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The Declaration of Helsinki requires that control groups receive the “best” current treatment, not the “local” one. This shift in wording has profound implications.
As the complexity of clinical development grows and the market for new medicines expands, it should come as little surprise that clinical trials have become truly global. The major drug development regions of the world are primarily North America, Europe, and Japan, but emerging markets such as those in Asia, Latin America, and Africa are playing a greater role in the global plans of pharmaceutical and biotech companies. This is illustrated by industry data showing that clinical trial spending in the Middle East and Africa rose from $10 billion (U.S. dollars) in 1998 to $75 billion in 2002.1
Although clinical trials are now taking place in diverse regions across the world, companies face numerous new challenges when incorporating emerging regions into their clinical development plans. In North America, Europe, and Japan, the regulatory, ethical, and clinical research environments are fairly well defined, and so companies have sufficient previous experience to help them adapt to further changes in these regions. However, in emerging regions of the world, these environments are less clear-cut and guidelines acceptable elsewhere may not necessarily apply.
Anyone wishing to work in so-called developing countries, such as those in Africa, must take great care that they do not come across as having a "superior attitude." Clinical trials carried out in developing countries must be run to the same high quality and ethical standards as elsewhere in the world. Everyone involved in clinical development has a duty to look after and care for patients involved in trials wherever they are. Commercial objectives should not compromise this stance. It is likely that difficulties will be encountered when running trials in regions such as Africa, but overcoming them can help provide valuable information for the development of a new medicine and can be a rewarding experience for those involved in such projects.
Although this article will refer to Africa, it must be remembered that the region is vast and encompasses a range of countries (Table 1) with myriad cultures, customs, languages systems of communication, and widely varying conditions for clinical trials. A certain degree of generalization is impossible to avoid when discussing Africa, but this must always be balanced by a consideration that the region's diversity makes it impossible to predict every scenario for every country or subregion with respect to clinical trials. Therefore, it is important to obtain as much up-to-date information as possible on the locations of interest and seek advice from those with first-hand experience carrying out clinical studies in Africa. Those seeking to work in Africa must therefore conduct an in-depth and well-planned feasibility study before embarking on any project, to avoid potential problems and guard against complacency.
Table 1. United Nations definition of major areas and regions in Africa
In the major world regions for drug development, clinical trials are run to ICH GCP (International Conference on Harmonization—Good Clinical Practice) standards. When extending beyond these areas, researchers expect to run trials to a similarly high level. If trials are run in South Africa, then ICH GCP standards can be expected, but this is harder to achieve in other countries in the region.2 This presents a significant challenge to companies wishing to work in Africa, as ICH GCP standards would be desirable in order to generate data that is acceptable to both regulatory authorities in ICH regions and to national governments.2 However, developing countries were not involved in the development of ICH GCP, and so its application in these countries should not be taken for granted, or even be expected.1 Thus, companies running clinical trials in Africa will need to carefully select the centers and investigators to ensure that ICH GCP standards can be maintained. They will also need to carry out thorough training and monitoring to ensure that these standards are followed. Proactive management of sites is important to eliminate or at least minimize events that would have an effect on the smooth running of the study and that may cause delays or quality issues.
There has been a degree of negativity in the media concerning the work of pharmaceutical companies in developing countries. Therefore, it is extremely important that the same level of diligence and ethical adherence is not only performed, but is applied in all geographic sectors. One must be aware of how a pharmaceutical company is perceived to carry out its clinical research tasks. It is all-important that patients in one hemisphere of the world must not appear to be at a disadvantage with respect to those in another hemisphere.
It is imperative that adequate attention is paid to informed consent procedures so that potential patients understand their involvement in a clinical trial. As part of this, it may be necessary to consult with community representatives to develop innovative and effective means to communicate all necessary information in a manner that is understandable to potential participants. Potential participants should be allowed sufficient and adequate time to confer with anyone else of their own choosing to discuss the particular features of the research, and to minimize the possibility that they may be subjected to undue influence or coercion.
