Discussion of solutions to ethical issues in real-world study

Abstract

In recent years, the paradigm of real-world study (RWS) has been at the forefront of clinical research worldwide, particularly in the field of traditional Chinese medicine. In this paper, basic features and nature of real-world clinical studies are discussed, and ethical issues in different stages of RWS are raised and reviewed. Moreover, some preliminary solutions to these issues, such as protecting subjects during the process of RWS and performing ethical review, are presented based on recent practices and basic ethical rules to improve the scientific validity and ethical level of RWS.

Keywords

real-world study / ethics / strategy

Introduction

In recent years, real-world study (RWS) has been at the forefront of clinical research all over the world, particularly in the field of traditional Chinese medicine (TCM). The concept of RWS has been presented on the basis of pragmatic randomized controlled trials in which “real-world samples” are used as representations of the actual world population. This method was first used to monitor the adverse reactions of humans to medications. Adverse events that occurred in clinical application are analyzed via pharmacoepidemiology analytical methods to identify whether they are indeed negative reactions or not [1]. Subsequently, RWS was used to re-evaluate the efficacy and safety of marketed drugs, as well as re-evaluate medical interventions to examine their effectiveness in conditions without limitations [2].

Baoyan Liu et al. proposed a real-world clinical research paradigm for TCM based on the integration of clinical practice and scientific research. The main feature of RWS is collaboration among patient-centered, data-oriented, and problem-driven techniques, alternated with applications of medical (clinical) practice and scientific computing [3]. In this paper, ethical issues and solutions to these problems in the RWS paradigm are discussed.

Basic features and nature of real-world clinical studies

The RWS paradigm has three core elements. The first is compliance with actual clinical practice without limitation in the treatment process. The second is building a structured information collection and analysis system through which information on clinical practice and scientific research can be shared. The last is combining medical practice and scientific computing to solve practical problems through extensive data mining.

Clinical research is significantly different from clinical practice. The purpose of clinical research is to create or increase universal knowledge, and the purpose of clinical practice is to meet the needs of individuals or specific groups of people [4]. The Belmont Report, published in 1979, describes the difference between practice and research as follows, “For the most part, the term ‘practice’ refers to interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide diagnosis, preventive treatment, or therapy to particular individuals. By contrast, the term ‘research’ designates an activity designed to test a hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships). Research is usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective” [5].

As mentioned, real-world clinical research is based on the idea of integrating clinical practice and research. The participants in RWS include both clinicians and investigators. From a subjective point of view, the goal of doctors in RWS is not different from that of doctors in regular practice. From an objective point of view, the risk faced by RWS subjects is not higher than the risk they face in clinical practice, and their interests are not affected either. Therefore, real-world clinical studies have the same characteristics as clinical practice. In fact, the process of clinical practice is also a research process. Clinicians prepare the most effective treatment plan for each patient by thoroughly considering clinical manifestation (i.e., patients’ signs and symptoms), best evidence, as well as personal experience and preference of patients. Then, clinical capability is enhanced through continuous practice, and a summary is made after a large number of patients are treated. RWS is based on comprehensive studies using massive data collected during the process of clinical practice. RWS is a continuation of clinical practice. Therefore, further studies on ethical principles in real-world TCM research are expected to provide guidance for establishing ethical review technology and RWS methods that have practical value.

Main ethical issues in real-world clinical studies

A complete RWS can be divided into three stages: data collection, data calculation, and publication of results. Each stage involves different ethical issues.

First, the process of data collection in RWS is conducted simultaneously with clinical practice. According to some experts, patients become subjects of RWS once their data are collected and a study is conducted. Other experts believe that patients whose information has been collected into the clinical research information integration system are subjects right from the beginning because their information is likely to become research data. In any case, informed consent is a key issue at this stage. When the clinical research information integration system is used, avoiding an increase in the workload of clinicians should be considered.

