Ethics in Clinical Cancer Research
Evidence-based medicine (EBM) has proven to be fundamental in the modern era. The clinical data derived from rigorous research protocols to support EBM has moved towards a high level of complexity to achieve the best level of evidence. However, the pursuit to retrieve organized data intersects with routine medical care. To accommodate significant advances in the area of precision medicine and to streamline the drug development process, newer and even more complex clinical trial design approaches have emerged. In this context, medical innovation not only creates new ethical concerns, but also prompts new considerations in long-standing ethics discussions. In this chapter, we will explore some of the major ethical concerns that arise in the course of modern clinical cancer research, as well as proposing recommendations to protect the rights, safety, and welfare of study subjects.
KeywordsClinical cancer research Early-phase trial Ethics Informed consent Oncology Precision medicine Therapeutic expectation
Cancer care is fraught with various ethical issues. We may find frequent dilemmas in providing access to care and treatments, palliative and end-of-life care, and treating vulnerable populations. These issues often concern any physician in their routine setting. The application of evidence-based medicine (EBM) has proven to be fundamental in the twenty-first century. The clinical data derived from rigorous research protocols to support EBM has moved towards a high level of complexity in order to achieve the best level of evidence. The pursuit to retrieve organized data, however, intersects with routine medical care. To accommodate significant advances in the area of precision medicine and to streamline the drug development process, newer and even more complex clinical trial design approaches have emerged, such as adaptive, basket, and umbrella trials .
To navigate cancer research ethically, strategies should be constructed carefully, because some new clinical experiments tend to move close to unacceptable ethical boundaries. Cancer research develops in the setting of the risks of a life-threatening disease, and this scenario may lead to misinterpretation in over-emphasizing benefits over risks. Historically, the famous 1747 scurvy trial conducted by James Lind contained most elements of a controlled trial and provided meaningful results, but the intervention lacked any potential for toxicity . Over the years, scandals, such as the elixir of sulfanilamide that killed 107 people in the United States in 1937, have raised concerns regarding what can be offered to the population. The pharmaceutical company involved in that incident was not undertaking any illegal activity in marketing the product . In response to deliberate abuses, of which the most infamous were the torture of and experimentation on Jewish people during World War II and the experiments conducted on black people in Tuskegee, Alabama , there have been ethical advances in human protection, such as the Declaration of Helsinki, which has been discussed and updated constantly . Other ethics codes have become the basis of clinical research regulations: the Nuremberg Code (1947); the Belmont Report (1979); the International Conference of Harmonization—Good Clinical Practice (1996), and the Council for International Organization of Medical Sciences (2002). Ethics committees have been created, based on ethical and regulatory guidelines, to critically review projects and to obtain consensus on research validity.
Participation in a clinical trial entails an essentially unknown (and often unpredictable) level of risk. Indeed, the equipoise principle determines that a participant should be enrolled in a clinical trial only when there is uncertainty. This principle aims to avoid the conduct of biased clinical trials, as for example, when a known inferior control intervention is chosen to increase the chances of achieving a positive result, with false claims that the experimental treatment is better .
Information that makes a participant’s consent valid is generally thought to include an understanding of the risks and benefits of the intervention, understanding and acceptance of the procedures that the participant may undergo, comprehension that participation in the research is voluntary, and an understanding of the research goals. Checking for a participant’s comprehension of the consent process is of great importance, because each participant has a particular history, cultural background, and beliefs. Thus, the desire to participate in a clinical trial and the willingness to complete the study are multifaceted. It is critical to address, a priori, individual education and values from the patient’s perspective and expectations from the physicians’ perspective. Shared decision-making may be defined as “an approach where clinicians and patients share the best available evidence when faced with the task of making decisions, and where patients are supported to consider options, to achieve informed preferences” . This approach should be applied in any decision taken in the clinic, including participation in clinical trials. The informed consent process, however, is not sufficient to make any research ethical. The scientific question should be meaningful and valid; the risks should be minimized and realistically favorable; and patient accrual should be fair . Medical innovation not only creates new ethical concerns, but also adds new considerations and paradigms to long-standing ethics discussions. In this chapter, we will explore some of the major ethical concerns that arise in the course of modern clinical cancer research (i.e., clinical trials), and we will propose recommendations to protect the rights, safety, and welfare of study subjects.