Following the Edinburgh 2000 revision of the Declaration of Helsinki, there has been considerable discussion concerning the use of placebos in clinical trials and the ethics involved. It is considered unethical to use placebo controls when a proven effective treatment exists.3 These issues need to be addressed in order to ensure that there are appropriate safeguards in place to protect participants in placebo-controlled trials, and that subjects are not exploited because they happen to be in a developing region of the world.
Although an argument can be made that a placebo-controlled trial was ethically justifiable because it was still uncertain whether prophylaxis would work, it should not be argued that it was ethical because no prophylaxis is the "local standard of care'' in sub-Saharan Africa. The Declaration of Helsinki requires control groups to receive the "best'' current treatment, not the local one. The shift in wording between "best'' and "local'' may be slight, but the implications are profound. In addition, the Department of Health and Human Services' own regulations governing U.S.-sponsored research in foreign countries, as well as joint guidelines for research in the Third World issued by WHO and the Council for International Organizations of Medical Sciences, require that human subjects receive protection at least equivalent to that in the sponsoring country.
Regulatory affairs is a complex and ever-changing field even in the major markets of the world, where the processes are considered fairly well defined. Therefore, it should come as little surprise that devising a regulatory strategy to suit the numerous operational considerations in Africa can be a daunting challenge. In this regard, it is extremely beneficial to gain the insight of those from Africa who have direct experience working there and who understand the mechanics of the region. These individuals can ensure a realistic approach to working in Africa, so that potential benefits in terms of clinical trials can be identified and evaluated in the context of the overall global project.
The political and economic instability of Africa as a whole, poverty, unemployment (Figure 1) and the continual requests for aid make the region an unattractive investment opportunity for most multinationals. These problems impact on the market for the sale of products, and sponsor companies are reluctant to put too much time, energy, and money into growing their products in this area.
Figure 1. Estimates of unemployment rates in African countries (%).
Marketing authorizations can take years before they are approved depending on which country they are submitted to— some countries have no approval procedure at all, while others are extremely slow and bureaucratic (Table 2). The dossier content varies from the bare minimum to the large dossiers of the same content submitted in Europe.
Table 2. Africa marketing authorizations-Variance between countries
Clinical trials require a large investment from pharmaceutical companies, and the process is fraught with countless problems and endless delays. However, it is an international regulatory requirement for many products to be thoroughly investigated in all ethnic environments before coming to market, and there are many diseases that occur in abundance in Africa.
Companies that have successfully carried out clinical trials in Africa have taken the time to understand the issues of the region and have devised strategies to overcome obstacles. If they are clear in their objectives and take the advice of those experienced in working in Africa, then there is no reason why they cannot derive benefits for their overall development program.
Before a sponsor can proceed with the applications for clinical trials, feasibility studies need to be conducted to identify hospitals and clinics with suitable skills and expertise. The drain of skills from many African countries has seriously jeopardized the health industry, and it has often been quite difficult to find the skills required in a specific therapeutic area. On the other hand, many of Africa's skills are hidden from the world's view due to inability to access the Internet, extremely poor communication systems, and the banning of foreign media in some countries.
Access to possible sites is often difficult, as security and transport in much of Africa are limiting factors. Physical visits are the order of the day, but they are costly and not time-efficient. Setting up a good network of people on the ground capable of identifying possible sites and familiar with the local institutions and doctors would be beneficial. Careful selection of committed sites and investigators must be undertaken firsthand.
The next problem encountered would be the compliance of the site and investigator to good clinical practice, and the avoidance of protocol deviations. Intensive quality training is required to ensure that the understanding and the importance of this compliance is impressed on the staff. Frequent monitoring would be recommended in order to maintain this approach.
