Ethical considerations in the biomedical research: analysis of national biomedical research ethics guidelines in Iran.

The national guidelines for biomedical research ethics are approved by the "National Committee for Ethics in Biomedical Research" at the Iranian Ministry of Health and Medical Education as the regulatory body for biomedical research in the country. The focus of these guidelines should be on the ethical issues related to different stages of the research process, which would lead to increased research integrity and better supervision of research activities. The present study analyzed the contents of these national guidelines to clarify the ethical considerations connected to the five stages of a research process including 1) proposing, 2) approval, 3) operation, 4) documentation and 5) publishing. The findings showed that the assessed guidelines laid more emphasis on the ethical considerations related to the research operation stage rather than the proposal stage. In other words, activities such as identification of the research problem, formulation of hypotheses and questions, financial evaluation, data analysis and data interpretation did not receive adequate attention in these guidelines. Most of the guidelines presented subject categories such as the rights of participants and supervisory considerations in the "research operation stage", ethical considerations in the "evaluation and approval procedure stage", and editorial responsibilities in the "research review and publication stage". In general, despite noticeable content for guiding researchers for ethical conduction of research the national guidelines are not adequately developed to cover comprehensive and sufficient ethical considerations regarding all the activities of research.


Introduction
Ethical codes stipulated in research ethics standards include responsibilities and considerations that are set to prevent violation of research integrity during the research process. These ethical considerations must be extended to all research activities from research design to publication (1), because every stage of the research process is prone to irresponsible behaviors and research misconducts, which can cause deviations in research activities (2,3). Despite the development of standards for research ethics, however, researchers encounter additional challenges that are not specifically addressed in the standards; such inadequacies may jeopardize research integrity and increase the risk of misconducts in all stages of the research process (4).
Thus, one of the most important functions of research systems is to develop ethical standards for all research activities from research design to publication (5). Due to the significance of following these standards throughout research stages, most developed countries exercise systematic supervision over all stages of the research process (6). The Iranian Ministry of Health and Medical Education (MOHME) has approved national guidelines for biomedical research ethics as a comprehensive framework of ethical considerations to improve research quality. These guidelines focus on the necessity and importance of observing research ethics standards not only in publication, but in all research stages (7).
The ultimate goal of research ethics standards, including guidelines and instructions, is to develop and modify a comprehensive framework for ethical responsibilities and considerations in research (7). Therefore, assessing the content of officially approved guidelines for research ethics allows us to understand the present state of the considerations already issued by MOHME as the main authority. A number of studies have been conducted to investigate the research ethics in Iran and have proposed ethical considerations for different stages of the research process (1,5), but they have not addressed the ethical considerations related to activities in biomedical research. The present study, however, tried to investigate the research ethics guidelines approved by MOHME to assess implementation of the ethical considerations in various stages of the research process. In other words, it aimed to determine which activities of the research process have received more attention in the guidelines, and what ethical considerations pertain to each stage of research. In order to perform a solid and accurate analysis of the ethical considerations related to research stages in the guidelines for research ethics, it is essential that we acquire a deep understanding of the research process in the biomedical research environment in Iran. Previously (8), we described the process of biomedical research in five stages and fifteen steps (Figure 1), and the present study adopted this framework to investigate ethical considerations in research.

Methods
For a textual investigation of research ethics standards, a qualitative content analysis was used to examine the text of the codes and general and specialized guidelines approved by MOHME. Additionally, the concept of a multi-stage research process was used to formulate the ethical considerations in research (5). Stages of the research process in Figure 1 were considered as predefined categories for recording information. Because of these predefined categories, we employed directed content analysis, which is more systematic than other methods of content analysis (9). The units of analysis included concepts of the ethical considerations stipulated in the ethical codes of the guidelines, where information such as ethical considerations is categorized based on the stages of the research process. Ethical considerations included behaviors that one must or must not engage in and are clearly pointed out in the codes of ethical conducts (10), for instance, the obligation of researchers to fully inform research participants about the benefits and risks of their study. Accordingly, we tried to extract the concepts and considerations implicitly mentioned in the ethical codes and match these concepts with the stages of the research process.
Open and axial coding were used to extract and collect data. In open coding, the information stipulated in the ethical codes was segmented into independent concepts.
The results of open coding are shown in Table 2. The extracted concepts of the ethical considerations are categorized in the steps of the research process as depicted in Table 2. For axial coding, the results of open coding were reorganized and subdivided into subcategories. The results of axial coding are shown in Table 3, where the stages of the research process are presented as the main categories, and issues such as financial contracts or the rights of research participants as the subcategories. Finally, two medical ethics experts who were familiar with research ethics guidelines and the coding process were asked to evaluate the validity of the data collection and analysis.

