Introduction

In October 2016, a group of researchers met under the name of Ethics and Medicines Research Group, sponsored by the Department of Bioethics of El Bosque University, Bogotá, Colombia, to agree on a research project entitled «Research Ethics Committees and the protection of participants in biomedical research residing in Latin America». Its objective was «to seek mechanisms that help strengthen the capacity of Latin American CEIS to evaluate clinical trial protocols financed by the pharmaceutical industry or by foreign research centers, and to monitor the implementation of approved protocols from a bioethics and human rights approach» ⁽¹⁾. Eight countries were present: Argentina, Brazil, Chile, Colombia, Mexico, Panama, Dominican Republic and Peru.¹ This analysis of the situation in Panama is part of the multinational project.²

1. Clinical research funded by pharmaceutical companies

Clinical research is an essential requirement for biomedical research and for the commercialization of new medicines, because it ensures that they are effective and safe for society ⁽²⁾. However, history has revealed numerous examples of abuses that gave rise to international and national standards. Among them are the Declaration of Helsinki, the recommendations of the Pan American Health Organization (PAHO) and the Organization for Science, Education and Culture (UNESCO), which have systematized the requirements for the formation of RECs, whose function is to protect participants (until now called «subjects») in clinical research ⁽³⁾.

Panama’s development is based on its capacity for trade and services, and on the fiscal advantages it offers for international investment ⁽⁴⁾. In this framework, clinical research financed by pharmaceutical companies has had a progressive increase since 1990, recruiting local researchers in the medical body with an absence of national research laws until 2019,³ but with CBI recognized by law since 2003 ⁽⁵⁾.

2. Purpose

The purpose of the study has been to evaluate the criteria, principles and regulations that guide the members of the IBC in the evaluation of clinical pharmacological and/or pharmacogenetics research sponsored by the pharmaceutical industry in Panama.

3. Method

Within the framework of the National Meeting on Research Ethics at El Bosque University in 2016 ⁽¹⁾, discussion workshops were held to carry out this proposal. This is a qualitative research, and the following instruments were used: a self-evaluation form, review of official IWC documents, their information on web pages, and semi-structured interviews that were tested prior to application.

At the time the research began in Panama, there were eight IWCs accredited by the National Bioethics Committee (CNBI). Three committees were eliminated because they did not evaluate clinical trials, and another one because it was being reorganized at that time. Letters of invitation to participate were sent to the presidents of four committees evaluating funded clinical trials: three from the public health sector⁴ and one from the private sector, and to the directors of the three public institutions for acceptance of the study. The CNBI was added, due to the relevance of its regulatory and supervisory role of the IWCs in Panama.

The necessary documentation to obtain the registration of the research in the General Directorate of the Ministry of Health and for the endorsement of the Bioethics Committee of the Social Security Fund (which did not review funded clinical studies) was submitted and obtained in October 2017. During 2017 the maximum amount of data was collected and the first results were presented in a second multicenter workshop in 2018. During 2018-2019 the field study was carried out: collection of more documentation, self-evaluation forms made to the participating CBIs and 13 interviews in the selected Committees.

The interviewees were chosen according to the established selection criteria. The interviews met the criteria of privacy, consent and confidentiality; they were recorded, transcribed, reviewed, corrected and coded. The recording, processing and analysis of the data collected followed the steps agreed upon in the general multinational protocol.

The coordinators of the multinational project reviewed all the results collected and completed the information provided at a second meeting in May 2019.⁵ All original documentation and recordings will be kept for five years after the publication of the multicountry analysis and then destroyed.

4. Results

5. Discussion

The right to life and health implies that the medicines used must be effective, safe and accessible. To this end, the medicines made available to patients, doctors and pharmacists must comply with a series of research stages before being marketed, without ignoring the stage of permanent pharmacovigilance after consumption ⁽¹⁶⁾. The history of drug research has been plagued by violations of participants’ human rights, which have led to the establishment of international laws, standards, and guidelines that have served as models for local laws and regulations ⁽³⁾. Despite these legal standards, the media report corruption scandals in clinical research, which impact on the safety of participants and then on the sick ⁽¹⁷⁾.

Indeed, the production of medicines is an important economic industry ⁽¹⁸⁾, which finds a positive echo among Panama’s economic decision makers. The Panamanian economic vision insists on the advantages of its geographical position and fiscal incentives (Cabinet Resolution No. 1, January 7, 2020). Within this framework, the installation of pharmaceutical companies in Panama «towards the position of a pharmaceutical pole» is attractive, both for the ease of distribution of medicines in the region and for «the State’s agenda for attracting direct foreign investment; for the country’s labor conditions and the good receptivity of Panamanian governments».²⁶ This facility has been preceded and accompanied by the realization of clinical trials with medicines and vaccines whose results have changed some public policies,²⁷ and have consolidated the conviction in the treating physicians, researchers and general public of the absolute benefits of clinical research. However, it is important to consider the institutional position and the social influence of researchers linked to pharmaceutical companies for the IWCs when making decisions.

