Havana meeting on Medical Research and International Cooperation

PUGWASH MEETING NO. 259

Medical Research in Cuba: Strengthening International Cooperation
15-17 February 2001, Havana, Cuba

By Amina Aitsiselmi

The Pugwash workshop on Medical Research in Cuba: Strengthening International Cooperation, took place from 15-17 February 2001 in Havana, Cuba and was hosted by the Cuban Pugwash Group. More than 30 participants from seven countries attended the workshop. The meeting opened with welcoming remarks from Lic. Orlando Fundora Lopez, President of the Cuban Pugwash Group, and Prof. George Rathjens, Secretary General of the Pugwash Conferences.

The workshop began with an overview of Cuban achievements and the current state of Cuban biomedical research. Beginning in the early 1960s, biotechnology and medical research became a top priority of the Cuban government, with over one billion dollars invested in biotech R&D in the 1990s alone. Today, Cuba boasts a ratio of 1.8 scientists per 1000 inhabitants, a level comparable to the European Union (though with a far smaller GDP). Cuba also holds 400 patents in the biotech field.

In 1965, Cuba’s national Center for Scientific Investigation was founded, leading the way for the opening of numerous other research facilities. Today, there are 38 biotech centers, grouped together in a science park to the west of Havana, which integrate research, development, production and marketing. A highly focused research strategy has enabled the country to eradicate numerous diseases and to control epidemics in remarkably short periods of time. For example, soon after the outbreak of a dengue epidemic in the early 1980s, Cuban scientists discovered that their own interferon, which had been perfected in under two months, was effective against internal bleeding resulting from dengue fever. Vector control measures are now in place and Cuba is currently free of the disease.

As a result of its overall strategy, Cuba’s research effort has produced a variety of products ranging from vaccines and cancer therapy drugs to fetal monitoring equipment. Some of the many examples include:

• Monoclonal antibody and interferon, for the treatment of cancer and viral diseases;
• Anti-meningitis B and hepatitis B vaccine, both have been certified by the WHO;
• Recombinant streptokinase for the treatment of heart attacks;
• biomodulin-T;
• blood derivatives (albumin, anti meningococcal immonuglobulin);
• vaccines (rabies, small pox, tetanus, diphtheria; salmonella tiphi).

Cuba also has several products in the pipeline, including: combined vaccines, cholera vaccine, cancer vaccines; AIDS vaccine; new radioactive monoclonal antibodies, interleukin-2, and new interferon combinations, all currently undergoing clinical trials.

Workshop participants asked about quality control and safety standards, and were told that Cuba abides by World Health Organization (WHO) standards and that a WHO certification team visited Cuba’s Center of Genetic Engineering and Biotechnology production facility in November 2000 to assess the Hepatitis B vaccine, which the WHO plans to purchase from Cuba in the future. At present, Cuba exports its products to over 20 countries, including the UK and Canada, and is therefore subject to the scrutiny of their regulatory authorities. Mention was also made as to lengthening drug timelines in the evolution from research to product development to marketing (8 years in the 1960s from the pre-clinical stages to the marketplace, 12 years or longer in the 1990s). There was also discussion about the effects of the WTO TRIPS agreement on biotech research in developing countries as well as the negative consequences of that agreement on access to drugs and healthcare.

Questions were raised as to how the Cuban experience in biotech could be replicated in other developing countries. It was noted that Cuba employed a positive ‘strategic intention’ strategy; it invested in a variety of projects, both short-term ( low risk-low reward) and long-term ( high risk-high reward). An example of the latter is the meningitis B vaccine which Cuba started developing in the 1980s to tackle its meningococcal epidemics. The result was both a resolution of domestic health problems as well as the development of products which can be marketed on a global level, generating a positive cash flow for the country. Export of the meningitis B vaccine (and now the Hepatitis B vaccine) provides income which is both reinvested in research and used to develop local vaccination programs.

