minds of clinical trial officers.

5.3.2. Vocational history

It is early in the fieldwork, and I am meeting for lunch with Carl, a manager from the Clinical Trials Department. We know each other from an introductory course in which we have both participated, and he has agreed to introduce me to some of his employees.

Beforehand, we are meeting for lunch so that I can tell him a bit more about my research. I start introducing him to the project and my affiliation with the Global Ethics Office, but after a brief description, however, he interrupts and says that if I am looking at ethics in the company, then it would be a good idea for me to look into GCP. At that moment, this abbreviation is not familiar, and I ask him what it is. “Good Clinical Practice”, Carl says and explains that this is a set of guidelines for how to conduct clinical trials, and that these guidelines have their origin in the Declaration of Helsinki, yet another document about which I know nothing. The Declaration of Helsinki was the outcome of some ‘very unethical clinical studies’ conducted during the Second World War on concentration camp victims, Carl tells me. He explains that GCP is about ensuring that the risks to which patients are exposed in a clinical trial must be commensurate with the results expected to emerge out of the trial.

I will elaborate on the historical events leading up to the creation of the Good Clinical Practice

Guidelines shortly, but for now, I want to highlight how Carl immediately referred to the GCP guidelines

148 and to the historical events surrounding them when I mentioned my interest in ethics. During the fieldwork, whenever ‘ethics’ comes to the table, I have heard numerous similar references to the Second World War and previous misconduct within the pharmaceutical industry, and the presence of these historical events in the minds of clinical trials officers is one of the reasons why I define them as a

‘community’; these events are part of the community’s ‘origin myth’, which like many myths, begins with a Fall from Grace, to which the group must now atone by formulating and adhering to a code.

Back at lunch, Carl continues speaking and explains that ‘Within recent years, we have had some accidents where it has gone terribly wrong, so that’s also why we are extra cautious’. My facial expression must have revealed my surprise, because he quickly added that by ‘we’, he does not mean Ferring. The accidents happened in other companies, and he is merely referring to ‘we’ in the industry, as he explains and goes on to tell me about one of these trials that went wrong. It was a drug from the German drug development company TeGenero Immuno Therapeutics that unexpectedly attacked the immune system of the trial participants.

During the fieldwork, in my conversations with clinical trials officers, they often referred to this particular case. Horvath and Milton (2009) describe the incident as follows:

‘At 08:00 on March 13, 2006, the first healthy volunteer was administered TGN1412 as a three– to six–minute intravenous infusion (…) By 09:10, six volunteers had been

administered TGN1412, and two volunteers had been administered a placebo. Within ninety minutes, those who had received TGN1412 had a systemic inflammatory response that was characterized by a rapid induction of proinflammatory cytokines and

accompanied by headache, myalgia, nausea, diarrhoea, erythema, vasodilatation, and hypotension (Suntharalingam et al. 2006). Between twelve and sixteen hours postdose, they became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation (DIC). Severe and unexpected depletion of lymphocytes and monocytes occurred within eight hours, reaching a nadir at twenty-four hours. By midnight, they had been transferred to an intensive care unit, where they received intensive cardiopulmonary support (including dialysis), high-dose

methylprednisolone, and an anti–interleukin–2 receptor antagonist antibody. Prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients, who required intensive organ support for eight and sixteen days (Suntharalingam et al.

2006). It was soon concluded that TGN1412 had caused a ‘‘cytokine storm’.’ Although all

149 six volunteers survived, the long-term prognosis for these subjects is unknown. One of these patients has since had all of his toes and the tips of several fingers amputated’

(Horvath and Milton 2009:373).

During the fieldwork, I have heard numerous accounts about misconduct and accidents in the past and about the importance of having and adhering to the GCP guidelines. When asking questions about these guidelines and why they find it so important to maintain them, clinical trials officers most often reply by referring to scandals, and historical events where pharmaceutical development has gone horribly wrong, such as the TeGenero example. Moreover, clinical trials officers use these examples to emphasize that ethics is already an integrated part of what they do (by virtue of GCP and industry awareness of past scandals) and, often, that Ferring’s code of ethics is therefore not of much use for their vocational group.

