Clinical and Pharmaceutical Development: Standards for Developing Countries

Dr Philippe KOURILSKY
Director General, Institut Pasteur

Introduction

I am by no means an expert in the field of ethics. However, I am faced by a number of problems that raise issues of ethics. During my three years in industry, as head of research of a international vaccine company, I had first hand experience of the some of the subjects I will be discussing. I now head the Institut Pasteur, which faces a number of problems. About half of our research on infectious diseases at the Institut Pasteur relates to diseases that have no market. They are therefore "neglected" diseases in that they are not driven by a market. In addition, some time ago with Doctors without Borders we became part of a new consortium, the Drugs for Neglected Diseases Initiative. This consortium has about USD 50 million in funding with the aim of developing eight drugs for so-called neglected diseases. However, we all know that developing one single drug represents about USD 800 million. Can this gap be breached?

Clinical and Pharmaceutical Development

I will begin by presenting my understanding of clinical and pharmaceutical development at the scientific level, and the changes that have occurred in this area in the past few years. The classical scheme for clinical development involves phases 1, II, III and IV. Today, Phase IV is partially incorporated into the Phase III process. An ongoing trial in the US involves 80 000 volunteers. The objective now is to document the adverse effects at the level of almost 10-5, while in the past 10-3 was documented. There is thus an increase in the dimension of what is now being considered in terms of adverse effects. This obviously represents a huge cost, which is part of the increasing costs associated with research in this area.

There have also been changes in the standards used for manufacturing, which is part of the development process. As automation increases, and fewer people are located in the manufacturing zone, the risks of contamination infection will be lower. For example, research buildings are now designed on the basis of a double-shell system. This also leads to increased costs. The increase in the cost in terms of vaccine development in the last 15 years represents a factor of two or three. This represents an enormous amount of money.

What are the benefits of these increases in costs, which parallel an increase in the standards of clinical development and manufacturing? I believe that these benefits have not been carefully evaluated. I know of no study that clearly shows that the increase in standards has been paralleled by a significant increase in safety and benefits for human health. We have all been vaccinated. In terms of BCG, the limits are not in the safety of the product but in the limits on human genetics.

We would all agree that any gain in safety is a benefit. However, is there a limit to such improvements in safety? Is there any control on the increase? Do regulatory bodies have a genuine counterbalance? Where does the balance of power lie between regulatory bodies and other bodies in society? Industry is not a real counterbalance, as industry will always adapt and comply to all relevant rules, passing on the additional costs to the consumer. I believe that we are reaching the stage in the Western world where the search for maximum safety and reduction of risk leads to a conflict between the ethics dealing with individuals and the ethics dealing with communities. This is a particularly important issue for the Third World.

The Non-Universality of Ethics

In my opinion, ethics are not universal; they do not amount to human rights. Ethics have a cultural component, which must also be taken into account. This is highlighted, for example, in relation to debates on stem cell research, which are very impacted by local culture. Singapore has set up its own set of ethical rules in order to be able to carry out its own research. Western countries tend to export their ethical rules to the South. Often this is not adapted to the developing country in question. In addition, we often export our own confusion. Even now, GMOs are seen an non-ethical by half of the European population. In France, the link between vaccination against hepatitis B and multiple sclerosis is an issue, although this is not substantiated by any correlation data. In the UK, a similar issue has arisen in relation to ROR and autism. I was recently asked by an African Minister of Health if vaccination against hepatitis B should be stopped. Either willingly or unwillingly we export some of our confusion to other countries.

The Perverse Effect of Standards

Another issue that arises is that the exportation of our standards can be a way of preventing the developing world from producing products at the same standards that would allow them to be exported to the Western world. A well documented example of this arose in Cuba, where Fidel Castro decided that biotechnology would take Cuba forward. Much work and investment took place in Cuba with a view to manufacturing vaccines. In fact, Cuba was prevented from exporting its vaccines by the US boycott. I am not sure that Cuba has now been able to catch up with Western standards, and if so, at which cost. The increase in standards can thus be used to prevent the importation of products from the developing world.

