Research paradigms

Clinical research is vital to further understand human health and to advance prevention, diagnosis, and treatment of disease. ¹ Research paradigms consist of

• • basic science research,

• • translational or bench-to-bedside research, and

• • clinical research.

Basic science discoveries can lead to trials that involve partnerships and collaboration in academia, government, and industry. ² Translational research often utilises animals as subjects for preclinical assessment to translate basic scientific discoveries into clinical therapies. Clinical research consists of ³

• • phase I, II, III, and IV trials;

• • management and analyses of local, national, and international databases;

• • case reports and reviews of literature; and

• • multi-institutional studies.

Importance of research in developing countries

Research is an essential component to a viable paediatric cardiac centre in developing countries and provides the means to define the size of local problems and the incidence of neglected diseases, and to generate specific solutions thereto related.Reference Yacoub ⁹ Research can lead toReference Yacoub ⁹

• • the development of local expertise and eventually improved technology,

• • opportunities for talented people,

• • the generation of additional financial resources, and

• • the enhancement of the dignity of the people and morale of researchers resulting from global participation.

Increasing demands are being placed on researchers to provide opportunities to resolve current health problems making research indispensable. ¹⁰ Currently, the research community is focused on solving the health problems of the poor and disadvantaged, which will inevitably stimulate the development of vaccines, drugs, and diagnostic capabilities where they are currently insufficient. Owing to changes across the world in public health and research, there is a need for a thorough and widespread approach to management of research. ¹⁰

The International Children's Heart Foundation, ¹¹ a non-governmental organisation that supports the establishment of paediatric cardiac surgical programmes in developing countries, calls for research in those countries because the non-governmental organisation has found that a healthcare facility that performs research is interested in advancing itself and improving care. In addition, engaging medical colleagues in research projects stimulates further education and self-evaluation, thus promoting growth and quality improvement.

Incorporating research into the infrastructure while initially establishing a paediatric cardiac centre ultimately improves quality of care while efficiently utilising resources that can be employed for both patient care and research: buildings, equipment, and human resources such as physicians, nurses, and administrators who can serve as principle investigators, research assistants, and study coordinators.Reference Yacoub ⁹ Some type of management needs to be in place with the purpose of overseeing and educating the team. Optimally, recruiting and training local individuals identified as appropriate to provide healthcare and perform research will thereby improve understanding of congenital heart disease and increase quality of care locally. Continuing education programmes and audits of individual performances, as well as audits of laboratories, technology, and epidemiology, are crucial.Reference Yacoub ⁹

Financial aspects

Establishing a congenital heart surgery programme in a developing country, or anywhere for that matter, is costly. In many developing countries, the facilities and funds necessary for basic research are simply not available. Resources are scarce, and countries are competing for the limited resources that exist.Reference Fenton, Castillo, Claro and Novick ¹³ In a developing country, the healthcare system as a whole may be lacking, and scarcity of financial resources makes it problematic to purchase and maintain up-to-date medical equipment and supplies, as well as to pay and retain adequately trained and experienced personnel.Reference Fenton, Castillo, Claro and Novick ¹³

While trying to establish a paediatric open heart surgery programme in Nicaragua, Fenton et alReference Fenton, Castillo, Claro and Novick ¹³ report that the programme was jointly financed by two non-governmental organisations. Each non-governmental organisation was responsible for different specific expenses. Recognising that a programme in a developing country may never have the resources that a developed country has, there were times when the medical team had to search out and receive further donations for specific necessities to provide optimal patient care, such as milrinone, fine vascular clamps, and a cerebral oximetry monitor. The programme grew and surgical volume increased. For various organisational, financial, manpower, and logistic reasons, the programme later moved to the only hospital in the country that performed adult cardiac surgery. Case volume is currently financially limited as the vast majority of patients are low income, and surgery is paid mostly by donations. Recently, the government approved social security insurance for a few specific congenital cardiac diseases.Reference Fenton, Castillo, Claro and Novick ¹³ This case in point demonstrates that depending on philanthropy (Fig 1)Reference Fenton, Castillo, Claro and Novick ¹³ for sustainability of a paediatric cardiac surgery centre in a developing country is not a long-term solution for self-reliant programmes. Complete programme development requires establishing a self-sustaining local system with local resources such as

