i. General background
Early phase oncology clinical trials are becoming increasingly complex with a rapidly increasing array of investigational agents, combinations of these agents and a variety of trial designs which incorporate the importance of personalised approaches and the hope of fast tracked drug discovery. Informed consent for early phase oncology trials has always been a contentious area, and now it continues to be of relevance for the wider oncology community and the Phase 1 trial community. A 2018 study demonstrated significant gaps in understanding of patients regarding the nature and intent of early phase oncology trials. There has been a longstanding debate in the medical oncology community about the nature of Phase 1 trials and the ethics of allowing vulnerable patients to participate in clinical research where the primary purpose is to establish the safe dose. Opponents of the argument point to the need to understand both sides and that patients need to understand enough to consent, which is not necessarily full comprehension. The fact that this group of patients is hopeful, optimistic and desperate has been well characterized and no doubt plays a role in their ability to process information presented to them by the clinical research team.
ii. Empirical research showing patients misunderstand early phase clinical trials
Multiple studies have shown that advanced cancer patients (ACP) misunderstand the nature and purpose of Phase 1 oncology trials. Most recently, Hlubocky et al. demonstrated through audiotaping clinical encounters between 101 ACPs, and 29 oncologists that ACPs had a poor understanding. Only 26% were able to recall the primary purpose of the trial as safety and only 7% were able to recall that there was a risk of major adverse effects such as organ damage. The study also demonstrated deficiencies in clinician communication, with only 40% of encounters containing a direct statement on the research purpose being to establish safety, toxicity and dosage. In 2010, a similar study of 17 oncologists and 52 patients in the United Kingdom showed that several key areas of information including prognosis were omitted from the clinical encounter.Joffe and colleagues also conducted a survey of trial participants (including phase 1, 2 and 3 clinical trials) and investigators and showed significant deficits in understanding. Furthermore, in a survey of 95 patients on Phase 1 trials, Pentz and colleagues demonstrated that 68.4% of patients had a therapeutic misconception by failing to answer two core questions correctly ("Is the research study mostly intending to help research and gain knowledge or mostly intending to help you as a person?" and "Does the research study or your doctor decide the treatments?"). There was also a misunderstanding of the risk associated with participating in an early phase clinical trial and that they do not correctly grasp the key difference between individualized care and clinical research. There was a correlation between lower education and lower family incomes with therapeutic misconception. Overall there is extensive empirical evidence to suggest that a significant proportion of advanced cancer patients considering early phase oncology clinical trials harbour misconceptions about the nature and design of these trials.
iii. Participant Information Sheets are too long, too complex and fail to meet the information needs of patients
It has long been recognised that Participant Information Sheets (PIS) or Informed Consent Forms (ICF) are highly complex and lengthy across all the phases of oncology clinical trials. In 2007, Beardsley and colleagues showed that PIS were increasing in length and that an objective measure of informed consent (the QuIC-A), understanding decreased as PIS's increased in length. There have been no published studies on the PIS used in Phase 1 studies specifically. However, in the era of combination trials, Bayesian adaptive design, and seamless Phase 1/2 designs, the PIS for Phase 1 trials can be particularly complex. There is regulatory requirement for disclosure and there are certain regulatory requirements but these documents have ultimately become unwieldy, disliked by investigators and anecdotally, not read at all by participants. This further magnifies the issues on therapeutic misconception that were highlighted earlier. We note that the Hastings Center has published a 3 page Phase 1 consent form, but to the best of our knowledge this is not in widespread practice. Overall, in this era of increasingly sophisticated trial design, PIS are becoming lengthier and are becoming less useful as adjuncts to the informed consent process.
iv. Paucity of interventional research to improve understanding
We performed a review of the literature looking at interventions that have been tested to improve participant comprehension of Phase 1 trials which yielded two relevant studies. The first, a simulated teaching intervention to improve clinician confidence by Fallowfield et al. (2012) showed that an intensive 8 hour educational intervention on clinicians involved in early phase trials improved their self-confidence along with patient simulator ratings of understanding(7). Secondly, Kass et al. (2009) randomized 288 participants to receive either a 20 minute educational computer based presentation or a standard pamphlet on clinical trials and showed that they could improve patient understanding of trial purpose from 16% to 34%(8) and also showed that there was no significant differences in likelihood of enrollment. We note that there have been multiple efforts directed towards empowering cancer patients in later phase trials including audiovisual techniques such as multimedia presentations(9), question prompt lists(10), and decision aids (11). Promisingly, sponsors are already taking steps towards improving their information sheets and there are already attempts to incorporate audiovisual materials and electronic assessment of patient understanding.
v. Justification for CONSENT
CONSENT will be a randomised controlled trial examining the effect of both a short, jargon-free, plain language participant information sheet and a suite of online educational videos, on participants considering consenting to an investigator initiated trial within the Drug Development Unit. Early phase trials have dramatically changed over the last decade and there have been no interventional studies published in this area in this time and consequently this is a significant area of unmet need for both patients and investigators. This trial will use a validated measure of informed consent (Quality of Informed Consent - Part A) and powered to test a statistical hypothesis, and will also examine the acceptability of the two interventions for patients. While the trial will employ a randomised design, it will ensure all participants are provided access to the enhanced consent materials prior to their actual consent visit to ensure fairness. This trial will be conducted in compliance with the protocol, standard operating procedures, policies, local R\&D management guidance, Good Clinical Practice including the UK Policy Framework for Health and Social Care.
Research Governance Framework 2005 (2nd edition)
2\. Rationale
Given the ethical imperative to ensure patients understand the nature and conduct of clinical trials, the clearly documented lack of understanding in the literature, we propose this trial to examine whether a pragmatic and deliverable program of "enhanced" informed consent can impact upon patient objective and subjective understanding. The first part of this enhanced consent will be a summary PIS (example attached in appendix) which contains the absolutely necessary information for patients - we have already conducted a qualitative study of patient focus groups and have asked patients directly their priorities. The top three priorities identified patients were
1. Will this trial work for me?
2. What are the side effects?
3. How often do I have to come? This will consist of an easy to understand flowchart.
The second part of this enhanced consent will be an online link to 10 video modules (transcripts attached in appendix) covering key areas of the consent. During the development process of these educational tools, we performed a qualitative analysis of transcripts of interviews of consultants, study managers, clinical fellows, clinical research nurses and patients of the DDU and identified the key areas that the various stakeholders wished to communicate to patients. We asked about the key areas that need to be communicated, common areas of misunderstanding and preferred ways forward of improving patient understanding.