Bribery and corruption are rife throughout Africa, but we must remember that there are still many investigators out there who are genuinely concerned for the welfare of their patients and would be fully committed to the clinical trial. The issue for companies is therefore how to find such investigators.
Africa is a poor continent (rich in natural resources but poorly managed), and material rewards must be carefully considered—money might not be the only payment appreciated, as this is easily squandered. Sponsor companies should consider the payment by way of alternative methods such as equipment to those committed investigators and institutions. The acquisition of the latest equipment is a major logistical and financial problem to many hospitals, but the management of those hospitals still have the desire to be up to date and to be capable of dealing with difficult and emergency situations.
There are no standard requirements in Africa, and every country is different in its procedures and legislation.
There was an attempt at harmonization in Southern Africa using Southern African Development Community (SADC) as a baseline with regards to a number of issues, including Regulatory Affairs for the health care industry. SADC was formed in Lusaka, Zambia, on 1 April 1980, following the adoption of the Lusaka Declaration—Southern Africa: Towards Economic Liberation—by the nine founding Member States. The Declaration and Treaty establishing the Community, which replaced the Coordination Conference, was signed at the Summit of Heads of State or Government on 17 August 1992, in Windhoek, Namibia.
SADC has 14 Member States: Angola, Botswana, Democratic Republic of the Congo, Lesotho, Malawi, Mauritius, Mozambique, Namibia, Seychelles, South Africa, Swaziland, United Republic of Tanzania, Zambia, and Zimbabwe.
The Southern & Eastern African Medicines Regulatory Affairs Conference (SEAMRAC) was the initiative that was launched using the SADC as a background. SEAMRAC originated after a delegation from the Pharmaceutical Manufacturers' Association (PMA) of South Africa visited the Drugs Control Council (DCC) in Zimbabwe during 1993 to discuss labeling issues between the two countries. However, after a follow-up meeting in Pretoria, South Africa to explore the prospects for collaboration, it was realized that a harmonized approach on labeling requirements with respect to medicines between South Africa and Zimbabwe had several shortcomings. In particular, the differences in labeling and package insert requirements caused substantial difficulties in the timely provision of medicines between the two countries.
A number of objectives were established (Table 3), and to ensure success various task forces whose role was to review issues and then publish recommendations for the benefit of any interested parties were set up (Table 4). Following a meeting of these Task Groups, when the recommendations would be finalized, the intention was for the Lead Team to review them at their meeting during August/ September 1997. Following Lead Team approval, a second SEAMRAC meeting was scheduled for January 1998, when it was hoped that the recommendations would be approved. Upon final approval, the delegates from each country would submit these recommendations to their respective Health Departments and Industry bodies for their review and comments.
Table 3. Objectives of SEAMRAC
This highly ambitious plan was set to culminate in a meeting of the Lead Team in 1999, where the formal SEAMRAC recommendations would be submitted to the various governments. The process of implementation and legislation with respect to the recommendations would then follow.
Table 4. SEAMRAC Task Forces
Unfortunately, despite the enthusiasm of those involved, this "road-map" for harmonization in Southern Africa never really progressed, and each country still relies on its own internal legislation and guidelines. Generally it is accepted that ICH guidelines are applicable in most countries in Africa. The more developed countries such as South Africa, Namibia, Zimbabwe, and Botswana, to some extent, do have reasonably sophisticated medicines control bodies who carry out application evaluations, inspections, and licensing procedures.
Every African country does have a regulatory body of sorts, but in practice some are more active and responsive than others. Meeting the regulators face to face will definitely be of benefit as personal contact is much appreciated in Africa. Reliance on electronic media in the first world for communication is time-efficient and economical, but encourages people and companies to become insular and lack a true understanding of the local problems and peculiarities. Discussing issues eye to eye is far more beneficial and creates a good understanding of how that particular regulatory authority works and what their requirements are. Again, a good network of local people is recommended.
