Ethical considerations in clinical trials, and responsibilities of a principal investigator
Ethics can best be thought of as the moral principles that underpin good behavior. However, how this is defined is open to wide interpretation, and depends on factors such as societal norms and religion. Thales of Miletus (624 BC – 546 BC) advised his contemporaries to avoid doing what they would blame others for doing, and similar expressions of this concept abound throughout a range of moral philosophies. In medicine, the concept of non-maleficence (i.e., not harming the patient) is established as a pillar of physician behavior.
However, the distinction between what is good and bad is not always clear, and an example of this in medicine is when doctors might induce serious adverse events in a patient through toxic treatments for their incurable cancer, which would be objectionable in circumstances that are not life threatening. Balancing the risk of harm with the potential benefits requires careful evaluation. This is especially the case where there is controversy over the evidence of benefit, or where an individual is being asked to expose themself to harm for no personal advantage, but only to provide information of benefit to the community if a treatment is successful. In this instance, it is especially important that patients who are involved in clinical trials are not used as a means to an end. It is particularly important to evaluate any proposed research project in light of the actual harm that might arise, and also to ensure that people are not included for reasons that are not in their best interest. Any competing interests of researchers must be disclosed and weighed up when determining whether they might have vested interests in including patients in trials that pose personal risk of harm to them.
Benefits and risks to the wider community should be taken into account as well. For instance, relatives have a right to know about genetic abnormalities identified in a patient, such as BRCA mutations, although this can also be perceived as potential harm for a person not directly involved in the research if it causes anxiety and they need to undergo invasive procedures in light of the knowledge arising from a study that they were not a part of.
Any clinical trial is preceded by an application for ethical approval of the research, which must be obtained by the investigator before the start of the project. In this document, the researchers are required to explain how they are going to ensure the best interests of the patient versus their own competing interests. The application should be self-explanatory and self-sufficient, and should provide a detailed evaluation of any risks and how they will be managed and reduced. Institutions have different requirements regarding applications, but in general, they require a description of the study, a consideration of the ethical issues, and examples of the advertising materials, participant information sheets, and consent forms used. Also, details about how the safe conduct of the study will be monitored generally has to be provided, as well as who will review the data to determine whether early stopping of the trial is necessary if it proves useful or futile at an earlier stage than that defined in the study protocol.
A number of guidelines define appropriate behavior in the context of medical research, and almost all contemporary documents have their origins in the Declaration of Helsinki (http://www.wma.net/en/30publications/10policies/b3/), which was developed by the World Medical Association in 1964, and was itself modeled on the Nuremburg Code. Those engaging in medical research should as a matter of principle familiarize themselves with the guidelines in their country, and ideally take the time to read the Declaration of Helsinki. In general, they state that the patients must give their consent to their participation in any research project; that the treating physician must take all necessary precautions to prevent or minimize the risk of harm, that any harm and inconvenience must be fully disclosed, and that the potential participants has sufficient information and time to make valid decisions.
In addition to ethical guidelines, regulatory authorities require adherence to Good Clinical Practice (GCP) (http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/good-clinical-practice.html). GCP guidelines are an international framework that encompasses standards for ensuring ethical and scientific quality in the design, conduct, recording, and reporting of trials that involve the participation of humans. GCP compliance provides public assurances that the rights, safety, and well-being of participants are protected, that the clinical trial data are credible, and that conduct is consistent with the principles that have their origin in the Declaration of Helsinki.
Core values of clinical research
Core values of clinical research include research merit and integrity, justice, beneficence, and respect (Table 1).
- With regard to research merit and integrity, trials can only be considered ethical if they are designed well and have a reasonable chance of meeting their endpoints . Appropriate expertise of researchers as well as sufficient resources and equipment must be in place. In addition, the researchers have to make sure that the question that is addressed in a trial is worth asking. All of these issues need to be considered from the outset of the planning process. Basically, research should be ethical by design, and good research will be inherently ethical if it is worthwhile and the researchers abide by ethical principles in their conduct.
- The term ‘justice’ relates to the equal distribution of opportunities to participate in trials for certain patient groups. It also means that certain groups should not be exploited or over-sampled. For instance, patients with COPD tend to get involved in numerous trials, which can put a considerable burden on them.