Figure 1 Annual donations received by Programa Corazon Abierto (local Nicaraguan organisation involved in a Twinning program). *Estimated data. **Through June 30 only. Reproduced with permission from Fenton et al.Reference Fenton, Castillo, Claro and Novick ¹³

• • governmental funding and insurance or social security,

• • staff,

• • equipment, and

• • infrastructure.

Medical students who train abroad should be given incentives to return to their home countries.

International non-government organisations

Non-governmental organisations date back to the mid-1800s and were active in the anti-slavery movement and women's suffrage.Reference Davies ¹⁶ Non-governmental organisations play an important role in the collaboration with governmental agencies to improve congenital cardiac disease care throughout the world. Fenton et alReference Fenton, Castillo, Claro and Novick ¹³ believe that it is crucial for an established local non-governmental organisation to provide necessary complementary financial support, public awareness, and fund-raising for the paediatric cardiac surgery centre being established in a developing country. A prominent example (Table 1)Reference Pezzella ¹² is the International Children's Heart Foundation, whose mission that every child has the right to be born into a world where he or she can thrive is being met by sending medications, surgical supplies, and diagnostic equipment that helps train surgeons and medical staff in developing countries so they ultimately may care for their own. ^{11 ,} Reference Pezzella ¹²

Table 1 Sample of international voluntary/humanitarian non-governmental organisations.

Reproduced with permission from Pezzella.¹²

World Health Organization

The World Health Organization, the directing and coordinating authority for health within the United Nations system, in 1948 signed its constitution allowing them to ^{10 , 15}

• • provide leadership on global health matters,

• • shape the health research agenda,

• • set norms and standards, and

• • articulate evidence-based policy.

Two core functions of the World Health Organization are ^{10 , 15}

• • to achieve the highest possible level of health for all people and,

• • by shaping the research agenda, stimulate the generation, translation, and propagation of valuable knowledge.

According to the World Health Organization, high-quality research is essential for improving global health and economic development and provides the greatest potential to improve global health security, accelerate health-related development, and right health inequities. ^{10 , 15}

Elements of a successful twinning partnership

According to the World Health Organization ^{10 , 15} , a paediatric cardiac centre in a developed country optimally should be able to perform 300 to 500 operations annually per 2 million people. Yacoub estimates the number to be closer to 1 centre per 1 million people in the population.Reference Yacoub ⁹ Regrettably, many countries with 15–70 million people do not have a single paediatric cardiac centre able to perform modern therapies.Reference Yacoub ⁹

In the past, strategies to deal with the maldistribution of care for children with congenital heart disease primarily involved transporting children to developed countries for surgical care and organising surgical medical missions to developing countries.Reference Dearani, Neirotti and Kohnke ^{4 ,} Reference Larrazabal, Jenkins and Gauvreau ^{17 ,} Reference Liu ¹⁸ More recently, a new paradigm has brought about the creation of local paediatric cardiac centres partnered with established centres from developed countries, aptly named twinning.Reference Dearani, Neirotti and Kohnke ^{4 ,} Reference Larrazabal, Jenkins and Gauvreau ^{17 ,} Reference Liu ¹⁸

The first basic requirement in establishing a successful paediatric cardiac surgical twinning programme involves the active participation of an established healthcare institution to create a mutually beneficial partnership, and in so doing establish an association with an already successful paediatric cardiac programme.Reference Dearani, Neirotti and Kohnke ⁴ Dearani et alReference Dearani, Neirotti and Kohnke ⁴ have instituted a systematic approach to the design, support, and implementation of paediatric cardiac surgery programmes in developing countries, which includes

• • forming the vision and then generating incentives and resources,

• • comprehensive education,

• • local governmental support,

• • consistent leadership from the medical staff, and

• • a committed faculty.

