Specific aspects of clinical drug trials

Learning objectives and introduction
Key issues
Regulations and guidelines
Case studies
Resources

The Regulation of Clinical Trials in Europe

The problem

Drug development is potentially dangerous. The vast majority of citizens hope that, should they become ill, medical science and care will have solutions to restore their health. Those solutions are, very often, toxic to the human; the solutions involve the controlled use of compounds that uncontrolled would be extremely harmful to the individual. Equally, the effectiveness of particular compounds as responses to particular diseases (increasingly it is understood in particular individuals) is not self-evident, and the process of identifying, refining and producing the drug is extremely challenging on a number of levels.

Further, historically, medical research has not necessarily been undertaken for the benefit of humans or conducted in a way that has respected the fundamental rights and freedoms of the participants. International agreements have been made in response to particular atrocities, and local laws and practice have been developed to govern this commercial enterprise. And that is the balance that has to be struck in governance: within a free market, how can the interests of innovation, science, commerce, society, and individuals be balanced appropriately?

An interpretation of the response

Pharmaceutical developments are international business. Drugs are developed with a view to local and international markets. These developments occur both in a fierce business context and in a fierce safety context; free markets govern the business choices, but the safeguarding of the rights of patients and of those who participate in the three stages of clinical trials has been a matter for domestic law, balancing local sensitivities and ethical concerns with creating an environment in which pharmaceutical industry is attracted, encouraged and retained.

Rightly, much is made of evidence of historic and historical medical research malpractice. As discussed in earlier pages, it is clear that industry in this area will not regulate itself, or at least it is clear that historically researchers have not always acted in ways that respect the fundamental rights and freedoms of participants in research. In this area, the most prominent international response has been the Nuremberg Code, followed by the Helsinki Declaration of the World Medical Association. This, along with the more general expressions of human rights found in the Universal Declaration, European Convention, and national human rights law, binds medical research (and health care) to a common agenda to safeguard human dignity and the specific rights of individuals. These requirements need specific translation into law at binds natural and legal individuals.

Increasingly, pharmaceutical enterprise has become a European activity rather than simply a Member State concern. Whilst stand-alone clinical trials are still conducted at the local, individual site level, they are often now conducted as multi-centre trials, and increasingly in multiple jurisdictions. Clinical trials are therefore an area that have been regulated at the European level since the Directives 2001/20/EC on clinical trials and 2005/28/EC on good clinical practice. Whereas at first sight, given the ethical and scientific focus of the regulatory regime, it might appear that this area is not one over which the European Union has competence, the legal justification for this harmonisation is for the creation of the single economic market (also taking into account duties towards public health)[1]; harmonisation of approvals for clinical trials enhances efficiency in the European market, and avoids unfair advantages for individual Member States that might operate a system below standards at other states felt bound to employ to safeguard the fundamental rights and freedoms of human participants in the trials and ultimately the consumers of the drug.

Specific requirements:

The EU has sought to harmonise the regulation of clinical trials since 2001. The Clinical Trials Directive (2001/20/EC), in terms of its commitment to ethical review, enshrined the Helsinki Declaration in European clinical trials governance. Of itself, the Helsinki Declaration, as an agreement of the World Medical Association does not have binding legal effect. However, as in the case of the Clinical Trials Directive, it can be given legal impetus through contract law (e.g. as an employment condition) or through national, EU or international law. Under the Directive, Clinical Trials governance follows the principles and expectations of the Helsinki Declaration.[2]

Following concern that the Directive did not sufficiently effect harmonisation of trials, the Directive has been replaced by the Clinical Trials Regulation (536/2014). There are a number of issues that cause problems under the Regulation in relation to ethical review and the place of RECs. It should be remembered that the first proposal for reform of the Directive removed ethics review from the ambit of the European regime, leaving it with the Member States. Under the final, accepted Regulation, ethics review by RECs remains a part of European clinical trials governance. There are three major questions for the RECs posed by the Regulation: the place of ethics in the process, the timing of ethics review, and the potential for operating a more centralized ethics review. The first two are, arguably interlinked. First, however, a general note about the Regulation.