- Beneficence can be thought of as the benefits that are likely to arise from the study, but also the balance of risks to the individual against the potential benefits to humanity. Even an ethical study can expose patients to risk, and this can be acceptable as long as the risk is managed effectively. Equally, not all studies will provide a benefit to participants, and indeed overselling potential benefits must be avoided, to ensure that the patients are not influenced to participate against their best interests. Evaluation of beneficence requires some sophistication, and should not be confused with risk-management strategies.
- ‘Respect’ refers to ensuring that the participants are recognized as autonomous beings and that they are not just a means to an end. The inherent dignity of a person is recognized through their autonomous right to decide whether to participate in any study or not, based upon sufficient information to make fair judgment. During their participation, respect can be expressed by continued commitment to ensuring that their confidentiality and privacy are not breached, and that they have a right to withdraw at any time.
Whilst consent is of significant importance, it is only one part of the ethical considerations of a study, and it does not replace ethical behavior by the investigators. Respect for patients is demonstrated through obtaining their consent, which should be voluntary and given after providing sufficient information about the risks and benefits. Consent is an expression of autonomy, but also of empowerment; it is a gift that must not be taken for granted. As trials often provide no genuine benefit for the patient, particularly in advanced cancer settings, consent can be an expression of altruism. The least appreciable argument for gaining a patient’s consent is compliance with guidelines/ legal requirements, and the concept of ‘getting consent’ for regulatory compliance breaks the spirit of demonstrating respect for a person.
Mutual understanding is a prerequisite. It should be established that the adult patient is competent. They must be able to understand and retain the relevant information, to believe it, and to weigh it up, and thus to arrive at a valid choice for themself. The physician should abstain from coercion of, or inducements for, the patient.
Pertinent versus less pertinent information
As consent forms currently often run to enormous lengths, patients tend to sign them without reading them in their entirety. However, certain issues need to be pointed out to them. The investigator needs to disclose the type of study, the names of the investigators and sponsors, the goal of the trial, what the patient must do, how long their participation will take, what burden it will place upon them, and any risk of harm that might arise.
Consent forms are frequently grossly inflated with regard to the description of potential side effects, and written in a language that does not appear to reflect an intention to communicate effectively with the patients. Whilst the risk of side effects and dangerous toxicities must be disclosed, it is reasonable to expect that treatments in use in standard care should only need to be disclosed in a manner consistent with routine care. The type of toxicity that should be brought to the patient’s attention in information related to a study is the additional toxicity conferred by a new treatment, or by its combination with existing treatments. Moreover, highlighting risks, such as the risk of secondary malignancy due to radiation exposure during imaging, is most certainly futile in a cancer patient who has a limited life expectancy. However, these items are part of consent forms, and often their disclosure is required by law or according to guidelines.
At present, there is a debate as to whether or not it is legitimate to offer payments to patients for trial participation, and what, if any, the appropriate amount of money should be. This is not an easy question to answer, as it appears reasonable to provide a person with compensation for loss of earnings to participate in a study on the basis that if this was not available, they could not participate, and this in itself would be unjust. However, defining what this amount should be is very difficult, as trial participants span the socio-economic spectrum. Equally, a fixed amount might be insufficient for some and yet an inducement to participate for others. Investigators should consider this as part of the recruitment strategy, as limiting access to specific parts of the community might lead to bias in the reported outcomes if certain sectors are excluded.
Role and responsibilities of the Principal Investigator
Good Clinical Practice sets out clear guidance for the responsibilities of a Principal Investigator (PI) who is responsible for a particular study at an individual trial site . PIs are mandatory from both a regulatory point of view, and the point of view of the sponsor. If a sponsor is missing, as for investigator-initiated trials, the PI is the sponsor-investigator, or their institution may take on this role. The chief or lead investigator (CI) is usually the overall study lead, and it is particularly important to define their role in multicenter studies. However, the PI at the site bears a great deal of the responsibility, as identified by GCP.
Qualifications and duties of a PI
The PI should be qualified for their function, according to their education, training, and experience. Responsibilities of a PI include ensuring they have adequate provision for insurance and indemnity, for recruiting patients and ensuring their safety, and for the appropriate data collection (Table 2). The PI is obliged to establish structures for optimal trial conduct (e.g., trial clinics, fellows, study teams) and for holding regular meetings and updates with the research team. In practice, many functions will be performed by the study coordinator, although delegation is permissible as long as this is clearly defined and recorded. The PI must read the protocol, however, and confirm that they have done so by signing of the document. They are also legally responsible for any harm that comes to a patient if the protocol is not followed.