15.2 Early-Phase (Phase 0 and Phase 1) Studies and Therapeutic Expectations
Early-phase oncology clinical trials are an important step in translating basic research into clinical practice. Very different in structure from phase 1 studies, phase 0 trials were introduced by the United States Food and Drug Administration and the Pharmaceutical Research and Manufacturers of America in 2006 . Phase 0 trials can be designed to determine whether a mechanism of action defined in non-clinical models can be achieved in humans; to refine biomarker assays using human tumor and/or surrogate tissue; to provide pharmacokinetic/pharmacodynamic relationship data for an agent prior to phase 1 trials and to select the most promising candidates; and to determine the dose ranges of an experimental drug. This type of study typically involves the administration of a single dose or a short course of micro-doses of a new pharmacological compound . Phase 0 trials are useful because they can compress timelines for the overall development of an anticancer drug or even prematurely halt a drug development program. This would prevent subsequent studies and the unnecessary exposure of volunteers to undesirable drug effects and an unacceptably lower probability of success. Nevertheless, the lack of any potentially direct medical benefit in parallel with the exposure of study subjects to small risks is problematic. Moreover, in routine settings, biodistribution assessments require multiple blood draws and biopsies of relevant organs . This scenario is of great challenge to applied science and ethical responsibility . While studies have reported that cancer trial participants commonly report that altruism contributed to their decision to enroll, it is rare for this to be the primary motivation for study participation. Indeed, the decision to participate frequently stems (at least partially) from the possibility of direct benefit, which is understandable given the lethality of cancer. In early-phase trials and among patients with poor prognoses, altruism is least often the motivator [13, 14]. The common understanding that participants in phase 0 trials should have chances (even minimal) of direct benefits from trial participation or access to the best therapeutic method identified as beneficial during drug development is unsustainable. Because cancer patients who are eligible to enroll in phase 0 trials are end-staged, their chances of receiving direct clinical benefits from proven therapy during the course of drug development are highly limited . Reconceptualization of the investigator-subject relationship and a deep evaluation of the subjects’ understanding of phase 0 trials are essential for achieving subject enrollment. Paying modest quantities of money to encourage enrollment in phase 0 trials has been considered by some authors . This idea should have a well-thought-out rationale, especially in developing countries where most participants are in a vulnerable economic condition owing to their low per-capita incomes. Undoubtedly phase 0 trials comprise an important step of the drug development process in clinical cancer research. However, the inclusion of indirect benefits and the potential lack of direct benefits, in terms of tumor control, must be explicit in the consent forms of phase 0 studies.
Phase 1 studies are designed to escalate the dose until toxicity is observed, to determine the recommended safe dose and schedule of an investigational agent in order to move forward to phase 2 trials; phase 1 trials often assess the pharmacokinetics/pharmacodynamics of an experimental therapy and explore the development of relevant biomarkers. The American Society of Clinical Oncology Policy Statement claims that phase 1 trials have the potential to provide clinical benefit, including improved quality of life, positive psychological effects, and the potential for tumor response . Meta-analyses of phase I trials have reported growing rates of objective responses, of 5–11%, a toxicity-related death rate of only 0.5%, and an episode of a grade 4 toxic event in approximately 14% of the participants [17, 18, 19]. Even though the efficacy and safety of investigational treatments in early-phase trials are still under evaluation, empirical studies have found that phase 1 oncology trial subjects often report high and unrealistic expectations of personal therapeutic benefit [12, 20]. Unrealistic optimism may cause distortions in risk/benefit assessment, with patients overestimating their prospects of benefit and/or underestimating their susceptibility to the risks. In addition, media ‘hype’ about laboratory discoveries, as well as cancer centers promoting their medical services by advertising the number of clinical trials they conduct—highlighting that their patients will have access to the newest investigational treatments—can foster therapeutic misconceptions [21, 22]. Such advertising promotes patients’ unrealistic hopes of clinical benefit, as well as interfering with the ability of study participants to distinguish between research and standard of care . Therefore, while research participants can, and should, be optimistic about their chances of response to investigational treatments, they must still understand that the treatments are experimental, and that they have potential toxicities and low chances of tumor response . It is challenging to determine whether patients’ unrealistic expectations are the result of the patients’ optimism, or a result of their lack of understanding during the informed consent process, or both [20, 24]. Although the vast majority of study participants have reported that they understood most of the trial information, fewer than 50% were able to correctly describe the purpose of the phase 1 trial as a dose-determination and safety study [25, 26, 27, 28, 29]. These findings raise concern about subjects’ misunderstanding of specific information regarding early-phase clinical cancer trials, and make their voluntary decision about whether or not to enroll in the research burdensome.