A clinical database should be initiated in order to critique and optimise quality of care. Ideally, a minimal volume of 100 surgical cases per year is available, with the potential population to increase to 300 to 500 surgical cases per year over a 5-year period.Reference Dearani, Neirotti and Kohnke ⁴ Finally, Dearani et alReference Dearani, Neirotti and Kohnke ⁴ feel it is essential to perform risk assessment and track and measure results by reporting data and ultimately using aggregate clinical data to contribute to professional societies and national and international journals.

One critical component for a twinning programme to succeed is a financial plan.Reference Dearani, Neirotti and Kohnke ^{4 ,} Reference Jonas ^{5 ,} Reference Fenton, Castillo, Claro and Novick ¹³ It is important to have a philanthropic partner with long-range plans to stay involved, but using only the philanthropic model is the least effective method to provide care in the developing world.Reference Jonas ⁵ It is imperative that the local government take financial responsibility for patient care, salaries, and infrastructure, thereby solidifying a self-supporting paediatric cardiac surgery centre.Reference Jonas ⁵

Database participation

Society of Thoracic Surgeons Congenital Heart Surgery Database

Of the ∼125 congenital heart surgery centres in the United States, 100 centres participate in the Society of Thoracic Surgeons Congenital Heart Surgery Database (Figs 2, 3, and 4).Reference Jacobs, Jacobs, Mavroudis, Lacour-Gayet and Tchervenkov ^{19 ,} Reference Jacobs, Maruszewski and Kurosawa ²⁰ Participation in the database and biannual harvesting of data allows for an accurate account of local congenital cardiac surgery, including volume, and outcomes, while providing an opportunity to compare with other programmes and thus improve quality.Reference Jacobs, Jacobs, Mavroudis, Lacour-Gayet and Tchervenkov ^{19 –} Reference Mavroudis and Jacobs ²¹ Furthermore, it generates annual reporting to hospital administrators, payors, and governmental agencies, all supporters in the care of children with congenital cardiac disease.

Figure 2 The graph documents the annual growth of the STS Congenital Heart Surgery Database by number of participating centres submitting data. The aggregate report from Spring 2012 Harvest of the STS Congenital Heart Surgery Database includes data from 103 Congenital Heart Surgery Centres in North America, 100 in the United States of America, and 3 in Canada. Reproduced with permission from Jacobs et al.Reference Jacobs, Jacobs, Mavroudis, Lacour-Gayet and Tchervenkov ¹⁹ STS = Society of Thoracic Surgeons.

Figure 3 The graph documents the annual growth of the STS Congenital Heart Surgery Database by the number of operations per averaged 4-year data collection cycle. The aggregate report from the Spring 2012 Harvest of the STS Congenital Heart Surgery Database includes 127,685 operations performed in the 4-year period of January, 1, 2008–December, 31, 2011, inclusive, submitted from 103 centres in North America, 100 in the United States of America, and 3 in Canada. Reproduced with permission from Jacobs et al.Reference Jacobs, Jacobs, Mavroudis, Lacour-Gayet and Tchervenkov ¹⁹ STS = Society of Thoracic Surgeons.

Figure 4 The graph documents the annual growth of the STS Congenital Heart Surgery Database by the cumulative number of operations over time. The current number of cumulative total operations in the STS Congenital Heart Surgery Database is 240,343. The aggregate report from the Spring 2012 Harvest of the STS Congenital Heart Surgery Database includes 127,685 operations performed in the 4-year period of January, 1, 2008–December, 31, 2011, inclusive, submitted from 103 centres in North America, 100 in the United States of America, and 3 in Canada. Reproduced with permission from Jacobs et al.Reference Jacobs, Jacobs, Mavroudis, Lacour-Gayet and Tchervenkov ¹⁹ STS = Society of Thoracic Surgeons.