Infectious Diseases and Vaccination Programs

Cuba has a rich experience in terms of handling infectious diseases, being the first country in the world to eradicate smallpox (1923) and polio (1962). Other diseases which were endemic but have all been eradicated include cholera, yellow fever, bubonic plague, malaria, diphtheria, measles, rubella, and mumps. Other diseases such as meningeal tuberculosis, whooping cough and tetanus have been reduced to levels of around one case per 10,000 inhabitants. Cuba’s success in dealing with infectious diseases, despite being a developing country, is such that the country’s leading causes of mortality are heart disease and cancer, respectively. Many of Cuba’s health indicators match those of a developed country, and in a 2000 WHO report, Cuba’s Public Health System ranked 39 out of 191 countries.

Cuba created its National Immunization Program in 1962. Today, it is one of very few countries in the world to vaccinate 100 percent of its population against 12 different diseases. The meningitis B vaccine, unique in the world, was developed at the Carlos Finlay Institute in the 1980s and is now administered to all infants over three months. This has contributed to a 93 percent reduction in morbidity related to meningococcal disease.

[Editor’s note: As a result of the workshop, several participants from outside Cuba decided to nominate Cuba’s National Immunization Program for the 2001 Gates Award for Global Health, being given by the Bill and Melinda Gates Foundation.]

Infectious diseases are responsible for more than 17 million deaths a year worldwide (as of 1997), half of these being children under 5 years of age. In low income countries, 45 percent of all deaths (63 percent for children) are due to infectious diseases, with the most deadly being Acute Respiratory Infection (3.5m), AIDS (2.3), diarrhea, TB, and malaria. A majority of these could be prevented with existing, cost-effective strategies, but one-third of the world’s population lacks access to essential drugs. Moreover, the WHO has no guidelines at present curbing excessive use of antibiotics in countries where they are available to prevent the development of anti-microbial resistance.

Cuba’s public health system has developed strategies to tackle infectious diseases against which there is no vaccine. Prior to 1960, malaria was endemic among the two million Cubans living in Oriente and the eastern provinces. In 1962, the National Service for the Eradication of Malaria was established, and five years later, the last autochthonous case was reported. The campaign was based on vector control measures (DDT spraying, which Cuba banned in 1970, two years before a similar ban in the US), epidemiological control of each focus of transmission, and epidemiological surveillance of febrile patients in the whole country including the rural areas. There is now a surveillance system for imported cases.

Diarrheal disease and Acute Respiratory Infections are the most important infectious diseases in Cuba, even though the country has a very low rate of antibiotic resistance. There is also no multi-drug resistant TB. The unavailability of antibiotics due to the US embargo and subsequent drug rationing strategies may have a part in this, but no research has been done. Wide spectrum antibiotics are under clinical trials in Cuba.

Cuba has a very low rate of HIV transmission, and maintains a low incidence rate of around 7 per million (PAHO-1995). HIV patients are offered the opportunity to attend sanatoria where they can receive treatment and are educated about the disease and learn to live with it. Attendees continue to receive their salary during this period. Could education also contribute to the low prevalence (3200 AIDS cases)?. In 1959, only 25% of Cuba’s population was literate, and only two or three scientific institutes and one medical school existed. Now over 98% of the island’s children regularly attend school and there are 22 medical faculties.

The role of education in cutting HIV transmission lines was brought into question when mention was made of Zambia, where the highest HIV/AIDS transmission rates are found among university graduates. Discussion also focused on the importance of national leadership, with Uganda mentioned as a positive example of how political leadership can affect public health. In Uganda, important state figures publicly admitted that the country had an HIV/AIDS problem, which helped galvanize political and public momentum to tackle the situation. This contrasts with the situation in South Africa, where the government only recently acknowledged the links between HIV and AIDS.

The US Emgargo

In place since the early 1960s, the US embargo against Cuba is the only embargo in recent history that has explicitly included food and medicine, compared even with international embargoes against Iraq and North Korea. In so doing, US policy is in direct violation of Article 4 of the Geneva Convention, Article 12 of the UN Charter on Human Rights and various other international human rights accords.

With the fall of the USSR, Cuba’s public health financing experienced a dramatic reduction, from over $250m a year in the late 1980s to $65m in 1993, only rising slowly to around $160m in late 1990s. The situation was aggravated by increased pressures on the public health system, including an aging population, increasing numbers of doctors and health practitioners, and increasing numbers of surgical procedures. The situation was further exacerbated by the US embargo (e.g., Cuba pays substantial shipping costs for imported materials because the US embargo requires that no freighters docking in Cuba may visit a US port within six months). As a consequence, imported pharmaceuticals soak up around 52% of Cuba’s public health expenditure.