Multi-centre clinical trials cause some difficulties for effective governance. A system where scientific and ethics review have to be carried out under procedurally (although not necessarily substantively) different rules causes inefficiency and delays that make Europe less attractive to potential clinical trial sponsors and researchers. The Regulation seeks to address this by aiming for a centralised system for the administration of the scientific review process: the “Reporting Member State” will manage the scientific review process. It must be noted, at the outset, that the ethics review does not share the same case-management structure. The process itself is essentially divided into two parts: Part I concerns primarily scientific substance; Part II concerns primarily ethical issues. The Reporting Member State receives the application and, under Part I, makes a preliminary assessment of the proposal. This is then opened to general review by the other Member States involved in the proposal, before the Reporting Member State gathers the Member States’ reviews in a final report. Under Part II, each Member State makes its own, independent review, communicated to the Sponsor of the trial. The communication, and the sharing of information, will be achieved across the processes (for Parts I and II), through a single European portal.

1. What is the place of ethics in the review process?

Part I primarily relates to scientific substance; Part II to ethical issues. However, this is not as neat in practice: the Regulation allows for ethics review under both Parts I and II. Is this sensible?

What are the ethics questions that have to be asked about a clinical trial proposal?

i. Is this the sort of activity that we (as a society) wish to pursue? (This is the sort of question that we are used to hearing in relation to, for example, human embryonic stem cell research. Some jurisdictions accept hESC research, others do not, as ethical decisions.)

ii. Is the science sound? (To be an ethical trial, the science must be sound – it being unethical knowingly to conduct ‘bad’ science.)

iii. Are the human participants in the clinical trial adequately protected? (And here there are established responses to the harm/benefit analysis of participation – for example, the primacy of informed consent and autonomy.)

Whereas the third of these questions can be answered in Part II considerations (and the Regulation outlines many of the typical safeguard issues that need to be taken into account), the first two questions are much more linked to Part I. Or rather, the Regulation’s acceptance that ethical questions can be asked in Part I cause something of a problem. And this is a problem about timing. We must street the “primarily” science and “primarily” ethics. It is problematic, to suggest that Part I is only concerned with scientific issues.

2. Can the timing operate effectively given the current nature of RECs in Europe?

Much of the criticism of the new Regulation from RECs has been about the timetables. This is in part understandable, but the problem goes beyond the simple timetable problems. On its face, the arrangement of Part I and Part II looks as if they should follow chronologically. Having assessed the science, the three ethical questions can be asked. Of course, this is inefficient – would it be sensible to continue with a scientific review of something that fails the first question? Equally, is it sensible to continue a review where the science is not good? This also indicates that there is a question as to which personnel in review should answer the different questions.

The concern of the RECs seems, from an outsider’s perspective, to be, ‘how can we as an under- funded, part-time, voluntary committee fit into the tight timeframes imposed by the Regulation?’ Clearly, if the REC considers that all three questions have to be answered within Part I, the traditional ethics review cannot be achieved. However, if the three questions are separated, there might be a chance to ensure that the review is possible, essentially within the Part II timeframe. Whereas Part I starts with the Reporting Member State’s initial view, and then moves to a short period for Member State assessment before the final report writing by the Reporting Member State, Part II has a longer potential period for the REC reviews.

RECs will have access to the documents of the application through the portal. They can immediately start to answer the three questions described above. They can feed their answers to the first two questions into the Part I process (asking about the general acceptability of the research first, and then responding to the scientific review to assess whether the science is sufficiently robust), and answer the third question explicitly within the Part II timetable.

3. Is ethics review given to harmonisation?

The presumption behind the structure certainly of Part I of the Regulation, if not of Part II, is that harmonisation of review is possible. Science has an international language and an international set of standards. There are arguments that science has local meaning and constructions, but there is a much greater harmonisation than is to be found in normative review and standards. It is possible, as, for example, in the way that the European Court of Justice operates, with a starting point of a preliminary opinion being written by an Advocate General, before it is given over to wider discussion by the judges and other interested parties in the dispute. There, there is a common language of the Law – perhaps with local accents – but not local dialects, going to different vocabularies and grammar. Ethics, and especially the ethics of the REC, is a matter of dialect.

One of the purposes of an REC is to bring local sensitivities to the evaluation of a protocol. This mitigates against harmonisation. A harmonising, preliminary opinion model presumes that there is a common ground – that one reviewer can make a first assessment of the materials that others can then review as a starting point for their own work. For the Law or for science, this is possible to a very large extent. The first reviewer presents their opinion, certainly, but from a common disciplinary language. Subsequent reviewers can take that starting point and review the reasoning within the preliminary draft. In REC, local sensitivity-based-review there is not a common starting point. REC ethics might have similarities, but the subsequent reviewer cannot assume that the first reviewer is asking the same questions that s/he is required to ask, or chooses to ask on behalf of his or her local community. There is not a harmonised substantive ethics so each REC cannot assume that the first reviewer has approached the materials in a way that covers the same grounds or reflects the same ethical views. (We will leave aside just how each REC gathers that local sense and assume that it is present.) It is not that the secondary reviewers do not trust the first reviewer to have done a good job – the question in the ECJ or scientific review – or whether they agree with the conclusions drawn; RECs simply do not know, without a full assessment of all the materials, whether they would place weight on the particular parts relevant to the first committee.