Contributing to ethical challenges are the complications of conducting research in patients with advanced cancer who have not responded to other types of therapy and have few, if any, remaining treatment choices. Terminally ill cancer patients may seek to enroll or may be actively recruited to participate in early-phase oncology clinical trials while desperately hoping to find something to reverse or delay the course of the disease . Vulnerability, which is closely linked to the disease severity, may affect the informed consent process [25, 31, 32, 33]. The debate on the enrollment of such patients focuses on the misinterpretation of risk-benefit ratios, inadequate information disclosure, and subject decision-making capacity . In this context, one can argue that, in high-risk clinical research, the study subjects could be more vulnerable to exploitation and less capable of protecting their own interests, thus requiring special safeguards in this type of research [34, 35]. Nevertheless, after an extensive literature review of almost 10,000 participants in phase 1 oncology trials, Seidenfeld and colleagues concluded that “the demographic and health status (…) are not those of a conventional vulnerable population and suggest little reason to assume that, as a group, they have a compromised ability to understand information or to make informed and voluntary decisions” .
220.127.116.11 Improve Subjects’ Understanding of Goals of Early-Phase Trials
During the informed consent process, researchers should clearly discuss with the subjects the objectives of the trial and its potential benefits and risks; in particular the low chance that the subjects will experience clinical improvement.
Continuing medical education should address the structured training of trialists in communication skills to reduce the frequency of participants’ poor understanding of the key concepts of a clinical trial and its objectives . Investigators have to be cautious in properly informing subjects of the low chances of benefit in early-phase trials in cancer, without hampering their hopes.
To assess and enhance participants’ understanding, researchers should use open-ended questions, such as: “Can you tell me in your own words the purpose of phase 1 research?” and “What might be the benefit from this study?” .
If unrealistic optimism becomes apparent during the informed consent process, investigators should attempt to clarify misunderstandings. If there is failure to appreciate relevant information, unrealistic optimism may impair informed consent [20, 24].
When considering participation in clinical research, especially in phase 1 studies, a shared decision-making approach may be useful when decisions are uncertain. It is important to address, a priori, the patient’s individual education and values and the physicians’ expectations.
18.104.22.168 Improve the Risk-Benefit Ratio for Patients in Early-Phase Trials
Researchers should use strategies to facilitate the inclusion of those patients, based on genetic or molecular biomarkers, who are most likely to respond to a specific targeted therapy. Based on a strong biological rationale, enriching the subsets of patients selected according to germline or molecular tumor profiling for matched therapies can improve the efficacy, and potentially the safety, of new cancer-directed experimental drugs [16, 37].
Researchers and sponsors should put efforts into moving phase 1 trial designs to dose-escalation approaches (e.g., accelerated titration designs and adaptive Bayesian designs) that allow more subjects to receive higher doses of investigational agents that are more likely to result in a therapeutic effect [16, 37].