The country responded by taking a number of important measures to ration and distribute its drugs more effectively around the country. Cuba implemented a program of import substitution and domestic production of drugs, encompassing a total of 422 pharmaceuticals at a cost of $75m. Cuba also designed and developed a Natural and Traditional Medicine Program (NTMP), covering acupuncture, homeopathy, phytotherapy and hydrotherapy. The National Medicines Program also was forced to more tightly control prescriptions, banning drug dispensing from hospitals and restricting doctors affiliations to only one pharmacy to prevent false prescriptions.

Although import substitution tactics have saved millions of dollars, Cuba nonetheless has to implement a VEN (Vital, Essential and Non-essential) system of drug classification and struggles to satisfy the population’s need. In addition, such basic drugs as Ibuprofen, Vitamin E and Erythromycin are not available in the country.

Prior to the 1990s, Cuba was able to minimize the impact of the US blockade by purchasing drugs in both western and eastern Europe. Following the collapse of the Soviet Union, East European supplies as well as the hard currency to purchase drugs in western Europe dried up. Moreover, the 1990s witnessed a period of smaller European pharmaceutical companies being bought out by US companies, and thus coming under the terms of the embargo. This situation was further compounded by the signing of the “Cuban Democracy Act” of 1992 and its effect on food and medicines, including:

• a ban on subsidiary trade, where European companies that are subsidiaries of US companies may no longer sell to Cuba;
• a licensing provision permitting the sale of drugs for humanitarian reasons which was so arduous and protracted it had no practical benefit;
• the prohibition on foreign ships docking in the US if they have visited Cuba in the previous six months;

The passage of the Helms-Burton Act in 1996 further tightened restrictions in that various components of the embargo could only be changed by an act of Congress rather than by executive order. This legislation was especially damaging as it also targeted the biotechnology sector, which had proven such a success scientifically and financially for Cuba.

In 1995 the American Association for World Health undertook a comprehensive year long study of the impact of the embargo on the health of Cuban people. This document provided hard data for those seeking to exclude food and medicine from the embargo, including:

• a widespread shortage of nearly all pharmaceuticals (only 889 of the 1297 medications available in 1991 were available, some intermittently);
• degradation of the island’s water supply due to a lack of access to water treatment chemicals and spare parts, which resulted in a rise in mortality and morbidity;
• serious nutritional deficits, particularly among pregnant women, due to the ban on foodstuffs;
• constraints on the exchange of information due to travel restrictions, currency regulations, etc. Although information materials are theoretically exempt from the embargo, scientists and citizens of Cuba, the US and other countries suffer as a result (one of the Cuban participants at the Pugwash meeting noted that a condition for him to attend a professional meeting in the US was to drop his Cuban nationality).

Are there political opportunities in the US for changing the embargo? While there has been some political momentum in recent years toward partial or full lifting of the embargo (among US food and drug companies, human rights groups, and even in Congress), the Bush administration and the Republican-controlled Congress give no indication of acting anytime soon.

One of the unintended benefits of the embargo for Cuba is that the country has developed a remarkable self-reliance in terms of both healthcare and biotechnology. Given severe resource constraints, Cuba has emphasized the fundamentals of medical practice (physical diagnosis and clinical judgment) and the implementation of a model public healthcare system. Thousands of medical students from the Caribbean, Latin America and elsewhere study in Cuba, including many from the US under the auspices of the organization MEDICC (Medical Education Cooperation with Cuba). Despite these programs, the fundamental violation of human rights imposed by the embargo remains unchanged.

Opportunities for International Cooperation

Meningitis B

In the early nineties, Cuba’s Carlos Finlay Institute finalized research on its anti-meningococcal B vaccine and started immunizing its population. The VA-Mengoc-BC vaccine was tested by a double-blind trial on 106 000 Cuban adolescents (10-16 years). The vaccine is now registered in 19 countries, with 45 million doses administered (85 percent in children under 5).