On the other hand, the current epidemiological profile in Panama is that of a society in transition. The first ten causes of death include cancers, cardiovascular diseases, hematological diseases and diabetes. Childhood and re-emerging infectious diseases are also a public health problem. Faced with this situation, health authorities have supported medical associations and international guidelines ⁽¹⁹⁾.²⁸ Funded research on medicines is part of the Panamanian epidemiological profile; the ethical problem lies in the State’s ability to negotiate access to medicines that have proven to be beneficial. The IWC has approved research extensions for the direct benefit of participants, but the ethics of equity and justice, as well as the right to access to medicines, go beyond the functions of these committees. Other ethical problems result from me too medicines, and from social and pharmaceutical pressure on doctors to use them as «new», violating the principles of beneficence/non-maleficence, transparency and justice.

In Panama, the State has delegated to the institutional CBIs the role of monitoring clinical research, and to the CNBI its accreditation. Therefore, the criteria and their periodicity allow «harmonizing the scientific standards and rationalizing the documentary and administrative procedures used in the conduct of clinical trials with medicines for human use», and are accompanied by an accountability of the IWCs regarding the protocols reviewed, accepted and rejected, in addition to the registration and publication on the website of MINSA. However, the difference in experience between the older and newer IWCs highlights more the importance of initial accompaniment and ongoing advice on rare issues ⁽²⁰⁾.²⁹

The collection of documents from the CBIs surveyed and from the interviews shows the conformity with current guidelines and the relative uniformity of the work and decision-making process of these committees. Each aspect of the review of a funded clinical protocol may represent a conflict of interest between different obligations: responding to the research and the funding company, and ensuring the protection of participants and society.

The transfer of knowledge and technology for the development of local and national capacities in research and health care is part of the social impact of research, and represents the expression of solidarity in international cooperation embodied in the DUBDH (^{UNESCO, 2005}). The specialized tests are carried out in a laboratory outside the country that is linked to the pharmaceutical company, leaving the common tests for the local laboratories. National and international standards and IWC regulations do not mention this point as part of the review they are required to conduct; therefore, no SOPs were found on this topic.

On the other hand, most international protocols do not present the research budget, invoking their multi-center character and the confidentiality of these data in the face of market competition.³⁰ This situation may lend itself to institutional and researcher corruption practices (21), and should be discussed.³¹

The IWCs require, as proof of transparency, that the IWC form indicate whether the research team receives fees, but they do not request the amount of these fees or the amount of compensation from the institution hosting the research. Weissman and colleagues ⁽²²⁾ report that more than half of CBI members believe that relationships with the pharmaceutical industry affect the integrity of research.³²

These situations were analyzed during the discussions for the drafting of Law 84 of 2019, which regulates research.³³ It is an important step and it is necessary to include the ethical values of equity and justice among the participants in the elaboration, analysis and publication of the research. The regulation of the law should take into account these principles in order to address the specific aspects of these possible agreements. Both in the case of technology transfer and in the transparency of research funding and management, the IWCs could act as facilitators between researchers and institutional managers within the framework of ethical principles of social responsibility.

Respect for the dignity of individuals implies respect for and protection of their privacy and the confidentiality of their data. IWCs have inscribed in their SOPs the monitoring of the confidential handling of participants’ data. Provisions to preserve this confidentiality (collection, retention and destruction) should be included in both the protocol and the informed consent form; this obligation has not been questioned so far by the financial sponsors.³⁴

Regarding the handling of biological samples, SOPs require that it be specified how and for how long the samples will be kept, who will have access to them, and how they will be destroyed. This same information should be included in the informed consent. However, it is common for IWCs to require their inclusion after reviewing the documentation provided. The General Law 3 on Anatomical Components Transplants of 2010, establishes the conditions for import and export of biological samples. Despite this, pharmaceutical companies use the possibility given by the law to carry out studies outside when they do not exist in Panama. Lately, the companies condition the participation in the research of a medicine to the consent to keep the samples for future research, which represents a coercion of the participant, who has the perception that this research represents a hope to prolong his life or to diminish his suffering.

CBI members should have knowledge of clinical research methodologies until scientific review committees are operational. Some articles postulate that it is the responsibility of members to review the investigator’s manual on the type of drug being studied, the methodology chosen, and possible biases ⁽²³, ²⁴⁾. However, these manuals are increasingly complicated, and the critical sensitivity of CBI members is very important in suspecting possible injury to participant safety.³⁵ It is important that at least one of the committee members is a pharmacist, and that the advice of a veterinarian can be sought on the types of animals used and the interpretation of the results in them, applying the risk-benefit, non-maleficence, prudence and benefit ratio.