15.3 Key Ethical Issues in Developing Precision Medicine in Oncology Clinical Trials
Precision medicine is an emerging approach that proposes the customization of disease diagnosis, treatment, and prevention tailored by individual variability in genomic, environment, and lifestyle factors. This concept is rapidly progressing with the recent advances in next-generation sequencing (NGS) technologies (using DNA, RNA, or methylation sequencing), genetics computational solutions for omics data, and large-scale biological databases (such as the gnomAD , The Cancer Genome Atlas , ClinVar , and the Catalogue of Somatic Mutations in Cancer ). Each cancer has its own genomic signature and the understanding of the key genomic changes in many types and subtypes of cancer has begun to influence risk assessment, diagnostic categories, and therapeutic strategies in oncology. On the treatment front, the use of predictive biomarkers to select patients for specific molecularly targeted anticancer drugs has established new, more effective and less toxic treatment options. Some examples of these successful approaches are imatinib for chronic myeloid leukemia and trastuzumab for HER2 breast cancer .
Precision medicine is powered by patient data. It relies on the integration of clinical, genomic, pathologic, and outcome data, as well as the availability of patient samples. Though these are clear indications of optimism for precision medicine, ethical challenges need to be acknowledged and addressed, particularly with regard to (1) informed consent, (2) privacy/discrimination concerns for patients and their families, and (3) the return of clinically relevant results.
First, for many decades, human biological samples were collected during the course of treatment without gathering any informed consent, or alternatively, the informed consent is now obsolete and inappropriate for use in unforeseen secondary research aims, such as genomic profiling for research purposes . Currently, the lack of individual informed consent imposes an enormous obstacle to the reuse of biological samples . Thus, there is an urgent need to update and standardize patient information and informed consent forms in order to integrate precision medicine into oncology research. The development of a fair informed consent document and the process required for its acquisition, without compromising broad ethical and legal principles, is essential . Many patients have difficulties in understanding the complexity of the information that needs to be covered, such as the tumor’s heterogeneity, its molecular evolution, and its relationship to drug response. Not only the content, but also the duration of obtaining informed consent can result in an excessive and undue burden on participants; the extrapolation of the traditional single-gene approach to detailed discussion about each gene being tested may be tremendously time-consuming, leading to information overload; as a consequence, this may interfere with the participant’s decision-making capacity . Adding more complexity to the consent process is the duty to warn patients about the potential identification of a genetic variant of unknown significance and incidental findings in medically actionable genes, as well as the potential psychosocial implications of germline and somatic genetic testing [47, 48]. These factors have become more and more common with the widespread use of NGS in routine and clinical research settings.
Second, the maintenance of the privacy and confidentiality of genetic information has been raising ethical concerns in research and ethics communities. On one hand, privacy considerations may restrict researchers from gathering additional information that might give them more insight into their research questions; on the other hand, these considerations are safeguards of anonymity and may prevent unintended consequences and potential risks to participants. A dominant issue of public concern is the potential risk of genetic information being used in ways that could harm people, such as for genetic discrimination by health insurance companies and employers. In the United States, the Genetic Information Nondiscrimination Act of 2008 is supposed to prohibit such use, but there are no similar or specific laws in most countries, particularly in developing countries. Despite researchers making every effort to maintain privacy and confidentiality, according to Neil Savage, “it may not be possible to protect the identity of genomic data” . Privacy should be ensured; however, anonymous data, particularly those shared in public databases, are vulnerable to re-identification [50, 51]. As genome databases are growing and algorithms for comparing data are improving, it is getting easier to link medical histories and other personal information (such as name and ZIP code) to DNA donors.
Finally, as genome and exome sequencing has moved into clinical practice, concerns over unintended/incidental findings and the return of results have emerged. There are several challenges, including the large number of results available, the need to interpret novel mutations that could be functionally deleterious, the reclassification of the variant pathogenicity over time, and the increased number of findings of potential clinical utility. The American College of Medical Genetics and Genomics published, in 2013 , and updated in 2016 , a report suggesting that, in clinical genomic sequencing, known pathogenic and expected pathogenic genetic variants in 59 medically actionable genes should be returned to the subjects, including when germline testing is done as part of a matched tumor-normal sample pair. Nevertheless, institutional review boards and investigators are raising the question of whether these or comparable clinical recommendations should be extended to research settings. It is important to acknowledge that standards for returning genomic results in a research setting, where investigators are seeking scientific discovery, might differ from the standards of clinical practice, where the clinician’s primary duty is to improve the health and wellbeing of the patient [53, 54].