Another key issue at the data collection and calculation stages is information security because RWS uses a structured electronic medical record system to regularly gather relevant information during medical practice. Through this system, some clinical information, particularly TCM signs and symptoms, can be automatically standardized and transformed into structured data. Clinical data from various research institutions are then transmitted to the data center through a number of methods, including the Internet [6]. Problems that occur in any of these methods may lead to information leakage, and may cause psychological, physical, and economic damage to the subjects. Using online networks, as well as transmitting data and distributing authority in an electronic medical record system, pose challenges to data security. The following issues also have to be carefully studied: initial data acquisition, setting up of different administrative authorities, information availability, ensuring information security, and preventing psychological or social influence on subjects.

At the result publishing stage, several questions have to be discussed. For example, which type of information can be published and which cannot? Do the subjects have to be informed about the results of the study? How can the benefits of research findings be shared? What benefits and risks do the subjects face during the course of benefit sharing?

Solutions to ethical issues in RWS

Since clinical practice, real-world clinical research, and clinical trials differ from each other and are closely linked at the same time, we have to understand and clarify the relationship among the three so that we can distinguish between the types of responsibilities associated with each one and protect the rights of involved parties.

According to preliminary exploration and practice, the ethical review of RWS should not only follow the general principle of medical ethics and medical research ethics, but also consider the synchronization of medical practice with distinct methods of communication with subjects, wherein patients provide the researchers with data. In addition to gradually building up a human research protection system that consists of governor, clinician, investigator, and sponsor [7], we can also consider the following principles and methods when reviewing RWS.

Ethical review system

Real-world TCM clinical studies conducted in clinical research institutions and non-clinical independent research institutions should be reviewed.

In the Code of Federal Regulations (45 CFR 46), six types of research can be exempted from ethical review. Two of them are those with a data source that is publicly available and those with subjects that cannot be identified [8]. In regulations published by the Ministry of Health of China, China Food and Drug Administration, and State Administration of Traditional Chinese Medicine of China, exemption from ethical review is not mentioned [9].

Since all of the data collected in RWS are obtained from clinical practice, the risk involved is minimal. Only medical practice information is collected, and the identity of vulnerable groups, as well as personal and sensitive issues, is not included. Expedited review procedures can be accepted, but the ethics committee, not the investigators, must decide whether the risk is minimal or which among the studies must be reviewed prospectively.

Clarifying the value and scientific validity of a study

A reasonable clinical study must have a definite or potential social, scientific, or clinical value. The value of a study does not depend on whether the statistical result is meaningful or not, but on the significance of the input to knowledge or on the ability of the study to solve practical problems. Unreasonable design, inadequate data, and inappropriate or infeasible methods lead to meaningless risks and waste of manpower and material resources. The data used in RWS are massive and entail significant investigative work. As a result, large amounts of waste data are left. So, how can a valuable, reasonable, and feasible protocol be created?

Fair subject selection

The Belmont Report points out that the principle of fairness is embedded in procedures and outcomes in the selection of research subjects [5]. Fair subject selection can prevent exploitation of vulnerable individuals and groups, as well as promote equitable distribution of research burden and benefit. The subjects of RWS are the patients in clinical practice. No research intervention occurs during the treatment, so the lack of fairness can be avoided at this stage. However, for a specific RWS, investigators have to set inclusion criteria and select suitable subjects without bias to ensure the scientific validity of the results and avoid injustice of risk acceptance caused by the publication of results.

Information security and privacy protection

Although RWS does not change the actual clinical practice process for subjects, their inclusion in a study and the collection of their biological sample data pose potential psychological and social risks to them. Therefore, information security and privacy protection should be reinforced to protect subjects.

First of all, appropriate measures should be taken to ensure the security of the information [10]. For example, the data in the clinical research integration system should be encrypted. A firewall should be updated regularly to protect the computer system and prevent invasion by unauthorized users. The data collection system, database, and data analysis system may be installed in different servers to improve the data security level. Private information of patients, particularly information without direct relation to medicine, should be encrypted and hidden during data transmission and application.

Second, each user should have only one unique account in the entire system. Different roles should have different levels of authority. For example, clinicians have access only to the information of their own patients. Meanwhile, investigators can extract all the information they need, but the type and scope of data are limited, and the investigators cannot get the contact information. In other words, the researchers can obtain only the relevant information.