Most of the researchers in these clinical trials are physicians who conduct research at research centers or at their private and sometimes public care facility. It is difficult for participants to separate care from research, even though all the documents mention that it is research, because the research physician has the title of the specialty that is treating your disease or will be treating it in the future. Even though he has been recruited by another doctor, it represents a bias that is difficult to resolve due to the size of the Panamanian population and the number of medical specialists.

The DUBDH, the Declaration of Helsinki and the CIOMS guidelines insist on the evaluation of the risk/benefit ratio as a criterion for the protection of the participant, and the application of these will depend on the knowledge and values of the members of the IWC. Evoking «reasonable risk» will depend on several factors, including the underlying disease, the research context, and ultimately the drug under study. We agree with Rudra and Lenk ⁽²⁵⁾ that risk assessment should be progressive and permanent from the design of the research to establish mitigation measures, and that it is necessary to put an absolute limit on risk, particularly in extremely vulnerable patients. An important aspect is the possible psychological effect of the drugs under investigation on participants. If these side effects have not been anticipated, it is difficult for participants themselves to associate them with the study medication ⁽¹⁶⁾.³⁶

On the other hand, previous rules on the renewal of IWC members every four years represented a handicap for the accumulation of experience in the management of clinical protocols and the inclusion of new members.³⁷ The lack of interest in bioethics until the last two years has meant that some IWC members have remained members who have administrative functions in their own institution. Therefore, some members remain in committees for several years and only now can they be progressively replaced, due to a greater interest in bioethics and the formation of new members.³⁸ To resolve this cause of conflict of interest, one IWC recently decided not to review the protocols in which the institution’s leadership is involved. The CNBI and society in general must address these conflicts of interest in order to propose ethical solutions for a better quality of the work of the institutional IWCs ⁽²⁶⁾. The continuing education programs of IWC members, and particularly IWC meetings and case studies, represent tools for improving the quality of their work. ⁽²⁷⁾ In no case can these issues be invoked in favor of the development of «independent» committees outside of the institutions, whose financial relationships with the pharmaceutical industry represent conflicts of interest ⁽²⁸⁾.

The participation of external members is important for the transparency of the discussions and the protection of the participants. The current IWCs have integrated people from outside the institution, with different results, due to the honorary nature of the members and the elitist image of science and scientists. The IWCs surveyed all have external members, but their capacity to intervene in discussions on the methodological and ethical quality of drug research is very uneven, despite their participation in the trainings.³⁹ Law 84 of May 2019 requires that IWCs have a minimum of 20% external members, and provides that they will be compensated for expenses incurred to attend meetings and trainings. What should be the profile of these external members to strengthen the protection of participants against possible institutional interests?

The IWC’s monthly reports allow for the recording of health research conducted in the country, reflecting the IWC’s desire for transparency and constituting an important source of information for researchers, health decision-makers and the general public, so as not to duplicate research and to be alert to unapproved research.⁴⁰ But they do not allow for the evaluation of the quality of research or the protection of participants, researchers and institutions. These complex issues of complete safety in drug research have yet to be addressed.

Public sector administrative and financial rules are intended to present an image of transparency and accountability. However, they constitute a handicap for the continuity of previously programmed activities; in particular for educational activities, and represent a serious obstacle for the continuous supervision of ongoing research. This lack of oversight is the most serious problem perceived by the CBIs, as internal difficulties can be progressively resolved.⁴¹ One of the ethical problems of the current situation is that the IWCs have no alternative but to rely on the ethical sense of the researcher and his/her team in the development of the research. Therefore, IWCs must insist on the ethical education of researchers and on the development of a climate of mutual trust, as a basis for working together to protect participants and without hindering research. At the same time, the establishment of clear standards that are mandatory for the pharmaceutical industry means that the IWCs must be able to enforce them.

The hope of a treatment, even if it is still under investigation, is in itself an incentive to participate in it, when there is no evidence based treatment yet. This situation represents a bioethical dilemma between beneficence (of a possibly effective treatment) and non-maleficence (not subjecting participants to unknown risks), which IWCs resolve according to their sensitivity. Is the ethics of individual and social responsibility a utopia?

6. Conclusions

Regulation of clinical research in Panama has progressed in favor of participants, as reflected in national laws and regulations adopted since 2003. However, two unresolved problems have been encountered:

Respect for life and human rights; health, safety and equality, as well as the protection of vulnerable persons and groups (Art. 3 and 15 of the UDHR); social responsibility and health (Art. 14); the sharing of benefits (Art. 15), as well as on ethical transnational practices (Art. 21) affirmed in the UDHR, and the ethical principles of autonomy, beneficence/non-maleficence and justice, should constitute the ethical references for the discussion and the search for solutions to these problems.