Accumulating evidence reveals that the majority of research participants wish to receive clinically significant individual study results, despite there being a potentially negative emotional impact . Study participants appreciate that the disclosure of study results has the potential for removing uncertainties, promoting discussions within families about risk management and increasing the understanding of a disease and its treatment, as well as reassuring the study participants about their right to know [53, 55]. However, respect for participants’ wishes requires taking their preferences seriously, including their right to refuse the return of genetic findings during the informed consent process [56, 57].
22.214.171.124 Improve the Process of Informed Consent
The time has come to rethink and consider an informed consent model that respects the privacy concerns of participants, but that releases constraints on the utilization of data, making the participants’ contribution to research more durable, broader, and efficient.
Researchers need to develop new variations of informed consent documents, such as tiered or dynamic consent (establishment of ongoing communication between investigators and participants regarding data access) , broad consent [59, 60], and open consent (volunteers consent to unrestricted re-disclosure of data, knowing that there is a certain risk of harm to themselves and their relatives and no guarantee of anonymity/privacy/confidentiality) .
The informed consent process should include the option of re-contacting the participant and obtaining re-consent when new medically relevant information becomes available or if further research is being considered.
Partnering with patients, as for example, in patient advocacy groups, is critical for understanding how to maximize the balance between the ethical/legal regulatory framework, researcher needs, and patient expectations .
126.96.36.199 Awareness of Limitations to the Safeguarding of Genetic Privacy and Confidentiality
Participants need to be fully aware that the linking of distinct databases and data sharing among researchers is intended.
Investigators need to clearly explain that the full purpose and the extent of further usage of their data cannot be completely foreseen.
Although the risk of re-identification is small, absolute privacy and confidentiality cannot be guaranteed; thus a certain risk of harm to participants and their family members may potentially exist.
Continuous efforts have to be made to ensure data safety. For example, remove obvious identifiers from the data sets before sharing the information in public databases and maximize privacy-preserving approaches using new data anonymization methodologies, such as differential privacy and k-anonymity, and modern cryptographic solutions .
188.8.131.52 Improve the Communication of Results
Participants need to be informed about the possibility of incidental findings during the consent process.
Researchers are not obligated to conduct a deliberate search of a predetermined list of genes not identified in the course of their research or related to their research purpose.
There is a duty to warn participants, but there is no duty to search for actionable incidental genetic findings. However, there is a duty to return lifesaving genetic information discovered in the course of the research process.
To respect participants’ autonomy—one of the ethical foundations of medicine—participants should have the right to refuse the return of their results. This right should be adequately explained to the participant at the time of consent.
At the time of consent, if the purpose of the study is dependent on the return of results, the participant must have the opportunity to decline participation.
15.4 Ethical Considerations in Placebo-Controlled Cancer Trials
The most well recognized method of evaluating the efficacy of a new treatment is the double-blind, randomized controlled trial with placebo (placebo-controlled trial—PCT). Beecher was the first to report the placebo effect, noting that, in about 35% of patients with various distinct medical conditions, the conditions could be improved or cured by placebos . From the time of that study, the concept of an intervention activity changed and took into account combined variables: the course of the disease; the specific effect of the intervention; and the nonspecific effects of placebos [64, 65]. Placebo effects have been well documented for the relief of pain  and for psychiatric disorders such as anxiety and depression . Responses to treatment in patients receiving placebo are more frequent when the effect is a change in a subjective sensation . In cancer clinical trials with objective responses as the primary endpoint, the use of placebo alone may result in an objective response rate of 2–7%. Although such percentages are considered low, these rates might be overestimated in terms of spontaneous regression or cytokine-mediated regression, or may even reflect measurement errors by radiologists . Analyses of objective responses in patients receiving placebo treatment are still controversial. Also, deleterious effects attributed to placebo may be found in patients who anticipate the potential side effects of the active drug.