The standards can in fact have a perverse effect when production is actually forbidden in developing countries for their own sake by the fact that they have adopted standards that they do not have the resources to attain. In certain cases, the use of Western standards by developing countries can make it impossible for them to manufacture drugs, even if they are not exported to the Western world. The question of standards is thus an extremely important point.

Confusion between Standards and Ethics

There is a confusion between standards and ethics. Some of these standards are claimed to be ethical, and it is claimed to be non-ethical to not use the standards. Certain developing countries have bought into this option. Of course, in the best of all worlds, everything should be done at the highest level of safety, regardless of the cost. However, we are not in the best of all possible worlds, and ethics can in fact lead to immoral results.

Conclusion

Developing countries should develop their own ethical rules for their own benefit. Even if this means that medicine will develop with different standards for a certain period of time, this is more realistic and will save many more lives than the attitude that has been taken by rich people and rich organisations. Industry will not address these issues. This is not the role of industry, which is concerned with the development and manufacture of products. Industry will not fight to develop other standards for developing countries. Instead, it is the duty of the academic world and of civil society to address these issues.

At a certain stage, minor and undemonstrated increases in safety cost a lot of money. We do not necessarily have to buy into the option that everything should be done in the same way everywhere around the world.

Dr Anne FAGOT-LARGEAULT

An acute controversy has been raised in the bio-ethics literature in the last ten years, in particular, in relation to research on AIDS vaccines. On the one hand, certain argue that very high standards of quality for research and health care should apply in all countries. On the other hand, certain argue that this is not realistic: only by having lower standards of research will research be possible at all in the poorer countries. Otherwise, these countries will be barred from access to any health care whatsoever.

Dr Adrian HILL

I agree with your point of view and congratulate you on its clear expression. What do you see is the next step? It has been suggested that the WHO or other organisations should facilitate the development of regulatory authorities that are appropriate for developing countries. It would be preferable to have regional authorities rather than national ones, which would have the relevant resources and expertise to make a real cost-benefit analysis.

Dr Philippe KOURILSKY

This is a major problem. The WHO is obviously a key player, but it does have internal constraints. I believe that it is necessary to document the benefits of what is being done and match this with the costs. I am very surprised that this has never been done before. If the data can demonstrate that the increase in safety in certain vaccines has not resulted in significant progress, this would be an important argument. Our colleagues who work in vaccines should work on obtaining such data.

Dr Adrian HILL

However, who would make the ultimate decision on this data? Most African countries do not have their own regulatory authorities, and would not have the relevant expertise to make such difficult decisions. A regional organisation should be established and supported to make the final decision.

Dr Philippe KOURILSKY

I would support that argument. This is an issue that academic bodies and civil society should take on themselves.

Dr Marc DOHERTY

The EMEA and the FDA are not in the business of carrying out ethical reviews. They are only interested in whether the drugs or vaccines are safe. Even in the Western world, there is no consensus on these issues. For example, France has a national ethics review board, while in Denmark, all review is carried out at the local level. It would be preferable to have a consensus rule, but I am not sure that this is attainable. As a first step, we could perhaps provide guidelines for local people to measure their local ethical review boards.

From the floor

Given that academic institutions increasingly have strong links with industry, who is responsible for developing these ethical issues?

Dr Philippe KOURILSKY

I am not sure that the links are that strong. There is a confusion between standards and ethics, and it is claimed to be non-ethical not to use the Western rules. The academic community could try and clarify this issue.

Dr Adrian HILL

Given that we are involved in reducing risk to infinitesimal levels, it would be very expensive to try and measure these almost immeasurably small risks. No academic institution could afford to try and measure these risks.

Dr Philippe KOURILSKY

This is one of the problems of the so-called precautionary principle: according to what I call the Heisenberg's law of epidemiology, a certain level of safety can never be assessed. However, we have all been vaccinated by vaccines that would be unacceptable according to today's standards. It is therefore reasonable to suggest that developing countries could use standards that applied in Western countries 25 years ago, if this is their independent decision.

Richard ASHCROFT, Imperial College, UK

There is no clear, objective way of deciding what level of risk is tolerable. The level of risk we are effectively tolerating has become lower and lower, without a discussion of the level of risk that we could tolerate. You propose that a higher level of risk is acceptable in developing countries where the problem being addressed is serious enough.

