Ethics in clinical research

Introduction

Some clinical trials have truly changed the course of medicine, and a few have changed the course of world history. The most well-known example is the first controlled clinical trial ever carried out in medicine, performed by James Lind in 1747. The author discovered that vitamin C can treat scurvy. A regulation of ethical issues in clinical trials was made much later. 

Indeed, until as recently as the 1970s, the medical investigator was considered the sole authority that could adjudicate the legitimacy of a study protocol. 

Actual regulations of ethics in clinical trials

If we take the definition from Britanica.com, “ethics, also called moral philosophy, is the discipline concerned with what is morally good and bad and morally right and wrong. The term is also applied to any system or theory of moral values or principles”.

“Ethics, when it comes to clinical trials, is very important and involves an examination of the study by a group of competent people, some without medical training, with no involvement in clinical research or the pharmaceutical industry. The purpose of respecting ethical principles is to protect patients from certain treatments that may cause them significant side effects without any benefit.

The goal of clinical research is to develop generalizable knowledge that improves human health or increases understanding of human biology. People who participate in clinical research make it possible to secure that knowledge. The path to finding out if a new drug or treatment is safe or effective, for example, is to test it on patient volunteers. But by placing some people at risk of harm for the good of others, clinical research has the potential to exploit patient volunteers. The purpose of ethical guidelines is both to protect patient volunteers and to preserve the integrity of the science.

The ethical guidelines in place today were primarily a response to past abuses, the most notorious of which in America was an experiment in Tuskegee, Alabama, in which treatment was withheld from 400 African American men with syphilis so that scientists could study the course of the disease. Various ethical guidelines were developed in the 20^th century in response to such studies. 

Some of the influential codes of ethics and regulations that guide ethical clinical research include:

• Nuremberg Code (1947)

• Declaration of Helsinki (2000)

• Belmont Report (1979)

• CIOMS (2002)

• U.S. Common Rule (1991).

• Using these sources of guidance and others, seven main principles have been described as guiding the conduct of ethical research:

• Social and clinical value

• Scientific validity

• Fair subject selection

• Favorable risk-benefit ratio

• Independent review

• Informed consent

• Respect for potential and enrolled subjects”⁽¹⁾.

The ethics committees play an important role also in real-world trials. The formation and working of ethics committees are one step ahead in making research on humans morally and scientifically sound. However, legality has never been an effective method of imposing or ensuring morality in any community. Morality can grow only as the value systems of people themselves undergo a slow, subtle and sustained change. In that effort, ECs have an important role to play, and this is what its members need constantly to keep in mind⁽²⁾.

In all European countries, the ethics of clinical trials is an element of utmost importance and it is not entrusted to the study team, which would be very subjective, nor to the sponsor. The Ethics Commission is responsible for evaluating the ethics of a study. Thus, in Spain: “The purpose of the ethics committee is to ensure that the rights, dignity, safety and welfare of persons involved in research projects are protected, ensuring the methodological, ethical and legal correctness of such projects and their corresponding monitoring, pursuant to the principles set forth in the Declaration of Helsinki, the Clinical Best Practices of the ICH (International Council for Harmonisation) and current Spanish legislation”.

In Ireland, the organization of the Clinical Trials Ethics Commission is a complex and judicious operation involving strict regulations, as it can be seen in the table below⁽³⁾.

GUIDANCE ON THE APPLICATION FOR RE­COG­NISED ETHICS COMMITTEE OPI­NION AND THE ETHICAL REVIEW OF CLINICAL TRIALS ON MEDICINAL PRODUCTS FOR HUMAN USE

Section1: Introduction ............................................................

1.1 Legal Basis ...........................................................................

1.2 Scope ....................................................................................

1.3 Definitions ..........................................................................

Section 2: Making an Application for Ethical Review ............

2.1 How to Make an Application ............................................

2.2 Site Specific Assessment ...................................................

2.3 Seeking Permission from the Site ...................................

2.4 Validation of Applications for Ethical Review ..................

Section 3: Review Process ........................................................

3.1 Specified Time Periods ......................................................

3.2 Request for External Expert Advice ................................

3.3 Request for Further Information ....................................

3.4 Preparing an Ethical Opinion ...........................................

3.5 Giving an Ethical Opinion ................................................

Section 4: Substantial Amendments to Clinical Trials given a Favourable Opinion ...............................................................

4.1 Application for a Substantial Amendment ........................

4.2 Validating an Application for a Substantial Amendment...

4.3 Review of an Application for a Substantial Amendment...

4.4 Urgent Safety Measures ....................................................

Section 5: Monitoring the Safety of Clinical Trials ................

5.1 Expedited Safety Reports on Adverse Reactions ..............

5.2 Review of Expedited Safety Reports on Adverse Reac­­tions .............................................................................................

5.3 Submission of Annual Safety Reports ...............................

5.4 Review of Annual Safety Reports ....................................

Section 6: The End of a Clinical Trial ....................................

6.1 Conclusion of a Clinical Trial ...........................................

6.2 Final Research Report .......................................................

Another example in Italy:

GUIDANCE ON THE APPLICATION FOR RECOGNISED ETHICS COMMITTEE OPINION AND THE ETHICAL REVIEW OF CLINICAL TRIALS ON MEDICINAL PRODUCTS FOR HUMAN USE

“Guiding legislation and associated bureaucracy for the ethical review of clinical trials observational studies and food related research play an important role in the competitiveness of a nation in the face of tough global competition to attract sponsors and investigators. This is of particular relevance in the case of multicenter trials and multidisciplinary research. Accordingly, in this report we tried to gather in-depth knowledge of the current role and practices of ethics committees nationwide in both clinical and research settings”.

