Explanation Thinking about Risk Communication -Outline of Risk Communication and the Ideal Consent Declaration Document

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The Pharmaceutical Manufacturers Association of Japan, Drug Evaluation Committee, Data Science Subcommittee, Task Force 5-2 in FY2021 / Continuing Task Force 5-2 in FY2022
Hironori Sakai, Eisai; Yasushi Komiyama, Pfizer; Hiroshi Kourei, Eisai; Masamichi Ueda, Chugai Pharmaceutical

Risk Communication (RC) is a process of interaction between individuals and groups to exchange information and opinions about risks. In obtaining consent for participation in clinical trials, we interviewed patients from the perspective of RC and the opinions of clinical trial coordinators who review the contents together with patients regarding the consent explanation document that clearly outlines the trial and its risks to patients. This paper presents an overview of the results of the survey and the findings of other drug-related documents such as the package inserts. We hope that this paper will serve as a starting point for RC discussions in drug development and drug development.

Why Risk Communication?

Patient-centered medicine and drug development based on the patient's voice are now global trends. At the International Conference on Harmonization of Pharmaceutical Regulations (ICH), one of the important themes of GCP Renovation, the first major revision of Good Clinical Practice (GCP) in a quarter of a century, is the reflection of patients' voices in drug evaluation. In addition, discussions on patient-centered drug development are continuing separately.

For the pharmaceutical industry, patients are essentially the end customers and partners in drug development that continues from drug development to post-marketing. However, when scientific approach, commercialism, and regulatory compliance are emphasized, a situation arises in which sincere concern for patients is considered secondary.

In the profile of a drug, the benefits are specified and can be explained relatively easily, although the benefits may be small or large depending on patient and environmental factors. Risks, however, are subject to a wide variety of events, and the evaluation of the causal relationship between the drug and the event, as well as the weight of the related evidence, make communication a difficult task.

In order to realize patient-centered drug development, drug development, and marketing activities, it is important to listen to the voices of patients and reflect them in the planning, implementation, and operation of research and activities, and communication with patients (individual patients or patient groups representing their opinions) should be the cornerstone of such communication. Communication with patients (either individual patients or patient groups representing their views) should be the cornerstone of such communication.

What is Risk Communication?

Risk as a general term is defined by the Oxford English Dictionary as the possibility that something bad may happen at some time in the future. 　In the medical and R&D fields, risk is used in two main senses: as a risk that something bad may happen at some time in the future, and as a risk that something bad may happen in the future.

This paper focuses on (2).

Risk is defined as the combination of the likelihood that an event will occur and the severity of that event, or the product if a quantitative approach is used.

In RC with patients, it is important to clarify whether you are trying to communicate the risk as a group or as an individual patient. Otherwise, it may not ring true for the individual patient, and interactive communication becomes difficult.

The risk to the patient of a pharmaceutical product is a relative concept. The severity of the same event (e.g., vomiting, headache, etc.) varies depending on whether the expected benefit is prolonged survival, relief of severe symptoms, or improvement of symptoms that do not significantly affect life or livelihood, and consequently the size of the risk. Individual patients may perceive the possibility (probability) differently; they may or may not be willing to accept the risk of an adverse reaction occurring in 1 in 10 patients. There is also a low-frequency probability that even cautious and rational people can act as if the probability is zero, even if the occurrence of the event is considered a great misfortune for the individual.

The origin of the concept of RC may be found in the 1989 National Research Council (NRC) report, "Improving Risk Communication, " *1 which defines RC as "an interactive process of exchanging information and opinions about risk among individuals, institutions, and groups. The NRC report defines RC as "an interactive process for exchanging information and opinions about risk among individuals, institutions, and groups. RC is also defined as a process of democratic dialogue that includes not only scientific and technical information and professional views on risk, but also a description of measures, policies, and institutions for risk management and their rationale, as well as the views of stakeholders and their personal opinions and sentiments on risk. In other words, RC is a process that is carried out by each member of society. In other words, RC is an activity to share diverse information and perspectives on risks and benefits, as well as their governance, and to foster trust through dialogue, thinking together, and collaboration among all segments of society.

In RC, seven elements are listed*2.

（Systemic risk in (7) refers to risks that are highly interdependent among themselves and among various background factors. In other words, modern risks are complex risks, requiring analysis from a comprehensive perspective that includes social factors and impacts, and inclusive governance across government, industry, academia, and civil society, rather than considering only single risks and their causal relationships.

RC is often conducted between experts and non-experts. Experts often believe that the general public does not understand the professional content of science and technology, its risks, and risk management, and therefore has an emotional and subjective perception of them. Therefore, they tend to believe that if correct knowledge is conveyed in an easy-to-understand manner and understood, their concerns and resistance will be resolved.