Thus, if the Regulation timeframes are going to be rigorously enforced, and RECs are going to be able to contribute without either a radical revision of their funding structures and operating practice (i.e. to become professional, full-time RECs) or a move to developing harmonised substantive ethics (i.e. moving away from local sensitivities), perhaps one solution is to ensure that the questions to be asked and answered by RECs in clinical trial situations are allocated most effectively within the Part I/II division.

4. Further questions

Whereas the three preceding questions are of fundamental importance to the operation of ethics review within the Regulation, there are some further issues that require consideration. For example, how will commercial and patient interests be balanced in relation to the presumption of transparency of information in the Regulation? How will the portal operate – particularly, to whom (and at what points) will the Member States give access rights? Much of the implementation process is still under negotiation at the European Medicines Agency.

Questions for Discussions

Is this an accurate assessment of the function and practice of RECs in relation to clinical trials? Particularly, does this make sense of the time frames?

How far is the Part II timescale workable for RECs as they are currently operating?

Does separating the sorts of questions that a REC asks help in trying to see a manageable timeframe for RECs?

What sort of recommendations can we make about ensuring that the process is manageable and workable under the Regulation?

Access to the documents?; working practice?; administrative support?

Are the exemptions to transparency sufficient (i.e. that the information is commercial sensitive or is personal data)?

How will your committees interpret those exemptions?

Are there further, bigger questions about the Regulation that need to be addressed by EUREC at this stage?

Learning objectives

to acknowledge the main differences between clinical drug trials and other types of biomedical research
to define regulatory framework for ethical assessment of clinical drug trials
to analyse ethical issues related to different phases of clinical drug trials
to explore regulatory and ethical issues in the light of presented cases

Introduction

The development of medicinal products is a long and resource consuming process. It normally begins with in vitro studies, is followed by pre-clinical studies with animals and in case of positive results, by testing on humans. CDTs is the most strictly regulated field of biomedical research in Europe and other parts of the world. General principles of research ethics that are applicable to clinical trial (see Module “Core issues of research ethics”) are also enforced by internationally harmonized regulatory framework mostly due to the influence of pharmaceutical industry acting on the international (or even global) level. However, the development of new drugs still raises specific scientific, ethical, legal and social challenges.

In the context of the EU regulations and international guidelines the term ‘clinical drug trial’ or ‘clinical trial’ refers to interventional clinical studies and does not include the so-called ‘non-interventional studies’[1]. Thus, only interventional clinical studies (clinical trials) that fall under the scope of the EU Directive 2001/20/EC[2] and the Clinical Trials Regulation[3] will be covered by this module.

Regulatory framework

The first step to elaborate ethically accepted international standards of clinical trials was made by the ICH Harmonised Tripartite Guideline on good clinical practice in 1996[4]. The GCP was defined as an international standard established to ensure that the clinical studies were scientifically and ethically sound and properly conducted which includes the design, conduct, monitoring, termination, audit, analyses, reporting and documentation of the clinical studies.

In the European context, the good clinical practice and ethical requirements for clinical drug trials were implemented by the EU Directive 2001/20/EC. However, the EU Directive 2001/20/EC was criticized for hampering the conduct of clinical trials in Europe. Therefore, the further harmonization of the requirements for clinical trials took the form of the EU Regulation. This was justified by the need to make it easier to conduct multinational clinical trials in more than one Member State, and to restore the EU’s competitiveness in clinical research and the development of new and innovative treatments and medicines.[5] Although the Regulation entered into force in 2014 the timing of its application depends on the development of a fully functional EU clinical trials portal and database.

Ethical Requirements for the Clinical Drug Trials

With the reference to the WMA Declaration of Helsinki[6] and other related documents, the EU Directive 2001/20 EC and Clinical Trials Regulation elaborated the list of criteria or safeguards under which a clinical trial should be assessed. These safeguards require that the anticipated benefit for the individual trial subject and future patients should outweigh the foreseeable risks and inconveniences; relevant information must be provided to a research participant (his/ her representative); research participant’s rights to physical and mental integrity, to privacy, and to the protection of the personal data should be assured. Other requirements, such as special measures of protection to recruit certain vulnerable groups should also be followed. Finally, it must be ensured that the medical care will be given by an appropriately qualified doctor or dentist and the provisions or indemnity to cover the liability of an investigator and sponsor are foreseen.