Moreover, the PI is responsible for patient screening and the selection of suitable patients. They must obtain the informed consent of each person to whom the drug/ agent/ device is distributed. Appropriate data collection is imperative to ensure the success of a trial. Furthermore, the PI has the legal responsibility for training the relevant staff, and for the consequences of any mistakes the study coordinator might make.
In principle, the PI’s duty is primarily to the patient . The patient’s welfare must always take precedence over the interests of science and society, and ethical considerations must take priority over laws and regulations.
Control of investigational drug/ agent/ device
Responsibility for the investigational product and accountability at the trial site rests with the PI, but can be delegated to a pharmacist or another appropriate individual under the PI’s supervision, in terms of the drug storage, and the keeping of accurate records and an inventory. The PI should distribute the drug/ agent/ device only to those under their personal supervision or under the supervision of a sub-investigator who is responsible to the PI. The drug or device must not be supplied to any person who is not authorized by the PI to receive it.
Investigator record keeping
Record keeping is required with regard to the Case Report Form (CRF) and Case Histories, as well as the disposition of the drug/ agent/ device. The CRF is a printed or electronic document that is designed to record protocol-required information on each subject. Here, the PI should ensure the accuracy, completeness, and timeliness of the data. These data must be consistent and verifiable with the source documents. Also, it is the PI’s duty to correct, as needed, the data in the CRF by striking out and initialing. ‘White-Out’ should not be used, and words should not be scribbled out.
For Case Histories, it is the PI’s responsibility to prepare and maintain these adequately and accurately. Case Histories should record all of the observations and other data pertinent to a study for each patient to whom the active treatment was distributed to or who was used as a control in the protocol. Case Histories comprise the CRF, supporting data, the signed consent forms, the patient’s medical records, progress notes, hospital charts, and the nurse’s notes. They should document that informed consent was obtained prior to the patient’s participation.
For the disposition of the drug/ agent/ device, the PI is obliged to maintain adequate records (e.g., dates, quantities, subject use, shipping, storage, return/ destruction). Furthermore, the PI is responsible for record retention.
The reporting duties of the PI include progress reports, safety reports, financial disclosure reports, and the final report (Table 3). In addition, the Ethics Committee needs to be kept informed of anything that might reflect on a continued favorable ethical view of a study. Any new information that becomes available during the course of a trial and that is relevant to the continued safe conduct of the trial or a change in the protocol must be forwarded to the Institutional Review Board (IRB)/ Independent Ethics Committee (IEC). Updated consent forms are necessary if the new information is relevant to patient participation, and these must be approved by the IRB/IEC prior to being given to the patients to confirm their willingness to remain in the study.
For trials conducted in the USA, sponsor-investigators are required to submit annual reports on the progress of the clinical investigation to the FDA, and also to report adverse effects that are both serious and unexpected, and/or deaths, to the FDA. Adverse events are defined as any untoward medical occurrence in a patient participating in a study, even though they might not necessarily have a causal relationship with the study treatment. The definition of serious adverse events extends to any untoward medical occurrence that meets one or more of a number of criteria, including a fatal outcome, a life-threatening situation, or the necessity for inpatient hospitalization.
The final report provides the sponsor or the FDA (for sponsor-investigators) with an adequate report shortly after the completion of the investigation.
Conflicts of interest
All investigators will have competing interests that can be described as financial, academic, or personal in nature. Table 4 lists types of conflicts and means to avoid them. Special considerations apply to the situation of the clinician-investigator whose dual allegiance might result in a conflict between their duty to recruit patients and their duty to complete a study; i. e., meeting their duty to offer the best advice to the individual patient and their contractual obligations . All options should be discussed with the patient, and the informed consent documentation must include disclosure of any competing interests that are real or can be perceived by potential participants.
- Emanuel EJ et al., What makes clinical research ethical? JAMA 2000; 283(20): 2701-2711
- http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf. Accessed June 10, 2015
- General Assembly of the World Medical Association, World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Coll Den 2014; 81(3): 14-18
- Miller FG et al., Professional integrity in clinical research. JAMA 1998; 280(16): 1449-1454