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European Pharmaceutical Contractor

Code of Conduct

Current regulations for clinical research are based on a combination of ethical thought and history. Ethics is contrasted with morality, which frequently relates to the values learned from parents, religion, culture, and other influences.

The foundations of clinical research ethical conduct are underpinned by the principles outlined in The Nuremberg Code, the Declaration of Helsinki, the Belmont Report, the US Code of Federal Regulations 21 CFR Parts 50 and 56, 45 CFR Part 46, and the International Conference on Harmonization (ICH) Good Clinical Practice guidelines.

But there are numerous ethical challenges associated with clinical research; the ethical conduct of a trial does not end with the formulation of study design or the obtainment of a signature on the informed consent form.

Human Perspective

Many alternative therapies are not supported by good clinical trial evidence; this will include lowerlevel evidence, such as theoretical justifications, anecdotes, and pre-clinical research like in vitro studies and animal model testing. Such non-human type studies can only be suggestive, and are never reliable proof of safety or efficacy. Actual evidence of safety and efficacy can only be studied in real patients, but inadequately controlled research can be misleading; we have seen in the past how promising results in early trials melt away when better, larger, more rigorous studies are done that contain better controls for bias. And it is not difficult to compile a large list of examples of the harm inadequately studied medical interventions can cause. Hence, experimental clinical trials in patients are unavoidable.

Overseeing Ethical Issues

Despite the existence of ‘check and balance’ frameworks, ethical challenges can still arise, even in highly regulated markets. For example, ethics bodies may include non-scientific personnel who lack the expertise to assess the appropriateness of patient inclusion criteria or proposed trial protocol. There is also a risk that those concerned approach the ethics aspect of a study as a ‘tick-box’ affair, focusing only on processes such as informed consent, without giving due consideration to the wider implications of a poorly defined participant criteria to a study’s outcomes.

Lack of training and/or expertise is a further factor. Without proper formal training in bioethics, personnel will have limited knowledge of complex ethical issues such as reduced autonomy, distributive justice, subject vulnerability and subject compensation. Ethical committee members may see their responsibilities reduced to providing approval to research proposals submitted for review, and be oblivious to the need for a continuous review.

Sometimes the issue of informed consent is a challenge on the part of investigators as a number of complexities can arise. For example, in India, regulations are based on Western guidelines and do not reflect the complexities of cultural factors such as the level of education, demographics and risks involved during the study.

Potential for Conflict

A further widely expressed concern is the potential for conflict of interest on the part of the investigators. In the context of ethical issues, this conflict can lead to bias in design, conduct, analysis, interpretation and communication of findings. Conflict of interest is generally considered in the financial context, but intellectual or other conflicts may also occur.

Ideally, no investigator would have any interests other than the well-being of the study participants and the generation of new knowledge that will improve clinical care and public health. That is unrealistic, however, given that most investigators receive research funding from the government, industry or others who are considerably interested in the study outcome. Many investigators have also spent their career attempting to advance the science and could be disappointed if their preferred theory turns out to be incorrect. Therefore, most clinical trials find it easier to manage conflict of interest than to avoid it completely (1).

This potential for conflict may be further complicated when significant monetary compensation is provided by pharmaceutical companies directly to private physicians, in order to encourage rapid recruitment and active retention of research subjects.

The extrapolation of study results from less developed regions to highly developed countries with very different healthcare systems and standards, and vice versa, has also been questioned.

Some studies suggest that the outcomes may indeed be different. The local study population will not significantly benefit from the research if the new therapies will not be affordable to them, although they are taking a higher proportion of risk (2,3).

Additional Issues

A further challenge is the trenchant notion of ‘personal care’ in clinical medicine – in other words, the confusion of roles of the physician as clinician and as researcher. Any clinician who conducts a clinical trial must follow the protocol, in which the notion of personal care must usually be abandoned in order to properly follow the dictates of the scientific protocol. The concept of personal care, however, is the physician’s first obligation. The physician makes decisions – with the patient’s input – that will most benefit the patient. But the application of this shared decision-making model is not necessarily the case in a clinical trial.

There is growing awareness that commercial pressures mean ethics bodies may be unduly influenced by researchers looking to get products to market as soon as possible, and with the most advantageous research data. This pressure clearly creates a conflict with the duty of care responsibilities of ethics bodies to protect trial participants and disclose all study data.

Finally, lack of awareness of appropriate clinical trials may also cause issues. Physicians are not always aware of available clinical trials; some may not be aware of the local resources, or may assume that none would be appropriate for their patients.

Informed Consent Challenges

The first principle of clinical trial ethics requires investigators to respect people and their rights. Informed consent ensures that individuals can decide to participate only when the research is consistent with their values, interests and preferences. Though written consent forms are used to document the consent, the process of informed consent is more important than a subject’s signature on the form.

Research involving clinical trials of drugs or treatments for a particular condition, and research into the causes is important in increasing a doctor’s ability to provide effective care for present and future patients. However, the benefits of the research may be uncertain and may not be experienced by the person participating in the research.

In addition, the risk involved for research participants may be difficult to identify or to assess in advance. If you carry out or participate in research involving patients or volunteers, it is particularly important to ensure that, as far as possible, the research is not contrary to the individual’s interests; and that participants understand that it is research and that the results are not predictable.

Providing Information

Investigators must take particular care to be sure that anyone they consider taking part in research is given the fullest possible information, presented in terms that they can understand. This must include any information about possible benefits and risks; evidence that a research ethics committee has given approval; and advice that they can withdraw at any time. It is also important to ensure that participants have the opportunity to read and consider the research information leaflet, and sufficient time to reflect on the implications of participating in the study.