Specific ethical issues related to the different phases of clinical trials

Each phase of investigational medicinal product development also rises specific ethical issues that must be evaluated by REC members[7].

The primary objectives of phase I clinical trials are to clarify the appropriate dose of the agent for subsequent trials, to define its preliminary toxicity profile, and to describe its pharmacokinetics[8]. Phase I trials usually enroll a limited number of healthy volunteers or patients.

The major ethical concern in phase I clinical trial is that study participants (most often healthy volunteers) are exposed to the risk of harm (such as potential adverse effects of a new medicinal product) and high level of burden in terms of study procedures (e.g. a large number of blood tests and biological samples taken for the research purposes) with no therapeutic benefit. It is estimated that only 9,6% of drugs tested in the phase I are successfully approved.[9] The risk to which these participants are exposed can be justified only by the value of the knowledge to be gained for future patients and for society. Lack of any benefit for the study participants rises another ethical concern – whether and what motivation by financial or other rewards offered for the participation in phase I clinical trials is ethically acceptable[10].

Although most often phase I clinical trials are conducted on healthy volunteers, in some specific fields, such as oncology studies, critically ill patients can also be involved[11]. The main ethical concern of these and other early phase clinical trials involving critically ill and other vulnerable patients is the so called 'therapeutic misconception' (i.e. a mistaken believe by the study participants that the study procedures will provide therapeutic benefit to them[12]).

During phase II trials patients with the medical condition of interest are exposed to the investigational medicinal product for a relatively short period of time to examine its the effectiveness for a particular medical indication, to determine the therapeutic dosage and assess short-term side effects.

The golden standard for phase II/phase III clinical trials is the placebo-controlled double-blind randomised clinical trial. Therefore, the most pressing ethical dilemma related to the design and conduct of phase II trials is the conflict between the patients' interests to get the best proven treatment for their disease and the need for a new knowledge essential to the development of evidence-based medicine. Thus, researchers and RECs are challenged by the need to maximise understanding of the trial participants and thereby minimise the therapeutic misconception[13],[14].

During phase III trials, the effectiveness of the investigational medicinal product is measured over a longer time period, for a higher number of participants. Phase III clinical trials can take months or years to complete, and sometimes are followed by a follow-up study.

Phase III studies raise almost the same ethical issues as phase II studies, but they are more likely to have a more favorable risk-benefit ratio as the treatment regimen and dosage is closer to the treatment regimen that will be used in clinical practice. On the other hand, more patients are exposed to the investigational medicinal product for a longer period of time, and thus they may face greater unforeseen risks, particularly those related to the long-term side effects.

Phase IV clinical trials are performed after the release of a new pharmaceutical product to the market. Their main purpose is to collect additional information on the long-term risks, benefits and optimal use. However, an important ethical concern is to distinguish these clinical trials from different post-marketing activities that are also used by the pharmaceutical companies to develop marketing strategies for commercial promotion of these products.

Undue inducement

Specific ethical issues are also related to the commercial nature of clinical drug trials as the main sponsors of clinical drug trials are commercial entities. In particular, there are different types of financial or fiduciary transactions that occur during clinical trials and need to be assessed by RECs.

Payments for research participants is a sensitive issue due to potential undue inducement in respect to study participants. The undue inducement involves the promise of excessive financial compensation or other benefits to encourage potential research participants enrollment in a clinical trial. The social and economic vulnerability of many study participants, particularly those living in developing countries, may also lead to undue inducement. The decision to participate in the clinical trial, for instance, might be influenced by offering access to health care interventions that are otherwise unavailable in the community (both diagnostic and therapeutic) as a condition of participating in clinical trial or clinical trial might be presented to potential study participants as a way to get treatment from experienced physicians[15]. Financial compensation or other rewards might also be undue inducements, at least in cases in which the promise of money causes research participants to undergo more risky procedures than they would otherwise be willing accept[16].

Procedural Requirements for the Clinical Drug Trials

It is also important to emphasize that the ethical review and approval by REC is not sufficient for a clinical drug trial to begin. In most EU countries the approval from relevant regulatory authorities must also be secured.