A review of Italian researchers also refers to the role of local ethics commissions: “We evaluated the impact of an institution’s ethical committee intervention on reducing the time required to obtain an opinion from Research Ethics Committees by guiding investigators in addressing ethical issues in their proposed studies (www.actabiomedica.it)”⁽⁴⁾.

The major international agencies dealing with the introduction of new drugs into medical practice also have strict regulations regarding the ethics of clinical trials, which are left to independent commissions.

The FDA has the following approach:

“The study was conducted in accordance with good clinical practice (GCP). For the purposes of this section, GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data and reported results are credible and accurate and that the rights, safety, and well-being of trial subjects are protected. GCP includes review and approval (or provision of a favorable opinion) by an independent ethics committee (IEC) before initiating a study, continuing review of an ongoing study by an IEC, and obtaining and documenting the freely given informed consent of the subject (or a subject’s legally authorized representative, if the subject is unable to provide informed consent) before initiating a study. GCP does not require informed consent in life-threatening situations when the IEC reviewing the study finds, before initiation of the study, that informed consent is not feasible and either that the conditions present are consistent with those described in paragraphs 50.23 or 50.24(a) of this chapter, or that the measures described in the study protocol or elsewhere will protect the rights, safety, and well-being of subjects; and (ii) FDA is able to validate the data from the study through an onsite inspection if the agency deems it necessary”⁽⁵⁾.

Also, the highest European forums have regulated the issues of ethics of clinical trials, regulations that must be respected in our country.

REGULATION (EU) NO. 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on interventional clinical trials with medicinal products for human use and repealing Directive 2001/20/EC⁽⁶⁾

“The member state concerned should have the power to determine the appropriate body or bodies to be involved in assessing the application for an interventional clinical trial and to organize the involvement of ethics committees within the time limits for the authorization of that interventional clinical trial, according to the current regulation. Such decisions are a matter for the internal organization of each member state. When determining the appropriate body or bodies, member states should ensure the involvement of non-specialists, in particular patients or patients’ organizations. They should also ensure that the necessary knowledge is available. In accordance with international guidelines, the assessment should be carried out jointly by a reasonable number of people who collectively have the necessary qualifications and experience. Applicants should be independent of the sponsor, the venue of the application intervention clinical trial and the investigators involved and be free from any other unwarranted influence”.

 “The accepted basis for the conduct of clinical trials in humans is founded in the protection of human rights and the dignity of the human being with regard to the application of biology and medicine, as for instance reflected in the 1996 version of the Helsinki Declaration. The clinical trial subject’s protection is safeguarded through risk assessment based on the results of toxicological experiments prior to any clinical trial, screening by ethics committees and member states’ competent authorities, and rules on the protection of personal data.

As a rule, authorization should be implicit – i.e., if there has been a vote in favor by the Ethics Committee and the competent authority has not objected within a given period, it should be possible to begin the clinical trials. In exceptional cases raising especially complex problems, explicit written authorization should, however, be required”⁽⁷⁾.

In Romania, since 2005, when medical oncology was not yet recognized as an independent specialty by the European forums, I have developed a book, with the participation of authors from several countries, which discusses the main issues related to clinical trials in medical oncology, radiotherapy and palliative care. 

Although many years have passed since the first book of good clinical practice in oncology was published, many presented aspects are still topical. Ethics issues represent an important chapter, because they must be an objective means of protecting the patient.

The preface was written by Prof. Heine Hansen, as former President of the European Society for Medical Onco­l­o­gy (ESMO) – as seen in the picture from the previous page.

Conclusions

The necessity of a research ethics distinct and independent from medical ethics emerged only in the moment of some episodes of research misconduct.

Our modern concept of research with human subjects is inspired by three influential documents, conceived in the aftermath of the episodes of research misdemeanor which were mentioned in the beginning. The Nuremberg Code is a legal and ethical code promulgated by the U.S. judges at the trial of the Nazi doctors at Nuremberg after World War II. Many consider it as the most authoritative legal reference on the subject of human experimentation. It is based on universal principles of natural law and human rights, and it establishes the basic principle that the participation in research requires the free, informed consent of the participating subject. The Declaration of Helsinki is arguably the most widely known and influential guideline in medical research worldwide. It is an official policy of the World Medical Association (WMA) which was adopted for the first time in 1964 and has since undergone a number of revisions. The Declaration can be regarded as the expression of the WMA’s effort in balancing the need to generate sound medical knowledge with the need to protect the health and interests of research participants. Finally, the Belmont Report is a short document on moral principles that was published in 1978 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, in the aftermath of scandals of research misconduct that were uncovered in the 1970s. The Belmont Report is especially known for establishing a framework of basic moral principles – respect for persons, beneficence, and justice, which should guide the conduct of research. At the European level, further guidelines are provided by the directives of the Council of Europe and the European Commission and, of course, by the individual member states’ National Bioethics Commissions⁽⁸⁾.

Clinical and real-world trials, the latest of which are gaining more and more credibility, are and must be overseen by independent ethics commissions. Only in this way can we be sure that the patient’s interests are fully respected and that the patient is protected from possible abuse.  

Conflict of interests: The author declares no con­flict of interests.