A step towards the harmonization of clinical trials inform consent forms
Authors: J. Remon, C. Ferté
Journal: Annals of Oncology (2017)

According to recent demographic projections and an aging population, the estimated annual incidence of new cases of cancer worldwide per year in 2030 will reach 22.2 million [1.Bray F. Jemal A. Grey N. et al.Global cancer transitions according to the Human Development Index (2008-2030): a population-based study.Lancet Oncol. 2012; 13: 790-801Abstract Full Text Full Text PDF PubMed Scopus (1446) Google Scholar], prompting the oncology community to deliver new cancer therapies with substantial benefit for patients and society. Randomized clinical trials (RCTs) provide the strongest evidence of therapeutic effectiveness in medicine, including oncology [2.Cherny N.I. Sullivan R. Dafni U. et al.A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).Ann Oncol. 2015; 26: 1547-1573Abstract Full Text Full Text PDF PubMed Scopus (532) Google Scholar]. Such studies are therefore mandatory for the approval of novel therapeutic strategies by regulatory agencies. Although the trial enrolment rate increased by almost 50% from 1996 to 2002 among cancer patients, it has been consistently estimated that fewer than one in 20 (5%) adult patients with cancer (breast, colorectal, lung and prostate) are enrolled in cancer RCTs [3.Murthy V.H. Krumholz H.M. Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities.JAMA. 2004; 291: 2720-2726Crossref PubMed Scopus (1492) Google Scholar]. Successful completion of a RCT is dependent on informed consent (IC) acquisition from patients. Interestingly, up to 40% of patients do not understand current IC documents [4.Davis T.C. Holcombe R.F. Berkel H.J. et al.Informed consent for clinical trials: a comparative study of standard versus simplified forms.J Natl Cancer Inst. 1998; 90: 668-674Crossref PubMed Scopus (222) Google Scholar] mainly because these forms are becoming increasingly lengthy and complex as language added is regulatory and legal in nature to protect the institutions conducting the research [5.Bartley C. Kaplan A. Murphy B. et al.Do patients participating in oncology clinical trials understand the informed consent form? A Brown University Oncology Research Group study.J Clin Oncol. 2012; 30: 23Google Scholar]. Understandable and non-technical IC may promote enrolment in clinical trials and hamper inclusion of patients who would not have accepted the trial if they had received more understandable information. Furthermore, the lack of homogeneity in IC [6.Koyfman S.A. Agre P. Carlisle R. et al.Consent form heterogeneity in cancer trials: the cooperative group and institutional review board gap.J Natl Cancer Inst. 2013; 105: 947-953Crossref PubMed Scopus (15) Google Scholar] hinders the standardization of a unique IC template that could be used worldwide across all oncology-related studies or even in other disciplines. In this issue of Annals of Oncology, the international Aide et Recherche en Cancérologie Digestive (ARCAD) Group propose a simplified version of IC, adapted to the specific oncology context [7.Bleiberg H. Decoster G. de Gramont A. A need to simplify informed consent documents in cancer clinical trials.Ann Oncol. 2017; 28: 922-930Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. This initiative is remarkable because of several aspects. First, this work results from the multidisciplinary collaboration of a number of clinical research experts, legal experts, linguists, etc., making the resulting document more likely to be accepted by the community. Second, the document distinguishes between the information necessary for the patient to make an informed decision, which is summarized in nine major points and no more than 1800 words, and the information not essential for the decision making-process, summarized in no more than 3000 words, creating a clear, understandable and legible document. Furthermore, the authors encourage reporting only the percentage of the main adverse events, and thus attempt to tackle the current lack of standard definition of adverse events across ICs. Although the proposed document covers the main items that are necessary to for inclusion in an IC, several points could be added in the future to improve the decision-making process from a patient point-of-view. First, it does not define how to explain the expected benefit (mainly overall survival) that a patient may obtain for participating in the trial. Second, both percentage and grade of severity of adverse events could be included rather than only the frequency of adverse events. In addition, future IC models should take into account the moving demographics of patients. In that regard, the proportion of elderly patients (≥65 years) is projected to rise from 16.0% in 2010 to 29.3% in 2060 [8.www.ilcuk.org.uk/files/Europes_Ageing_Demography.pdf (5 February 2017, date last accessed).Google Scholar], and elderly population are less likely to be enrolled in RCTs. Also, more racial and ethnic diversity is expected [3.Murthy V.H. Krumholz H.M. Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities.JAMA. 2004; 291: 2720-2726Crossref PubMed Scopus (1492) Google Scholar]. Enrolment fraction is not only dependent on the IC document and the process for delivering information for clinical trial participation is country-dependent (social, economic and cultural aspects should be kept in mind) and can also play a role in the process [9.Grady C. Enduring and emerging challenges of informed consent.N Engl J Med. 2015; 372: 855-862Crossref PubMed Scopus (207) Google Scholar]. All of these demographic changes should be kept in mind when designing a new IC and these aspects are not clearly included in the present document. Finally, the digitalization of clinical research could also be extended to ICs. This should increase the percentage of IC acquisition [10.Etoh T. Inomata M. Watanabe M. et al.Success rate of informed consent acquisition and factors influencing participation in a multicenter randomized controlled trial of laparoscopic versus open surgery for stage II/III colon cancer in Japan (JCOG0404).Asian J Endosc Surg. 2015; 8: 419-423Crossref PubMed Scopus (3) Google Scholar], and ensure the quality of clinical research procedures. Blood and tissue biopsies for identifying or validating putative predictive biomarkers with new technologies in oncology will be increasingly required in RCTs. Currently, the translational research section in IC is of great importance and should be included in the leading section. However, a challenge for IC emerges from the complexity and uncertainty of the information generated by advanced technologies, the constant reporting of new insights driven by cancer research at translational and clinical level [9.Grady C. Enduring and emerging challenges of informed consent.N Engl J Med. 2015; 372: 855-862Crossref PubMed Scopus (207) Google Scholar], and consequent issues surrounding how best to incorporate these considerations in IC documentation. It is widely accepted that improving clinical research standards is crucial to adopt reliable novel therapeutic strategies. Although improving the IC is a timely and important problem, the methodological quality of RCTs remains another unsolved pressing issue. In recent years, the lack of efficacy was the main reason for termination in up to 50% of phase II and III clinical trials, and oncology had the highest percentages of failures, with an increase from 23% for 2008 to 32% for 2015 [11.Harrison RK. Phase II and phase III failures: 2013-2015.Nat Rev Drug Discov. 2016; 15: 817-818Crossref PubMed Scopus (242) Google Scholar]. Moreover, less than one-third of contemporary RCTs with statistically significant results met clinical benefit according to ESMO thresholds for meaningful clinical benefits, representing only 15% of all published trials [12.Del Paggio J.C. Azariah B. Sullivan R. et al.Do contemporary randomized controlled trials meet ESMO thresholds for meaningful clinical benefit?.Ann Oncol. 2017; 28: 157-162Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. Not only good IC documents, but also high quality clinical trials should be a top priority in oncology for moving towards therapeutic advances. Overall, the IC model proposed by the ARCAD group is an important and noticeable first-step for improving the content and understanding of IC documentation. Demographic changes, new technologies and additional information related to the expected efficacy should be introduced into future versions of IC. Finally, and of upmost importance, further consensus and validation with other cooperative groups beyond the gastrointestinal oncology community, with global societies such as ESMO, EORTC, ASCO and even pharmaceutical representatives, will be warranted to ensure the widespread use of this new IC model. None declared.