Results
In this study, thirteen documents, all in Farsi and available through the website of the "National Committee for Ethics in Biomedical Research of Iran" were reviewed for content analysis during 2017 (Table 1).  Ultimately, duplicate and similar codes were merged.

Research Proposal
Analysis of the standards indicated that the  (Table 2).
Predicting and introducing a clearly defined protocol to ensure confidentiality and security of information 1,2,3,7,9,12 Determining and predicting follow-up with human subjects after study completion 1,2,3,7,9,12 Determining the exact location of the research site in the research proposal 1,2,3,7,9,12 Registering the proposals for clinical trials on the IRCT 1,2,3,7,9,12 Following official criteria and ethical codes while signing a contract with financial sponsors 1,2,3,7,9,12 Declining the financial sponsor's condition to remove or not publish undesirable findings in the contract between the researcher(s) and the financial sponsor 1,2,3,7,9,12 Declining the financial sponsor's condition to not declare conflict of interests in the research report in the contract between the researcher(s) and the financial sponsor 1,2,3,7,9,12  (Table 3).

Research
Step

Research
Step

Research Operation
The codes related to 'data collection' focused on accessibility and confidentiality of the information collected from participants, informed consent, protection of study subjects, and supervision of the study.
Text of the standards for other stages including 'data analyses and 'data interpretation' did not contain any specific details (Table 4).

Research
Step

Research
Step

Research
Step

Research Review and Publication
Activities  Table 6). Addressing complaints about the submission process or other stages in the procedures required by the journal

Acceptance for Publication
Respecting the editor's independence in accepting or rejecting manuscripts Ensuring confidentiality of the information of individuals and patients following publication of the article Referring issues and decision-making about publishing the identity of participants in the study to the research ethics committee Not forcing the authors to cite studies published in the previous volumes of the journal Asking the corresponding author to determine the contribution of all authors involved in a study Providing the conditions for publication of studies that use the right methodologies and produce undesirable results

Publication of Research
Editor and editorial board member' participation as author only in 20% of the articles of the journal Providing readers with the opportunity to criticize published papers Preventing placement of advertisements aimed at attracting readers by providing non-scientific and false information

1.All ethical codes are related to Guideline No. 1
In addition to classifying the considerations according to stages of the research process, an attempt was made to categorize these considerations deductively to obtain a better description of guidelines and instructions for each stage. As can be seen in Table 7

Research Design Considerations
Observing intellectual property rights when using research ideas proposed by others in proposals Observing publication ethics standards, ethical codes, and research regulations in preparing research proposals Promoting human health while respecting human dignity and rights as the main aim of research Conducting research based on a pre-defined proposal Preparing protocols for clinical trials Preparing informed consent forms Predicting and introducing a clearly defined protocol to ensure confidentiality and security of information Determining and predicting follow-up on human subjects after study completion

Research Financial Contracts
Following official criteria and ethical codes while signing a contract with financial sponsors Declining the financial sponsor's condition to remove or not publish undesirable findings in the contract between the researcher(s) and the financial sponsor Declining the financial sponsor's condition to not declare conflict of interests in the research report in the contract between the researcher(s) and the financial sponsor

Scientific Criteria
Evaluating and approving the scientific aspects and methodology of research proposals Disclosing conflict of interests of members of the scientific committee in relationship to the researchers and financial sponsors

Conflict of Interests for Research Evaluation
Declaring conflict of interests between members of the research ethics committee, and researchers and financial sponsors Disclosure of financial sponsors' identity by researchers Declaring conflict of interests among the researchers in a research team