Dr Philippe KOURILSKY

I am not sure that we have made progress in diminishing risk in certain cases. The data in support of this is not available. Second, it is not up to us to decide on the acceptable levels of risk; it is up to the relevant populations to decide. Similarly, cost effectiveness has to be determined by the people involved and not by us. We should be respectful of their right to make these decisions, and we should refrain from exporting our own standards. One parameter that is rarely taken into consideration is time. For example, if we lose three years in developing a vaccine, how many lives will thus be lost?

Dr Christian LIENHARDT

We would all agree on the need for ethics but there is never any discussion on what ethics actually are. When people say that they do not think that something is ethical, what criteria are they using? Usually, the criteria are determined according to their own points of view, which are based on their individual cultures and experiences. However, ethics involves an extremely variable geometry. For example, the European Commission is about to launch a major series of trials in Africa. What criteria will be used in deciding which proposals will be funded? In the scientific world, certain people consider themselves as ethicists. I would argue that ethics are often a poor ersatz of morals.

Dr Anne FAGOT-LARGEAULT

I am not convinced that standards and ethics can easily be distinguished. For example, the WHO guidelines on the conduct of clinical trials were considered to be universally accepted. They basically provide that when you conduct a clinical trial, first, fully informed individual consent must be obtained from all participants. Second, if someone in the trial falls sick during the trial he or she should be given the best possible therapy. Third, there should be insurance coverage for all participants in the trial. However, during the vaccine trials on AIDS it was argued that the guidelines could not be completed followed, at least in the trials in Africa. Thus community consent was considered acceptable in place of individual consent. If someone developed AIDS during the trial, he or she could not obtain the best possible therapy, tri-therapy, as this would cost too much. Therefore, it was considered acceptable to provide the person with the best therapy available in the country. Finally, insurance coverage for vaccine trials was impossible. The WHO thus re-wrote its guidelines in order to make the trials possible.

Dr Christian LIENHARDT

Let us suppose that a trial for a tuberculosis drug is carried out in Africa, where the decision is made to exclude HIV patients. In order to exclude HIV patients, they first have to be tested, and their consent obtained to such testing. If a person tests HIV positive, what do we then do? Do we simply tell them that they are HIV positive and therefore cannot be included in the trial? Certain people believe that, given that such a person would not otherwise have been aware that they were HIV positive, the fact that the test has been carried out imposes on us a responsibility to ensure treatment for the person, even though they have been excluded from the trial. It is very difficult to answer these questions, and we have no rules or criteria that could help us.

Dr Philippe KOURILSKY

The WHO example also shows that there is a problem in trying to achieve a world wide consensus. Personally, I am totally against the concept of a world wide ethics committee, where I am convinced that Western countries would dominate.

Dr Anne FAGOT-LARGEAULT

When the discussions were held on the WHO guidelines, Northern countries did not want to lower the standards for Africa. In contrast, representatives from African countries argued that this was being paternalistic. They wanted to have their own standards and make their own judgements as to what was acceptable for them.

From the floor

When international bodies go to developing countries to discuss standards, people consider them as the authority, and they assume that they cannot challenge these standards.

Dr Marc DOHERTY

Standards or ethical requirements cannot be formulated without an assessment of risk. I helped initiate a clinical trial in the US for people with HIV. We applied a completely different standard for those patients than to those HIV patients coming into the clinics. Given that their life expectancy was six weeks, anything we could try that offered a possibility of extending that was considered of benefit. It is therefore counter-productive to apply a single standard that applies to every disease and every country around the world. What is appropriate for a tuberculosis treatment in a country that has 350 000 tuberculosis-related deaths per year may not be appropriate in a country where only one person per year dies of tuberculosis.

Richard ASHCROFT

Ethics are often seen as arbitrary whereas scientific standards are not. In fact, I believe that many of the scientific standards are arbitrary whereas many of the ethical standards are well defined.

Dr Philippe KOURILSKY

I never suggested that ethics were arbitrary. I believe that, in certain cases, the so-called ethical rules are so counterproductive that they become immoral. We therefore should not hesitate in challenging them. I also believe that it is the duty of the scientific community to address these issues, because no one else will. This is the main message I would like to leave you all with today.