Unfortunately for clinical investigators in developing countries such as India, informed consent is a dispensable formality and there is limited explanation given to patients on what the trial is all about. The consent forms are lengthy, complicated and difficult to understand. Obtaining consent from a patient is often delegated in public hospitals to the most junior nurses or clinical research staff. Also, if the patients are poor and do not want to enter the trial, they frequently elect in as they believe refusing would displease treating clinicians who may deliberately ignore them during their hospital stay. On the other hand, doctors in the private sector are worried that on hearing the term ‘trial’, patients might choose to get treated elsewhere. Investigators will, therefore, often shorten the consent form or deliberately omit some ‘offensive’ parts that might deter patients from agreeing to participate (4).

World of Difference

Regulation in global geographies varies from highly regulated territories to locations where less stringent rules apply and regulatory enforcement capabilities are limited. An estimated 40 per cent of all clinical trials now take place in Asia, Eastern Europe, and Central and South America where there is no compulsory registration system for clinical trials, and limited experience or training for local physicians and site personnel on how to apply trial protocols.

As a result, the rights and welfare of study participants may be compromised, and impact on the integrity of the study data. Such disparities are most apparent when it comes to compensation; in the US, a strong framework exists to support applicants, while claimants in other territories may lack the resources or support to pursue a successful settlement.

The World Health Organization (WHO) recently lobbied for regulatory reform in India, citing the uneven application of informed consent and proper ethics reviews in the face of a booming clinical trials industry. In 2013, the Indian Ministry of Health and Family Welfare finally adopted more stringent regulations, including broader compensation for trial participants and their families.

The Good Clinical Practice (GCP) guidelines published by the ICH have been implemented and have become the law in some countries. Based on the GCP guidelines, regulatory authorities have installed national rules for the conduct of clinical studies. Finally, the standard operating procedures of pharmaceutical companies and clinical research organisations describe tactical aspects of clinical research. Those tools resulted in an increase in the scientific and ethical quality of clinical studies. However, it is crucial for clinical research centres to implement measures that allow the adherence to those guidelines in order to remain competitive, as well as safeguarding the rights and safety of participants.

Unresolved Problems

Daily practice in clinical research reveals many unresolved problems related to safety and ethical requirements. The GCP and other binding guidelines leave ample space for interpretation with regard to translation of the rules into daily practice. On one hand, this leaves flexibility to researchers; on the other, the standard operating procedure of partners (for example, pharmaceutical companies) creates conflicts which have the potential to jeopardise the implementation and constructive conduct of projects.

Because of the lack of a standard source of information and incomplete international harmonisation, it is still complicated for an investigator to obtain an overview of the current rules and obligations for the conduct of clinical trials on human subjects.

The different regulations of the national regulatory authorities are all based on the GCP guidelines. But often, because of poor specificity, these guidelines are not able to give completely satisfactory answers to daily practical problems that an investigator may have at a trial site.

Harmonisation Imperative

The harmonisation of clinical trial protocols has already been demonstrated as feasible across countries of the European Union, and coordination between Europe, Japan and the US has led to a joint regulatory initiative. Launched in 1990, the ICH developed guidelines for use in its regions – Europe, Japan and the US – and is now attempting to advance harmonisation initiatives around the globe in the interest of consumer and public health, preventing unnecessary duplication of clinical trials in humans.

Final Thoughts

The failure to take ethical considerations into account from the outset of clinical trial design risks confounding study outcomes and compromising the introduction of safe and effective drugs. For example, selection bias can cast serious doubts about the suitability or quality of data collected. Similarly, the lack of more specific global harmonisation of clinical trial rules and guideline protocols means maintaining bioethical and stringent vigilance on trials conducted in remote locations, which is paramount to minimising the risk of harm. Furthermore, the data collected may not be valid or transferable for US or Western European drug approval processes.

1. Levinsky NG, Sounding Board, Non-financial conflicts of interest in research, N Engl J Med 347: pp759-761, 2002
2. Vickers A, Goyal N, Harland R and Rees R, Do certain countries produce only positive results? A systematic review of controlled trials, Control Clin Trials 19: pp159-166, 1998
3. O’Shea JC and Califf RM, International differences in cardiovascular clinical trials, Am Heart J 141: pp875-880, 2001
4. Kalantri SP, Ethics of drug trials in India, National Medicine Journal India 15(3): p179, 2002

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About the author

Dr Ghanashyam Rao is Senior Medical Expert (Global) at ELC Group. Following an early medical career – which included roles with the WHO and the Indian government – he has worked with some of the world’s leading pharmaceutical companies. An experienced medical and regulatory report writer and project manager, Ghanashyam has extensive expertise in clinical R&D, including leading clinical trials and devising trial protocols. Today, he specialises in regulatory and medical writing, and liaison with clinical trial centres in preparation for regulatory submissions.

Indu Singh is Regulatory/Clinical Affairs Project Manager at ELC Group. A specialist scientific and regulatory writer with extensive expertise in European Union and FDA submissions, she has managed complex projects across all therapeutic areas. Alongside electronic submission and monitoring in-house studies, Indu specialises in generating summary study reports for ethics committees, as well as undertaking the safety profiling of investigational medicinal products and managing the generation of clinical trial annual safety reports.

Ghanashyam Rao
Indu Singh
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