Accessibility of Health Information
Clarification and facilitation of access to health data Appropriate registration, application and storage of health data Maintaining privacy in providing health information to researchers by health institutions or health databases Not requesting a share of research (such as author's rights) solely due to ownership and provision of health data Sharing health data

Rights of Research Participants
Providing human subjects of any information that may affect their decision to take part in research

Author's Task
Avoiding author's name fabrication (i.e., removing qualified names and adding unqualified names) Accountability of all authors regarding accuracy of the manuscript Assuming responsibility in terms of the general and specialized research ethics guidelines in research reports Authors' assurance of the capability of all persons involved in the research Informing all contributors and adjusting the final manuscript to include their names in the authors' list Avoiding services such as those that type hand-written texts and submit manuscripts to journals Avoiding reference to oneself or others for the sole purpose of increasing the number of irrelevant references Informing the journal to cancel publication before approval of the manuscript Considering the authors' freedom to select scientific journals for the publication of their articles

Intellectual Property Rights of Stakeholders
Observing the author's rights based on the four authoring conditions Observing the order of the authors' names based on their level of participation and by collective agreement Selecting the individual with the largest share in the presentation of the research idea as the first author Mentioning authors' affiliation when submitting the manuscript to a journal Mentioning the reference when citing a text or its translated counterpart, conclusion, summary or ideas

Category
Related considerations stipulated in the ethical codes Asking the permission of intellectual property owners to use tables, questionnaires and texts Making citations in agreement with the intention of the original authors Avoiding verbatim or partial plagiarism from articles or proposals by other authors Avoiding duplicate submission and publication of overlapping manuscripts in different journals Informing editors of journals about reprint of a paper published in another languages Obtaining informed consent from human subjects for publishing their data Preserving the confidentiality and privacy of individuals and their information when publishing research results

Clarity of Research Results
Publishing and making research results available in an accurate, timely and appropriate manner for other stakeholders Disclosure of negative and positive results as well as the side effects of the research Avoiding authors from limiting publication of research results due to issues such as sensitivity of the study participants, negative social consequences, or financial sponsors requests

Conflict of Interests for Authors
Declaring any potential conflict of interests among manuscript authors Declaring any conflict of interests arising from the contract between the researchers and financial sponsors Disclosing the organizational affiliation of authors Disclosing the financial resources of the research