In clinical cancer research, placebos are often utilized in randomized registration phase 3 trials. Here a placebo can be used exclusively; in combination with best supportive care, often when there is no active comparator (as for instance, in refractory metastatic solid tumors); or combined with cancer-directed therapies [69, 70]. The advantage of having a placebo arm is that it controls for observation biases in randomized trials (see Chap. 14).
The use of exclusive placebo in randomized trials is permitted in the Declaration of Helsinki, but “extreme care” should be taken. Exclusive placebo can be used when scientifically indicated and when there is no proven effective treatment for the condition under study, or when interrupting treatment poses acceptable risks. However, this idea of “extreme care” has not always been respected. In 1998, trials with azidothymidine (AZT) were being conducted to determine the minimum dose of AZT needed to prevent the vertical transmission of HIV from infected mothers to their unborn children. Volunteers were randomized to various dosage arms and to a placebo arm. The trial format was considered unethical because AZT already had proven efficacy in blocking two-thirds of transmissions of HIV to the fetus . As stated by Emanuel, research must be conducted in a manner that will produce reliable and valid data, and for that new interventions should be tested against the best current proven intervention. Sometimes it will be appropriate to test new interventions against placebo alone, or no treatment, when there is no current proven intervention or, where for compelling and scientifically sound methodological reasons, the use of placebo is necessary to determine the efficacy and/or safety of a new treatment and the patients who receive placebo exclusively, or no treatment, will not be subject to excessive risk or serious irreversible harm .
Some authors have justified placebo use in diseases in which worsening is likely to be reversible . In cancer research, however, this idea is unlikely to be acceptable. Indeed, one cancer patient-centered concern commonly includes the understanding of assignment to placebo or no treatment in PCTs . In this regard, accessible information and individualization are some important aspects that influence participants’ decisions. If these aspects are not addressed, participation would be compromised and this may result in poor protocol compliance and a higher probability of dropouts .
Another important aspect of PCTs is the willingness of patients and physicians to participate in such trials. In fact the use of placebos represents a known barrier to trial enrollment. For example, a survey of nearly 6000 American cancer patients demonstrated that among those who refused trial participation, one-third did so for fear of being administered placebo exclusively . In Brazil, we performed a cross-sectional study of 104 cancer patients and 25 oncologists who were the principal investigators in clinical trials; we asked about their perceptions of a PCT and we found that 41% of patients were not willing to participate in trials with placebos and half of the investigators surveyed objected to recommending a PCT to patients because they “felt uncomfortable to offer no treatment to their patients” .
Specific explanations about the risks and benefits related to the use of placebo should be emphasized during the consent process, including the information that subjects’ health status may worsen while on placebo. Clinical equipoise should exist in PCTs and this should be explained to patients in lay terms. We conducted a survey of PCTs in cancer published over a decade and showed that the results of half of the trials were negative, i.e., placebos were not worse, and were certainly less toxic, than the experimental agents under investigation .
To minimize participants’ time on placebo, trial withdrawal, early escape, and designs that permit cross-over can be used . However, justifying the use of placebo in cross-over designs should be carefully considered . This is because allowing patients from the placebo group to receive the experimental therapy upon disease progression likely compromises the analysis of overall survival, which may, in turn, preclude the approval of new drugs in countries where gains in survival are a regulatory requirement. Possibly a flexible solution would be to perform imaging tests shortly after treatment initiation, e.g., after 4–6 weeks, to minimize the use of placebo; this short period might not contaminate the survival analysis when there is significant cross-over.
To minimize risks associated with the use of placebo in clinical trials, investigators should increase monitoring for deterioration in the subjects’ condition and include state-of-the-art palliative care [78, 80].
The use of unbalanced randomization (2:1 or 3:1 allocation ratio) should be encouraged to keep the population placed on placebo smaller than the number in the active treatment arms ; this certainly encourages patients and physicians to accept PCTs.