Directive 2001/20 EC has also introduced an important procedural requirement regarding the RECs’ opinion for the multi-centre clinical trials (Art. 7). The so called single opinion requirement envisages that in case of multi-centre clinical trials, a single opinion shall be given for each Member State notwithstanding the number of research ethics committees. The Clinical Trials Regulation goes even further stating that the authorisation to conduct a clinical trial should address all aspects of subject protection and data reliability and robustness and the authorisation should be contained in a single administrative decision by the Member State concerned (Preamble 7). This rises the need to integrate the processes of ethical assessments performed by research ethics committees and the assessment performed by competent authorities as well as to collaborate closer to achieve a single decision per country in a timely manner.

An important trend in ethics of clinical trials is transparency of clinical trials. It is required to register clinical trials in public databases and to publish study results. The current version of the Declaration of Helsinki requires that every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject. The key public databases of clinical trials are the following ones: the EU Clinical Trials Register, NIH ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP). A very clear strategy of publicity is also envisaged in the new Clinical Trials Regulation.

[1] A broader term used in the Clinical Trials Regulation is a clinical study meaning any investigation involving human subjects intended to discover or verify the clinical, pharmacological or other pharmaco-dynamic effects of one or more medicinal products; identify any adverse reactions to one or more medicinal products; or study the absorption, distribution, metabolism and excretion of one or more medicinal products with the objective of ascertaining its (their) safety and/or efficacy. ‘Clinical trial’ is a clinical study which fulfils any of the following conditions: (a) the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice of the Member State concerned; (b) the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study; or (c) diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects. ‘Non-interventional study’ means a clinical study other than a clinical trial.

[2] 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 application of good clinical practice in the conduct of clinical trials with medicinal products for human use. Off. J. 2001;(34) EC No L 121.

[3] Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials in medicinal products for human use and repealing Directive 2001/20/EC. Off. J. 2014;L 158(27.05.2014):1.

[4] International Conference of Harmonization (ICH). ICH Tripartite Guideline for Good Clinical Practices E6 (R1) (1996, last update in 2016). https://www.ich.org/products/guidelines/efficacy/efficacy-single/article/integrated-addendum-good-clinical-practice.html

[5] European Commission (2012) Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. http://ec.europa.eu/health/files/clinicaltrials/2012_07/proposal/2012_07....

[6] WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

[7] European Medicines Agency. Note for guidance on general considerations for clinical trials (CPMP/ICH/291/95). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidelin...

[8] Joffe S, Miller FG. Rethinking risk-benefit assessment for phase I Cancer trials. J Clin Oncol. 2006;24:2987–2990. doi: 10.1200/JCO.2005.04.9296. http://ascopubs.org/doi/full/10.1200/JCO.2005.04.9296

[9] BIO Industry Analysis. Clinical Development Success Rates 2006-2015. https://www.bio.org/sites/default/files/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf

[10] Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/07/WC500232186.pdf

[11] Agrawal M, Emanuel EJ. (2003). Ethics of Phase 1 Oncology Studies: Reexamining the Arguments and Data. JAMA 290(8): 1075-82.

[12] Please see e-Manual, p. 67-68

[13] Kaufman KR. Ethical considerations in placebo-controlled randomised clinical trials. BJPsych Open. 2015;1(1):e3–e4. Published 2015 Jun 30. doi:10.1192/bjpo.bp.115.000919. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000495/;

[14] Millum J, Grady C. The ethics of placebo-controlled trials: methodological justifications. Contemp Clin Trials. 2013;36(2):510–514. doi:10.1016/j.cct.2013.09.003. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844122/

[15] Emanuel EJ, Currie XE, Herman A, Project Phidisa. (2005). Undue Inducement in Clinical Research in Developing Countries: Is It a Worry? Lancet 366(9482): 336-40.

[16] Dickert N, Grady C. “What’s the price of a research subject? Approaches to payment for research participation”. N Eng J Med 1999; 341: 198-203

Cases and Questions - Clinical drug trials

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Case 1 Placebo

The positive effect of lithium in the treatment of children and adolescents with aggressive behavior has been proven through clinical investigation. However, no published studies have included children with mental retardation. Investigators plan to conduct a two-arm parallel group study at a residential treatment facility for persons with mental retardation. Participants will be randomized to treatment with lithium or placebo.

Many staff members at the treatment facility have been using lithium to treat aggressive behavior of person with mental retardation. The institutional review board (IRB) approved the study, but many staff members continue to believe that using placebo would be withholding of an effective, established treatment.

Source: http://ethicsresearchcore.org/placebo-trials-prevalent-unproven-treatments

Question 1

- What are the conditions which justify the use of placebo in the clinical drug trials?

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