Discussion
The guidelines for biomedical research ethics offered by MOHME as the main authority may serve as a means to prevent research deviations and enhance supervision over research activities. However, our findings showed that the existing ethical considerations are not adequately developed to cover different activities in various stages of the research process. These guidelines do not provide comprehensive and sufficient insight about the ethical responsibilities and considerations related to all activities of the research process.
Research ethics guidelines have mainly focused on the stages of research operation, reporting and publication. One reason for this could be the dominant approach of corresponding authorities to the approval and supervision of the research activities related to these stages. Furthermore, prevention and control of research misconducts are not supervised continuously during the research process (11). As the stage of 'research review and publication' is more vulnerable to misconduct, it has received a lot of attention in the form of supervisory measures. Evident manifestations of research misconduct have received the most supervision by research ethics committees in universities and have been especially emphasized in research ethics standards. They are mainly comprised of deviations in the reporting and publication stages including plagiarism, data fabrication, data falsification, re-publication and overlapping of research results. Nevertheless, research misconduct constitutes an expansive range of irresponsible behaviors and is not just limited to the reporting and publication stages (12,13). Thus, it seems that in dealing with various representations of misconduct in the research process, it would be better to benefit from a more practical solution in view of the ethical considerations in research ethics guidelines.
The study results showed that the majority of these guidelines pay great attention to the rights of research participants including informed consent, ensuring the health and security of human subjects, preserving human dignity, subjects' physical and mental integrity, maintaining confidentiality of the subjects' information, and taking care of vulnerable groups. Research standards emphasize free and informed consent as well as a net balance of benefits over harms for all participants (14). Consistent with present findings, a study on the guidelines, regulations, and ethical codes of Arab countries in the Middle East by Alahmad et al. indicated that scientific validity and obligations for informed consent, confidentiality, and the balance of benefits and risks are mentioned in most of the documents (15).
In the examined research ethics standards, ethical considerations about pre-research activities such as research motives, research problems, and planning research design were less emphasized. There were very limited ethical codes related to research problems, which could be due to intangibility of some activities, and the low potential of certain issues for supervision and monitoring at this stage. Thus, research should be conducted based on the needs of health-care providers, and this is an ethical obligation for researchers also highlighted in research ethics guidelines and instructions. Notwithstanding, this matter has been neglected in research ethical codes. In other words, the relationship between research, the researcher and community research needs are overlooked. Lack of research in the field of health and medical sciences based on national and local needs and insufficient application of national research results are among the most notable problems that affect the effectiveness and efficiency of research in this domain (16). Therefore, it seems that ethical codes could serve as an indirect and useful intervention in the process of conducting research based on local needs. Indeed, in addition to a lack of need-based research, the proclivity of faculty promotion regulations and other research protocols toward quantitative measures may solely motivate researchers toward research results publication and earning quantitative privileges (17,18).
Another important issue that requires more attention is related to financial contracts. Some cases of research misconduct have been reported following the demand and pressure of financial sponsors for publishing desirable results. This is because the conditions and shares of parties (researchers and financial sponsors) are not clarified in contracts, and research ethics committees do not examine the contracts meticulously enough (19,20). It is necessary to define and clarify the conditions and shares of financial sponsors in research ethical codes. Another important point in research guidelines is the accessibility of data and information for researchers. Limitations in existing research ethics guidelines have subjected researchers to situations where owners of data or equipment make unjust and unconventional demands in return for access to information. Therefore, it is essential that officials and administrators develop independent guidelines and instructions to clarify the conditions and requirements for sharing health data and accessibility of data for research stakeholders.
Lack of ethical codes in the 'review of research proposal' stage is another issue that should be taken into account. The challenging issue that still remains unresolved is whether or not research ethics committees should attend the sessions for scientific evaluation of proposals. The scientific criteria mentioned in ethical codes are limited to methodology of research proposals and conflict of interests among research committees. It is necessary that the scientific review be conducted strictly because much of the deviations in the following stages including inappropriate criteria for inclusion and exclusion of participants or lower statistical power occur because of incorrect projection of the research process. The necessity for involvement of methodology and statistics experts in research ethics committees also attests the importance of scientific standards in research evaluation and approval. Generally speaking, scientific and ethical evaluations cannot be separated, and the research ethics committee naturally needs to consider these two simultaneously. According to the Declaration of Helsinky, medical research on human beings should follow approved and scientific principles and be based on comprehensive knowledge of scientific texts, related resources, laboratory experimentations and animal trials if necessary (21). Furthermore, failure to address issues of research methodology is evident in some activities in the 'research operation' stage. There was no ethical code for data analysis and data interpretation in the guidelines. In the end, it should be added that activities including quality control of research data or careful handling of statistical premises that entail serious ethical considerations may lead to research misconduct )22).

Conclusion
The contents of research ethics guidelines affect their interpretation and application, and therefore modifying and improving them can enhance their usage, prevent research misconducts and improve supervision of the research process. Although national research ethics guidelines stress the necessity of research integrity, a current evaluation of the guidelines approved by MOHME indicated that ethical considerations are not adequately developed to cover different activities involved in various stages of the research process. In order to implement a systematic supervision approach throughout the research process, it is necessary that responsible authorities revise and modify the existing research ethics guidelines. Thus, research ethics committees will consider these responsibilities and considerations in their supervisory function, and other stakeholders will be informed about the ethical considerations related to them.

Required
ethical considerations are extensive and should be observed throughout the research process, and the need for a comprehensive framework to organize these considerations is clear. Since studies on research integrity in the field of biomedical research have failed to describe it, the present study attempted to make its contribution by investigating the ethical considerations involved in the research process. The results of this study provide a better understanding of the basic function of the Iranian biomedical research system in the development of ethical standards for research. So far, studies on biomedical research ethics in Iran have been exclusively limited to investigations into researchers' observation of research ethics standards and considerations in their publications. Therefore, it seems that future studies must identify all research ethics considerations and the responsibilities involved in the research process. Furthermore, stakeholders could discover the pertinent inadequacies that can be overcome and modified in research ethics guidelines.