This idea that the general public lacks knowledge, which must be compensated for by experts, is called the "deficit model. Often, the deficit model is not only unhelpful, but also runs the risk of amplifying people's dissatisfaction and distrust. Therefore, the international trend has been to move away from a style that relies on the deficit model (public understanding of science) and toward dialogue, collaboration, and citizen participation in policy making. Today, the emphasis is on interactive and interactional "Public Engagement with Science and Technology.

The basis of RC is communication, and without an understanding of proper communication, proper RC cannot be implemented. Risk judgments and decisions are made under conditions of uncertainty, and collecting and analyzing information for all the various situations can be very costly. Therefore, it is often acceptable to use heuristics (simple and intuitive strategies used to make judgments and decisions under uncertain circumstances) to make broad judgments, although they do not always result in accurate judgments and decisions.

In RC, it is essential to keep in mind that the message should be easy to understand. To this end, it is important to always keep in mind that non-specialists are the target audience, for example, by using images and illustrations in addition to language, and by using plain language and avoiding jargon and katakana words. It is also important to allow recipients to verify the basis for information that is uncertain or of differing views (MEXT Committee on Science, Technology and Society for Safety and Security, 2014). To this end, prompt disclosure of the basis for risk information, the review process, and the revision/updating history of the information should be proactively made. As for studies and innovations regarding the presentation of probability information, it is necessary to devise numerical expressions of probability that are easy for the general public to understand. For example, when we say, "There is a 1% probability that an earthquake of intensity 6 or higher will occur in the next 30 years," most people will recognize that it will almost never happen, but in fact, earthquakes do occur. In such cases, it would be useful to present comparative incidence rates for familiar events. By presenting figures such as 0.2% of deaths from traffic accidents, 0.5% from typhoons, 3.4% from burglaries, etc. side by side, it is recognized that the occurrence of earthquakes is higher than the probability of encountering a traffic fatality.

In addition, forms of communication and the use of media appropriate to each should be considered.

Since even RC is a form of normal communication, only RC cannot work well if normal communication is not done well. For communication to work well, it is essential to have a relationship of trust on a regular basis.

The U.S. Environmental Protection Agency (EPA) provides the following basic rules for RC*3.

If these seven items are understood and shared not only in RC but also in communication in general, consent documents, etc., which tend to be systematic and inorganic, can become documents that are heartfelt to patients.

The main points of RC are (1) to (4),

The basic spirit that runs through all of (1) through (4) is

(1) to (4).

Figure 1 shows the outline of risk management for pharmaceutical products.

Figure 1 Risk Management of Pharmaceuticals
Source: Modified from Fujita, Sakai, Komiyama, and Tsubaki (2006) Risk Analysis Strategy Center, The Institute of Statistical Mathematics meeting materials

Consent Declaration (ICF) from a Risk Communication perspective

ICF was taken up as a case study from the perspective of RC, and in order to analyze the current status of ICF, we focused on the ICF template that is publicly available and discussed it. In addition, interviews were conducted with Clinical Research Coordinators (CRCs) and patient groups, and after presenting the insights gained from these interviews, the task team summarized its recommendations regarding ICFs.

Examples of ICF Templates

Many insights can be gleaned from the published ICF templates. The templates for clinical trials and clinical research cover the ICF items specified by the "Ministerial Ordinance on Standards for Conducting Clinical Trials on Pharmaceuticals" (hereinafter referred to as "GCP Guidance") *5 and the "Ethical Guidelines for Life Sciences and Medical Research Involving Human Subjects" (hereinafter referred to as "Guidelines") *6 respectively. Although ICFs created using these templates meet the regulatory requirements, it is not enough to have the examples described in the templates and explanations by physicians and CRCs, and there is room for improvement toward an ideal RC.

Some pharmaceutical companies are promoting the dissemination of uniform ICF templates among themselves, and the results of a survey on ICFs conducted in 2021 suggest that while there is a need for templates, the importance of the patient perspective in the template creation process is also essential.

Pros/Cons of ICF from CRC's point of view

Using ICF as a subject, we exchanged opinions with five CRCs on how to explain to patients and others when obtaining written consent, what they consider to be issues, or what to focus on when aiming for better RCs, and received useful suggestions.

What was repeatedly mentioned by several of them was the suggestion that "it would be better to make the content of the ICF more meaningful, rather than listing the items required by regulatory requirements. What is important is to accurately grasp what patients actually want to know, rather than what the sponsor or explainer thinks "patients want to know. It is important to accurately grasp what the patients actually want to know, not what the sponsor or the explainer thinks they want to know. It is also essential for the RC to reach a sufficient consensus among the patient, the explainer, and the sponsor on the level of risk that needs to be explained (shared).

