Process approach
Some positive aspects of what we have called the process approach have been suggested in the literature. By conveying the task of obtaining informed consent to an independent individual, the informed consent procedure is made more formal and clearly distinct from the practice of caregiving [
22,
49]. The physician could thereby communicate an explicit message to the patient, emphasizing the difference between research and usual practice [
3,
22].
To delegate the informed consent process to an independent individual is important in order to avoid patients feeling intimidated by their physician [
25]. It is mentioned that research nurses (or other study coordinators) are considered to be more neutral than physicians and researchers, making them better suited to obtain patient informed consent [
11] since they are not directly involved with the usual care of the patients [
49]. Their neutrality arises because they are independent from the treating relationship between patients and physicians. Since guidelines regard dependent relationships as problematic, this initial neutrality of the research nurse is thought to diminish the potential undue influence of the physician on patient decision-making [
2,
49].
However, considerable demands are often placed upon research nurses to recruit and retain a high number of patients to meet the study targets [
50,
51], and sometimes their employment depends upon their succeeding to complete trials in order to gain funding for subsequent studies. Therefore, it is questionable how neutral the position of research nurses actually is.
In addition, research nurses are frequently not as independent from the treating relationship with patients as is suggested. Although there is no generally accepted, standardized description of the tasks of the clinical research nurse [
52], an important aspect of their role is that in addition to their research related tasks, they are usually also involved in the care of the patients they have recruited for research [
51]. Clinical research nurses monitor the participating patients, explaining additional details, providing support and carrying out the distribution of medication [
53,
54]. Therefore, they must find a balance between the needs of patients and the demands of the research protocol [
55]. Qualitative studies have shown that research nurses themselves experience such a role conflict [
50,
51,
54], although they generally feel that their role as patient advocate is their primary one [
54].
The caregiving role of research nurses entails ongoing interaction with patients, which could result in a relationship between research nurses and the patients they take care of [
50,
54], similar to the dependent relationship between patients and physicians. A risk of such a relationship is that patients feel they are in some way dependent upon the research nurse, leading patients to think they should follow the nurse’s recommendations [
54]. This could in turn prevent them from withdrawing from the study, which is contrary to the demand that voluntary informed consent needs to be protected both at the start of the study and as the study progresses [
1].
In addition to factors specifically applying to the research nurse, several other challenges to the process approach can be assumed. The strategy to have an independent individual obtain informed consent instead of the treating physician starts from the assumption that such a person makes it easier for patients to refuse. However, two aspects of clinical research practice should be considered to assess the potential effectiveness of having a third person obtain consent.
First, the independent person is usually invited by the physician-investigator or appointed by the hospital where the patient is treated [
23]. As a result, patients may not perceive this supposedly independent person as truly independent from the relationship they have with their physician. Therefore, this person could just as well unduly influence the consent of the prospective participant.
Second, even though an independent individual obtains the informed consent of patients, several situations exist in which the physician of these patients will also be notified of their decision. When patients express their refusal to the independent individual, their own physician who conducts the study in question will typically be informed of this decision [
23] since he or she needs to know whether the patient participates in the study or should receive standard treatment. In a dependent situation the treating physician will always know whether the patient declined or accepted research participation, because this physician is the one who both conducts the study and has the responsibility for the treatment of the patient. So, the influence of the dependent relationship is not removed, meaning that some patients still consent against their wishes because their physician will know anyhow.
Furthermore, even when the treating physician is not involved with the study the patient is included in, it will in some situations still be necessary to inform the physician of the decision of their patient. For instance, in case research participation influences the usual care or when during the trial clinical problems arise that should be dealt with by the physician [
23]. Thus, the decision of whether a participant has given consent is always disclosed, irrespective of possible blinding of the physician for the study drug that a patient will receive if the patient has given consent. It is the disclosure of the decision to participate that is relevant in light of threats to voluntariness.
The use of counselors to support patients in decision-making and empower patients to choose their preferred option seems a useful way to improve voluntary consent [
54], since they should be able to ask relevant questions and provide support to patients [
25]. However, a challenge for this approach emerges when counselors lack medical expertise [
25]. This will especially be the case if the counselor is a friend or relative [
23].
Another challenge to the involvement of counselors is mainly practical. It will be difficult for many hospitals or other health care facilities to train and appoint a sufficient number of counselors to provide support for the large number of patients that is recruited within a dependent relationship.
Support of counselors or of other kinds of representatives is not unique for the context of dependent relationships. Several ethical guidelines also propose advocates or counselors for patients with insufficient mental capacity to consent on their own [
13,
14,
20,
21]. A factor that is often mentioned is that these advocates should consider the interests and preferences of the prospective participant in question [
14,
20].
Interestingly, in describing the role of the counselor who supports patients in dependent relationships, ethical guidelines merely state that these counselors should provide study details, be available for questions during and after the informed consent procedure and assess the advisability of further participation. As such, the guidelines do not explicitly mention that counselors should take the interests and preferences of patients into account.
Content approach
The rights to withdraw and refuse and the absence of negative consequences should also always be communicated to patients recruited outside the context of a dependent relationship to emphasize the voluntary nature of research participation [
21,
35]. Without this information, not all patients will be aware of their rights to refuse and withdraw without any retribution, which would be an ethically undesirable situation and would mean an infringement upon the validity of informed consent [
56].
However, the positive effects of the content approach on patients in a dependent relationship have hardly been studied. We think that this results from the content approach not previously being identified as one of two approaches to protect voluntary informed consent in a dependent relationship: most scholars and studies focus on introducing an independent individual in the informed consent procedure and more specifically on the role of the research nurse.
Therefore, advantages of the content approach are not readily supported by the literature. Although one study shows that some data managers (for example, research nurses, research assistants, study coordinators) feel that presenting information in a non-coercive manner and making patients aware of their rights to refuse and withdraw could ensure voluntary participation [
25], it is unclear how patients perceive this. Arguably, conversations with a research nurse or some other member of the research team could provide patients with robust knowledge [
57], which could aid them with their decision-making. Yet, at least two challenges remain for the content approach.
First, statements on the right to withdraw and the absence of negative consequences can easily become void expressions rather than effective ways to protect the voluntary informed consent. The disclosure of information is not sufficient to meet the requirements for informed consent [
25], since patients should also understand the information they receive [
58]. The manner in which the physician communicates the information is of great importance for patient comprehension [
58], something that ethical guidelines currently do not incorporate.
Second, although a review by Mandava
et al. has shown that at least 75% of research participants are generally aware of their right to withdraw [
59], in certain contexts a gap exists between knowing something and acting upon it [
60]. Understanding information on voluntariness does not equal voluntary informed consent. A recent study by Horwitz
et al. tried to untangle comprehension and voluntariness in the informed consent process for a HIV trial in Haiti [
61]. They found that even though the participants showed good understanding of the study details, including the voluntary nature of the study, 11% gave responses suggesting involuntary consent. One of these responses concerned the belief ‘that a “volunteer” is someone who makes an irreversible commitment to remain in the study’ [
61].
This study shows that even patients who had understood the provided information did not realize that they were indeed free to withdraw at any moment. For patients within a dependent relationship, the gap between knowing and acting upon that knowledge may be even greater, since patients depend upon their physician for the provision of care and treatment. Thus, although patients know and understand their rights, they could be hesitant to withdraw from the study even though they know they have the right to, since they do not want to disappoint their treating physician [
22].