Specialized research databases or strict extraction rules should be established in the clinical research integration system. A skilled worker responsible for coding is necessary. This worker can access the subject codes and other identifiable personal information, such as names and contact details, and then encode and convert this information but not access medical information. Data cleansing, removal of identifiers, and encryption are necessary to eliminate or hide the identifiable personal information that may be traced back to specific subjects and may cause harm to them if disclosed. This type of information includes name, ID number, phone number, medical record number, facial image, fingerprints, voice, and so on [11].

Different conditions of informed consent

The importance of informed consent has been emphasized in all related national and international laws, regulations, and guidelines. Informed consent is a widely recognized method to protect research subjects because it reflects the principles of fairness and respect. Subjects have the right to be fully informed and to make their own choices. All of the patients involved in the clinical research information integration system should be informed of the possibility that relevant information about them may be used in a particular study. The scope of application of this information, the workers who can access the information, and the patients themselves should be assured of their privacy and information security.

The conduct of RWS is based on the clinical research information integration system. Obtaining informed consent from each individual is difficult. However, informed consent may be obtained by setting up different requirements for different conditions.

With regard to the subjects of a prospective study, although no intervention is given and only their data are used, the Declaration of Helsinki states the following: “For medical research using identifiable human material or data, such as research on material or data contained in biobanks or similar repositories, physicians must seek informed consent for [their] collection, storage, and/or reuse” [12]. Thus, informed consents of patients are needed, and the patients should be assured that their treatment will not be affected even if they refuse to participate in the study. Their decision to opt in or out of the study will be respected, their personal information will not be revealed, and they can withdraw or quit at any time. If patients have a different opinion on using their information, clinicians should indicate it in the clinical research integration system and only provide regular treatment to the patient. The patient information cannot be used in any study. If the study results may have a significant effect on the subjects, the researchers should try to inform them to the best of their ability.

For retrospective studies, a waiver of informed consent can be considered if health information and biological materials taken in the course of clinical care are used, and the following criteria are met: the objective of the study is important, the risk is minimal, a waiver of informed consent will not threaten the rights and health of the subjects, privacy and personal information is well protected, and requiring informed consent is impracticable. Also, the records and specimens of individuals who have specifically rejected such uses in the past may be used only in the case of public health emergencies [13].

Other solutions

When the study results are published, special actions should be taken to protect the safety of subjects. For example, valuable results should be published and shared with the public, but personal information should remain undisclosed.

In addition, substantial training should be given to medical workers and researchers involved in RWS to strengthen their sense of morality, research integrity, and responsibility, as well as clarify their obligations and responsibilities, help them to form a legal concept of protection for subjects, encourage them to pay attention to psychological and physical risks to subjects, and make them aware of the importance of privacy protection and informed consent.

Furthermore, for studies that use data on human biological samples, ethical principles and regulations of establishment and using of a human biological sample library should be followed strictly.

Prospects

Throughout the history of bioethics, from the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report to the latest guidelines and regulations, ethics have developed in the process of searching for solutions to issues related to new areas and methods. This process is also a course of finding better approaches to achieve the vision of “respect, beneficence, and justice” [5] in a consistently balanced process.

As the RWS paradigm is used in a larger scale, it is expected to pose more challenges to medical research ethics, clinical ethics, and bioethics. The following issues are likely to surface: how to understand the inseparable relationship between medical practice and scientific research, the particularity of clinical studies that are combined with clinical practice, and the position of practice and research after being integrated; how to improve the ethical review capacity to ensure the legality, advanced nature, and ethics of RWS; how to assess the risks and benefits for ordinary patients as subjects; and how to obtain informed consent in an appropriate manner [14]. Relevant laws, regulations, and operating procedures are likely to expand in scope. Eventually, a new branch of ethics focusing on RWS may emerge.

Although a relatively complete paradigm and technological system for real-world clinical study has been established, it is still at the development stage. The methodology is constantly being improved and ethical problems need further investigation to find better solutions. What can be done at present is to combine traditional Chinese culture and features of traditional medical practice with international ethical rules based on an ethical review system for TCM clinical studies so that more solutions to relevant problems in RWS may be considered [15]. The objective is to contribute to the promotion of life sciences, including traditional medicine, and achieve the goal of “unity but not uniformity” in the field of life sciences [16].

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