Does more information mean better knowledge?
Authors: Ruth Cohen PhD, Regulatory Affairs Associate, CATO SMS
Recruitment and retainment of patients for clinical trials can be a major challenge, especially for complex areas such as oncology since the accumulating knowledge in these areas leads to a major increase in the types of therapies under development. The field is expanding, both in the approaches used, from personalized therapies to basket- and umbrella-trials, and in the types of drugs evaluated: micro RNAs, vaccines, chimeric antigen receptor (CAR)-T cells and other advanced therapeutic medicinal products. These advancements are positive developments for the potential therapies for cancer patients, but make it more difficult to explain to patients what the trial they are asked to participate in exactly entails. Before a patient with cancer can become a subject in a clinical trial, he/she needs to be informed on the investigational treatment and give voluntary informed consent. However, the information presented to patients is often complicated and misunderstood (Jefford and Moore, 2008; Anderson et al., 2017). Especially in early-stage oncology trials, where the design of the trial can be complex, there is still room for improvement of the conciseness and clarity of the informed consent form.
History of informed consent
Obtaining informed consent from patients who are going to participate in experimental procedures started after the publication of the Nuremberg Code in 1947 and was adopted by the World Medical Association in the Declaration of Helsinki in 1964. The purpose is to respect the potential participant’s autonomy and to protect them from potential harm. The investigator, often being the treating physician, has the task to inform the patient on the investigational treatment, followed by obtaining voluntary informed consent. The Declaration of Helsinki states that “the physician must be particularly cautious if the potential subject is in a dependent relationship with the physician or may consent under duress”. This can be a difficult task since patients rely on their physician to provide them with the best possible care, which inevitably creates a dependent relationship. In early-phase clinical trials, the goal is to evaluate safety and efficacy of compounds previously untested in humans, and side effects of the treatment might potentially be observed. To protect the patient and aid the physician in providing adequate information on the trial, the Informed Consent Form (ICF) was created.
ICF requirements and regulations
An ICF should not only adhere to the ethical principles of the Helsinki declaration, but also to the Guideline for Good Clinical Practice (GCP). Potential participants should be able to understand the design and risks of the clinical trials by reading an ICF and have the opportunity to ask questions to the treating physician. An ICF does not only include information that is specific for the trial, but also covers legal disclosure information about insurance, data protection, sources of funding, and possible conflicts of interest. Additionally, potential participants are informed that participation is voluntary. In total, the GCP requires to include 20 different topics in the ICF.
ICFs should be approved by Ethics Committees (ECs; Europe) or Institutional Review Boards (IRBs; United States of America [USA]) prior to the conduct of a trial (GCP 4.8, page 24). These committees or boards consist of specialists in different fields, i.e. physicians, ethicists, statisticians, lawyers, and pharmacists. Each of these experts has its own part(s) of the ICF to review. Many countries created national guidelines or templates to ensure that all topics required by the GCP are mentioned in every ICF that is sent for review and to save time in the reviewing process. In Western Europe, for example, the ICF process is not standardized, which leads to multiple between-country differences, e.g.:
- France has no documented guideline
- Spain has recommendations on the total number of pages (namely, 15 pages)
- The size and font used are different (Arial or Times New Roman, minimum 11 points)
- The requirement to mention national laws; Belgium, Germany and The Netherlands require the use of their national template
When conducting a trial in several different countries, this non-standardized process leads to development of multiple country ICFs and multiplication of efforts thereof.
Room for improvement
Templates and guidelines can aid to improve legibility, however the ICF still needs to be written. The biggest challenge remaining is to write a document that is understandable for any potential patient. ICFs are often written by healthcare professionals who have thorough understanding of oncology and clinical trials, among which treating physicians or employees of pharmaceutical companies and clinical research organization (CROs). These professionals might not always realize the importance of converting complex information into laymen’s terms. Studies have shown (Joffe et al., 2001; Schumacher et al., 2017) that more than half of the trial participants does not fully understand the text of the ICF, even though they are able to ask questions to the investigator.
Fortunately, there are several examples of groups that are actively working on improving the legibility of ICFs. The Aide et Recherche en Cancérologie Digestive (ARCAD) group, an international scientific committee of oncologists, recently suggested to split the document into two parts: (1) the leading part that enables a patient to make an informed decision and (2) the relevant supportive information that is not involved in the decision-making (Bleiberg et al. 2017). In the Netherlands, the Dutch Clinical Research Foundation (DCRF), a foundation with the goal to maximally facilitate clinical research for the benefit of the patient, has a specific work group focusing on improving the ICF. Experts from the industry, government and patient representatives combine their knowledge to improve the national template ICF of the Netherlands, with the latest update released in September 2020.
The most promising way to improve the process of informed consent is to use different types of media. In the last couple of years, there has been quite some development regarding eConsent: an electronic version of the ICF, where the content is delivered via multimedia. eConsent is becoming a more popular method and is being used by pharmaceutical companies in the clinical trial industry, such as DrugDev (an IQVIA company), TransCelerate Biopharma Inc. and Janssen. This method has the benefit that complicated text can be accompanied by a glossary of terms, icons, video, audio, and even knowledge checks, to aid in understanding the explained information. There are two ways to sign the eConsent; either with an eSignature or with a print-to-sign. With eSignature, the investigator and the patient view, discuss and sign the ICF by the use of a tablet. The form will be saved digitally, with an audit trail. This form of signing is allowed in the USA, Canada and Australia. Europe however does not yet allow this method because of the General Data Protection Regulations (GDPR). Therefore, the alternative of the print-to-sign can be used: instead of digital signing, the consent form is printed after the investigator and patient have discussed the ICF and both sign the paper version. This signed document will not be stored digitally.
CATO SMS is committed to facilitate the transition towards digitalization in clinical trials and for that purpose partners with THREAD as the leader in decentralized study approaches via their proprietary technology platform and supporting services. THREAD’s technology powers CATO SMS to seamlessly create eConsent in the near future. In the meantime, CATO SMS will focus on improving the layout and language that is used in the paper ICF for clinical trials. By improving the ICF’s legibility, we can help patients to better understand what they sign up for, leading to enhanced recruitment and retainment and a higher quality clinical trials.
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Joffe, S, Cook, E.F, Cleary, P.D, Clark, J.W, Weeks, J.C, (2001). “Quality of informed consent in cancer clinical trials: a crosssectional survey.” Lancet 359: 1772-1777.
Schumacher, A, Sikov, W.M, Quesenberry, M.I, Safran, H, Khurshid, H, Mitchell, K.M, Olszewski, A.J, (2017). “Informed consent in oncology clinical trials: A Brown University Oncology Research Group prospective cross-sectional pilot study.” PLoS ONE 12(2): e0172957.