European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Database

In Europe, the European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Database is an international registry that serves similar function to the Society of Thoracic Surgeons Congenital Heart Surgery Database, using identical nomenclature and database standards (Fig 5).Reference Jacobs, Maruszewski and Kurosawa ²⁰ The European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Database and the Society of Thoracic Surgeons Congenital Heart Surgery Database are truly “sister databases” that allow for collaborative benchmarking and quality improvement.

Figure 5 The graph documents the annual growth of the EACTS Congenital Heart Surgery Database by the cumulative number of operations over time. This figure was provided by Professor Bohdan Maruszewski, Chair of the EACTS Congenital Heart Surgery Database. EACTS = European Association for Cardio-Thoracic Surgery.

Building global coalition

Change can be effected in the world by improving paediatric cardiac care. Upgrading the paediatric cardiac programme in a developing country can lead to upgrades in other domains of medicine in that country. Unnecessary competition between providers/sponsoring organisations and duplication of efforts wastes time and resources, diminishes credibility with potential donors, and inevitably impacts negatively on the lives of the children who were the noble focus of beneficence.Reference Fenton, Castillo, Claro and Novick ¹³

The World Journal for Pediatric and Congenital Heart Surgery was established to provide a platform for congenital heart surgeons to present findings, to introduce important developments to peers, and to highlight efforts of surgeons from across the world (Table 2; Marshall L. Jacobs, MD, personal communication). Both Cardiology in the Young and The World Journal for Pediatric and Congenital Heart Surgery strive to have a global audience and a global authorship. These complementary journals share in this mission. In fact, Cardiology in the Young, The World Journal for Pediatric and Congenital Heart Surgery, and the World Society for Pediatric and Congenital Heart Surgery can and should serve as facilitators to help improve communication and fellowship among paediatric and congenital cardiac surgeons, paediatric and congenital cardiologists, and all other professionals interested in the care of patients with paediatric and congenital cardiac disease throughout the world.Reference Fenton, Castillo, Claro and Novick ¹³

Table 2 Country of origin of manuscripts submitted in World Journal for Pediatric Congenital Heart Surgery Volumes 1 and 2.

Marshall L. Jacobs, MD, personal communication

Ethics of research in developing countries

Clinical trials conducted in developing countries should meet the same ethical standards as trials based in developed countries. ^{1 , 10 , 15 ,} Reference Shapiro and Meslin ²³ Mandatory requirements that are consistent with all international regulatory commissions include: ^{1 , 10 , 15 ,} Reference Shapiro and Meslin ²³

• • prior review by an independent ethics committee that will ensure minimisation of risk to participants,

• • favourable risk–benefit ratio for the participant, and

• • completion of informed consent by all participants.

Furthermore, clinical trials performed in developing countries and sponsored by groups from developed countries should be restricted to those trials that respond to the needs of the developing country.Reference Shapiro and Meslin ²³ If the participants will ultimately not be able to afford the treatment being studied, it is unethical to ask them to participate. In the past, research participants in developing countries have been less likely to have continued access to the intervention than participants in developed countries. Shapiro and Meslin believe that any experimental intervention should be compared with an established effective treatment in that particular country. ^{1 , 10 , 15 ,} Reference Shapiro and Meslin ²³ It is of great ethical concern that participants in developing countries not be exploited because the population is less fortunate, less powerful, and therefore more vulnerable. It is controversial whether the control group in a developing country must receive the same intervention as that which would be provided in a developed country, specifically owing to whether the intervention is available or is standard of care in the developing country before or after the trial. ^{1 , 10 , 15 ,} Reference Shapiro and Meslin ²³

The European Group on Ethics in Science and New Technologies supports the implementation of funded research activities in economically challenged countries only when such research is consist with the fundamental ethical rules of justice, beneficence, and non-maleficence. ¹ Researchers have a moral duty to help participants overcome inequities. In countries where the standard treatment is too costly for participants, it falls to the research sponsor to continue to provide the treatment for free or at a low cost after the end of the trial, even for a lifetime. Clinical trials should benefit the community where the study is taking place. ¹