A data and safety monitoring board, with interim analyses of study results, should always be considered, with the possibility of early stopping or modifying of the study based on the findings . But again, this possibility has to be carefully considered, because early stopping may lead to trials becoming underpowered to detect differences in overall survival.
15.5 Understanding What Clinical Trial Participation Means
Importantly, a pivotal aspect of clinical research in any area of medicine is to guarantee that patients accept participation voluntarily. The issue is that, to make a voluntary decision, the person has to properly understand what he/she is getting involved in, which implies that the information provided for such a decision is clear, objective, and presented clearly in lay terms. Our perception is that this aspect is far from ideal. The consent forms for clinical trials often consist of more than ten pages, and they contain too much detailed and sometimes useless information for patients, making the whole process of reading tiring and potentially unfruitful. In an attempt to provide detailed information, the consent forms have become burdensome, time-consuming for readers, and confusing. For example, while it is mandatory that consent forms include information about risks, it seems unnecessary to go over the risks of performing basic blood and imaging tests, since these are already part of a cancer patient’s life. Mention of such risks may suggest that all interventions included in the trial are experimental, and may wrongly influence patients’ decisions to enroll. The other feature of modern consent forms is the great number of technical terms used, which makes the forms hard to comprehend. The list of potential adverse events is often long and described in medical terms, such as neutropenia, hand-foot skin reaction, and increase in QT intervals. This is of particular concern in low-socioeconomic settings. Nowadays most phase 3 trials are global trials that accrue patients from all over the world, including developing countries. In certain countries, like Brazil, the number of illiterate patients and those who have attended only a few years of school is not trivial. These patients are usually treated for their cancers in academic public institutions, where most clinical trials are conducted.
To evaluate the readability and complexity of informed consents for phase 3 trials and the level of education of cancer patients (n=137) who had been enrolled in clinical trials at an academic center in Sao Paulo, Brazil, we performed a transversal study, using widely available software (Flesch Index and Flesch Kincaid Index of readability). We found that understanding the complexity of the consent forms required at least 18 years of education, while half of the patients had attended school for less than 8 years . Making sure patients understand what is at the stake in terms of clinical trial participation is crucial for a transparent and ethical informed consent process.
There is a need to significantly reformulate the contents of informed consent forms, with less—but more direct and objective—information for patients. Lay terms have to be substituted for technical terms and conventional tests and procedures already performed in the routine practice of oncology should be mentioned, but only as ancillary measures/intervention, without listing all potential risks.
The language of the consent forms should, if possible, be adapted from—not only translated into—local languages, meaning that the use of certain linguistic terms may make it easier for participants to comprehend scientific terms.
Enough time must be given for subjects to read and discuss the consent forms with their families or caregivers so that they can reach a voluntary and well-informed decision.
As scientific advances continue, ethical and regulatory challenges requiring wiser updated adaptations will be the tenets of clinical research activities. Recently the International Conference of Harmonization—Good Clinical Practice guidelines were updated, focusing on more complex and globalized studies, with the use of technology applications, including mobile data collection and real-time monitoring of clinical data. The guidelines also recommended the application of a risk-based approach. The conduct of modern research will require critical responsibility on the part of investigators, research promoters, and regulators to guarantee that all terms of the research are within an ethical scope.
In particular, paragraph 8 of the Declaration of Helsinki (2013) emphasizes that while the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects. In the consent process, critical points still remain in regard to the vulnerability of volunteers; also local factors might be ignored. All efforts should be made to guarantee a valid consent. However, the informed consent process is insufficient to guarantee the ethical conduct of a research program. To guarantee such conduct will require broader monitoring mechanisms, involving regulatory bodies and ethics committees in the validation of the scientific values of research questions, in accrual activities, and in safety concerns. Finally, ethical requirements should not be viewed as clashing with scientific advances. Instead, current understanding of the requirements that make research ethical may be reinterpreted in the light of the modern clinical cancer research scenario and be adapted to boost specific studies and research strategies in the contemporary era.
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