What do patients want to know? It is best to create ICFs that allow patients to imagine their story after participating in a clinical trial, and to accurately grasp what they want to know. Patients may not only want to know knowledge, and it is important to fully discuss what patients really want to know, rather than creating ICFs based on what the sponsor or explainer thinks "patients want to know. It is important to fully discuss what patients really want to know.

Some patients "don't know what they don't know," so when asked, "Is there anything you don't know? we often see situations where the patient responds, "No, not at the moment" when asked. Therefore, it is beneficial to create the ICF with the viewpoint of clarifying what is not clear to the reader through the ICF.

Pros/Cons of ICF from the patient's perspective

We exchanged opinions with four representatives of patient groups, etc., on how to explain to patients and others in clinical trials or clinical research, what they consider to be issues, or what to focus on when aiming for better RC, with a focus on ICF, and received their opinions.

The age range of patients differs depending on the disease. For example, in the case of multiple myeloma, many patients are elderly. On the other hand, there are diseases specific to non-elderly people and younger people, and an ICF prepared without assuming the reader would not be appropriate as a document to promote dialogue between "patients (research participants)" and "healthcare professionals. It may lead to the creation of a good ICF simply by fully understanding what kind of patients the clinical trial or clinical research is intended for and considering what kind of readers (and who) to write for (the aforementioned basic rule (6) of RC). It is also necessary to consider factors other than age. Some patients have not yet had time to sort out their thoughts and feelings about dealing with a disease that they did not expect, because not much time has passed since their initial diagnosis, while others, for example, have been continuing treatment for more than 10 years. Even in the same clinical trial, it is impossible to create an ICF for each individual patient, given the diversity of each patient and his or her expectations for participation in a clinical trial. However, with the current emphasis on patient centricity, addressing this issue should be a top priority for pharmaceutical companies and healthcare professionals involved in conducting clinical trials when planning future trials.

It goes without saying that communication between physicians and patients is extremely important not only in clinical trials and clinical research, but also in daily medical practice. However, compared to interactions in daily medical care, communication with physicians must be even more substantial in situations where patients are considering whether or not to participate in a clinical trial.

Even when physicians believe they are communicating well with patients, communication may not be sufficient, especially with elderly patients. Patients may have difficulty expressing their true feelings to the physician because they want to communicate well and maintain a good relationship with the physician. In cases where a gap exists between physicians and patients, the CRC is expected to bridge this gap, and thus the role and significance of the CRC is significant.

Clear presentation of treatment options is equally important before and during participation in a clinical trial, but more careful explanation is required before participation in a clinical trial.

The ICF is certainly helpful to patients because they can take it home and take the time to read and understand it. It is very important that the explanation be in a form that patients can understand, and the ability of the physician or CRC to provide the explanation will be questioned, while the content of the ICF, which patients can read repeatedly by themselves, is extremely important.

There is room for ingenuity in the way risk/benefit is communicated. Even if the content of the message is the same, the reader's impression may differ depending on how it is written. While both overestimation and underestimation must be avoided, it is not a question of uniformly placing more weight on risk/benefit. Although it is often difficult to quantify the risk/benefit, the explainer is expected to make an effort to describe the risk/benefit in the ICF as clearly as possible and to explain it based on the content of the ICF. In addition, experienced CRCs have asked us, "Do ICF preparers think too much about risks? Since there is little content regarding benefits, it is easy to leave the impression that participation in clinical trials is scary". There may be a difference between the sponsor's idea of risk (hedging against litigation) and the risks that healthcare professionals "want patients to understand" (e.g., pages tend to increase when legal perspectives are included, text becomes stiff and difficult to read, etc.) ICF creators are required to provide information on risks/benefits in the "risk/benefit" section. item should be communicated in the ICF, while taking into consideration the psychological obligations*7 of the sender of the RC, it is necessary to fully discuss the content with the relevant parties.

Closing Remarks

In 2019, ICH E6 (R2) became Step 5 and was implemented in Japan.E6 (R2) newly added descriptions related to quality management and listed the following seven items as necessary initiatives in the quality management system for clinical trials as a guidance annex. These are (1) identification of critical processes and data, (2) risk identification, (3) risk assessment, (4) risk control, (5) risk communication, (6) risk review, and (7) risk reporting.

These are not independent concepts, but are strongly interrelated. Unfortunately, there are a few people who simply understand RC as "accurately communicating perceived risk information to stakeholders," as stated in the guidelines.

Finally, I would like to express my deepest gratitude to all the CRCs and representatives of patient groups for sharing their valuable opinions with me, which are not often heard in the course of normal business activities.

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