The anti-meningitis B vaccine, unique in the world, caught the attention of the pharmaceutical company, SmithKline Beecham (now Glaxo SmithKline), which subsequently reached an agreement with the Finlay Institute to market the vaccine globally. The Finlay Institute retains the vaccine patent and control over R&D, production and quality assessment capacities in Cuba.

Given the size of the US market, there was obvious interest in being able to market the vaccine in the US, a suggestion which Cuba welcomed. Currently, there are some 3,000 cases of meningitis (300 fatalities) a year in the US, many of which could be prevented by immunizing children and teenagers, particularly in high risk areas.

Although the initial US government response was negative, SmithKline Beecham managed to galvanize enough scientific and medical support to demonstrate that the Finlay vaccine was the only option available on the market. After two years of negotiations, SmithKline Beecham received a license from the US Treasury Department allowing them to finalize the deal with Finlay and bring the vaccine to the US market, providing these vaccines were produced in SmithKline Beecham facilities. Other conditions were imposed by the US as well, including minimizing the hard currency that the Carlos Finlay Institute could received (i.e., part of the royalties must be paid in kind, through delivery of medicines and other materials to Cuba). Additional trials for the vaccine are now being completed in Europe and New Zealand.

Of course, the conditions imposed by the US on Cuba and SmithKline Beecham would cease if the embargo is lifted. Along with the financial benefits received by the Finlay Institute, there is also the political and symbolic importance of a developing country vaccine being used in the north. As one participant noted, the VA-Mengoc-BC vaccine is a good example of the need to “step beyond narrow international constraints to work for a higher purpose and the benefit of humanity”. Other potential areas of joint research in which international collaboration would be particularly useful were noted as well, including: sickle cell disease, AIDS, clinical research methods, food and nutrition studies, and traditional medicine trials.

Sickle Cell Anemia

In the case of sickle cell anemia, Cuba has a strong research track record for two important reasons: its racially diverse population provides an interesting gene pool to investigate, and the primary care system provides excellent tracking of patients with the disease, even those not hospitalized. As a result, Cuban researchers have established that partial splenectomy is a better alternative to total splenectomy, reducing the need for hospitalization and transfusion, and recent double blind clinical trials have shown antisickling activity of the compound vanillin for the first time in vivo.

Established treatments of sickle cell disease include hydroxyurea, which was first used for sickle cell disease treatment in 1986-87. However, it took another ten years for extensive clinical studies to be completed. It was noted that international cooperation on such trials could have speeded up the process, and that cooperation between countries with a strong interest in the disease (the US, Cuba and France, especially) could advance testing and clinical trials of new medicines. The US is, of course, a major force in organizing multinational trials, but Cuba is prohibited from participating because of the embargo, and the US Federal Drug Administration won’t recognize Cuban institutes as partners for such trials. Here again, the embargo not only affects the target country, Cuba, but has wider repercussions on international research and global health.

Global Networks, Cooperation and Medical Ethics

This session opened with a theoretical overview on the meaning and utility of networks, which were defined as being complex interactive systems which are non-hierarchical, open-ended, dynamic, based on mutual benefit, and inherently chaotic (the butterfly effect). Networks were identified as part and parcel of the 21st century, being post-Newtonian and more in line with Heisenberg’s uncertainty principle; i.e., part of a probabilistic rather than mechanistic universe. Increasingly, modern networks are technology-driven, trans-national, trans-cultural and multi-disciplinary.

The purposes of networks include exchanging technical and scientific information; the testing and sharing of experiences; and exploring new approaches and solutions to scientific and social problems. At the same time, networks pose challenges to traditional concepts of national control and sovereignty, intellectual property, standards of order, and political leadership. Networks operate through understanding the principle of “boundary conditions”, including shared missions and values and commitments to interchange and a willingness to change.

Effective networks use information and ideas which serve multiple needs, have straightforward access, facilitate feedback and revision, and encourage a wide range of participants. These are the goals the Global Health Council has been working towards in order to improve equity in global health. Major tools used for networking include diversified loose-knit organizations, interactive meetings, the internet, and outreach.