Before turning to the Ferring Philosophy, let us return to these historical events of this vocational community that are often drawn out, and particularly an event referred to by Carl that dates back to the Second World War.

5.3.3. The Declaration of Helsinki

The guidelines for clinical trials today known as Good Clinical Practice (GCP), have their origin in the

‘Declaration of Helsinki - Ethical principles for medical research involving human subjects’ which was adopted on a meeting in the World Medical Association (WMA) in Helsinki in 1964. The declaration though not legally binding, is the foundation for all other significant international regulation and guidelines on ethical conduct in biomedical research (Darwin 2013:155). Preceding the declaration was what Carlson et al. (2004) describe as ‘One of the darkest episodes in the history of medical research – the horrific experiments carried out by doctors on concentration camp victims in Nazi Germany’

(Carlson et al. 2004:696).

In the wake of the Second World War, prominent members of the Nazi regime were prosecuted at the Nuremberg trials, including those who had conducted horrific medical experiments on concentration camp detainees. Upon completion of the Nuremberg trials, a set of guidelines for medical experiments, the so called Nuremberg Code, was formulated and published. This code laid the foundation for the

150 Declaration of Helsinki⁷⁷ (Darwin 2013:155), which was later developed into the guidelines for good clinical practice.

5.3.4. Good Clinical Practice guidelines⁷⁸

When mentioning the Good Clinical Practice guidelines, Ferring employees refer to the GCP guidelines of the International Conference on Harmonization⁷⁹ (ICH). Within Ferring, this is commonly referred to as ICH GCP or simply GCP. The ICH GCP Guidelines were developed during the early 1990s by the regulatory authorities for drugs in the USA, EU and Japan. Prior to the development of these guidelines was a growing public demand for safe and thoroughly tested drugs. However, replicating clinical trials across many countries involved high costs as well as a large number of animals used for testing, and these issues became the main incentives for harmonization. The goal was to reduce the need to repeat the same kind of studies in each country. In 1996, the final guidelines were approved by the ICH, and since then, the conduct of clinical trials has become increasingly harmonized within national public health legislation both among the USA, Japan and EU and within additional countries (Darwin 2013:156).

For example, in the US, the Food and Drug Administration’s (FDA) Code of Federal Regulations has its origin in the Declaration of Helsinki. The FDA is responsible for approving new drugs for the market in the USA, and apart from a few minor differences, the FDA has adopted the ICH GCP guidelines (Darwin 2013:155). Within the EU, two directives also have their origin in the Declaration of Helsinki. The EU Clinical Trials Directive (2001/20/EC)⁸⁰ describes in detail the legal requirements for how clinical trials of

‘investigational medical products’ (IMP) should be conducted within the EU. The EU GCP Directive (2005/28/EC)⁸¹ complements the Clinical Trials Directive and describes guidelines for GCP in such trials.

77 https://www.ich.org/page/efficacy-guidelines, E6(R2) Good Clinical Practice (GCP)

78 Besides the Good Clinical Practice Guidelines, a number of other guidelines also govern pharmaceutical development, such as ‘Good Laboratory Practice’ and ‘Good Manufacturing Practice’. These guidelines are often referred to together as ‘GxP’. However, as the GCP guidelines have been most commonly invoked by my interlocutors, I have chosen to focus on outlining these.

79 https://www.ich.org/products/guidelines/efficacy/efficacy-single/article/integrated-addendum-good-clinical-practice.html

80 Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the Approximation of the laws, Regulations And Administrative Provisions of the Member States Relating to the Implementation of Good Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use.

81 Commission Directive 2005/28/EC of 8 April 2005 Laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorization of the manufacturing or importation of such products.

151 Together, the Nurnberg Code, the Declaration of Helsinki and the Good Clinical Practice guidelines have shaped the historical and legislative context in which clinical trial officers operate and become a set of by-laws to which they continuously refer throughout my fieldwork. Moreover, as I have alluded to earlier, these guidelines and their inherent logics not only guide behaviour among clinical trials officers;

they also inform how these officers understand Ferring’s own ethics program.