In Cuba, a networking strategy has been applied within the public health system via both telematic and internet communication, encompassing one national node, three regional nodes and ten provincial nodes. Similarly, the University Medical School of Cuba incorporates tele-education, tele-medicine, and off-site research in its programs. The Cuban Infomed network seeks to provide universal access on issues of health and education, stressing prevention rather than cure.

There are currently two Infomed website projects: 1) a virtual library; and 2) a virtual university, both aiming to improve access especially in more remote, rural areas (utilizing local computer laboratories). Cuba’s Infomed could also help provide consultation services, surveillance of epidemics, and respond to different constituents (public, students, community health workers, academics and professionals).

It was noted that although equity is essential to health, developing countries are handicapped in access to communications technologies; the North-South digital divide being the most dramatic of all inequities in health or income. Tens of millions have access to the world wide web in America, whereas only thousands do in most African countries and usually at a slow intermittent rate. Telephones and personal computers are present in less than one percent of homes in low-income countries, and the increasing gap in wealth distribution holds out little promise of increasing access anytime soon.

The point was made about extending Infomed services for international access. This could be particularly useful in exchanging scientific information between different groups. Infomed plans to translate its information into English and Portuguese. Yet Infomed also shares the same problems of quality of information as other internet information services, and the ethical issues attached to such rapid dissemination of (at times unverified) information and technological developments are ones that face humanity as a whole.

The internet is revolutionizing information flows. The cost of sending journals every week for a year to Africa for example exceeds $70, whereas that of giving access to electronic editions is zero or close to it. What is more, those in poor countries can access electronic journals at exactly the same time as those in the developed world, and they can access what is relevant rather than the selection that was sent.

Successful information flow is always two-way; through the internet, servers such as PubMed, BioMed Central etc. make it easier for those from the developing world to bring their research to the world’s attention, as well as to actively participate in debates on health and research. One of the main obstacles to full participation is that of sustainability, not solely in terms of financial of investment but also, as was identified for Cuba’s Infomed, of having a critical mass of users. The way forward would be to exploit the full interactivity of internet services such as Infomed, enabling rapid feedback and change to continuously mould information flows into useful knowledge.

Concluding Remarks

A wide range of international efforts are underway to strengthen research capacity in developing countries, by the WHO, various NGOs, as well as foundations such as the Rockefeller Foundation. The most important lesson drawn from the Pugwash workshop in Cuba, however, was the contribution that developing countries can make to world health. Cuba is a specific and brilliant example of how scientific and medical developments can be made to address the country’s problems and how these can be exported for the benefit of people elsewhere. Accordingly, it is particularly unfortunate, as well as ethically wrong, that the US embargo hinders Cuba’s full participation in international medical research and healthcare. Several participants noted the essential rationale of Pugwash in working to overcome political, institutional and cultural barriers for the common benefit of humanity.

The workshop concluded with various suggestions for follow-on activities, including: maintaining contacts as an important factor for long-term influence; drafting a policy report on the negative effects of the embargo, not just for Cuba but for international medical cooperation; posting the report on the Pugwash Forum of the Pugwash website to stimulate comments and elicit other examples of the negative effects of the embargo; disseminating such information to other NGOs and the media; and providing assistance to the American Association for World Health in the preparation of an updated report on the embargo’s effects.

It was also recommended that Pugwash coordinate its work with the American Association for the Advancement of Science (which acts as a clearinghouse on scientific exchange with Cuba) and consider holding a seminar on Cuban medical research at the National Institutes of Health. Pugwash could also work with International Student/Young Pugwash in supporting the exchange of medical students with Cuba.

From a Caribbean perspective, a different but related issue raised was that of exploring the effects of the US embargo on Caribbean drug trafficking, given that Cuba is not allowed to contribute its resources and experience to such efforts. The suggestion was also made to explore the feasibility of a joint project involving the English-speaking countries of the Caribbean with US and UK participation.

Despite the twin constraints of a developing country economy and the US embargo, the Cuban medical research community and public healthcare system have much to offer both their immediate neighbors and the wider international community. To that end, international NGOs such as Pugwash have a special role to play in facilitating the free and open exchange of information and research with their Cuban counterparts.