The most important problem facing all African countries in applying the regulations and guidelines is the lack of skills and suitably qualified personnel. To the detriment of these countries struggling to compete with the first world, many such people have left to gain experience elsewhere. Sadly, this lack of staff can contribute to extensive time delays in obtaining approvals. For example, Namibia received so many marketing authorization application dossiers in 2003 that they were unable to process these themselves and declared a "submit-by" date at the end of January 2003. The Namibian authorities decided to adopt a previous system whereby they would accept a South African registered product (Table 2), provided that it had been registered in South Africa prior to the end of 2003. Any product that had not been registered in this manner by the cut-off point would require a normal Namibian registration application: the lead time for this is estimated at two years. Botswana has also been faced with problems in coping with demand. It recently subcontracted the review of submitted marketing authorization application dossiers to The Medicines Control Authority of Zimbabwe.
Effective communication is almost impossible as these countries have not been able to afford to implement the latest technologies. Although access to the Internet and email does exist, it often involves the use of unreliable systems prone to breakdown. Theft of existing cables and other hardware is an ongoing problem; it is certainly not unheard of for such equipment to be stolen again as soon as it is replaced. These considerations must be borne in mind when dealing with investigators in Africa, as there is no guarantee that an email would have reached the intended recipient. Personal research on the various Web sites has shown them to be quite deficient in many of the countries.
The public transport systems employed are antiquated and unreliable, with continual breakdowns and lack of adherence to time schedules. This is considered to be a great disadvantage for the region, but in reality there are many established transport systems in the developed world with a poor track record for punctuality and reliability. For example, in London, where nine out of ten workers use public transport, the unreliability of the city's Victorian transport system is conservatively estimated to cost employers £230 million (US$370 million) a year.4 This is seen as a major disadvantage for London in competing with other major world cities for business, and a number of companies have chosen to relocate out of the city. Interestingly, it is also seen as a potential weakness in the United Kingdom's bid to host the 2012 Olympic Games. Although it is important not to become too carried away with the failings of other countries' transport systems, the examination of such examples can at least result in a more objective view of the situation in Africa. In a sense, because such delays are expected in Africa, study personnel know not to rely on public transport, and hence you are able to plan your time more efficiently and ensure that space is not a problem.
Crime and security are extremely important to the travelers, as they are often unaware and ignorant of safety issues in various countries. Events move quickly in Africa, and political considerations should also be factored into the general approach to working in the region, particularly with regard to travel within and between countries. It is far better to employ carefully selected local people to deal with all the issues, as they are accustomed to dealing with such problems.
It is easy to become pessimistic and negative about working in Africa, but in reality it is an exciting and challenging world region. In short, if a company can carry out business in Africa successfully, then it is well set up to carry out business anywhere in the world. In essence, a company needs to be prepared to endure some frustrations and delays before it achieves its objectives. Sponsors should be prepared to deal with people and systems on a different level—they must not be overinfluenced by the practices they are accustomed to in Western countries.
There is also a real need to appreciate the individuals with whom the company will deal with and not to prejudge them. Africans have different values and place importance on things the Westerners may never consider important. Face to face meetings are more beneficial in Africa, and companies that take the time to involve themselves this way will reap the rewards. African people prefer personal contact and enjoy discussing all aspects of the proposed study. In all studies, the enthusiasm of investigators and study staff is known to be enormously beneficial to the conduct and outcome of a study. The African attitude to personal contact should be considered an advantage.
It is extremely important not to exhibit any form of condescending behavior to the African investigators and study staff, or to imply that they may not understand the issues at hand. In reality, they are likely to be more aware than sponsors might expect, and the learned physicians place a great deal of emphasis on ensuring that they keep up to date with the latest treatment plans and techniques.
It is also important to understand that the attitude to time in Africa will be very different to the West. Adherence to timelines and efficiency may be completely different to those experienced elsewhere in the world, even though the commitment to the study is absolute.
It is necessary here to reiterate the importance of having local, committed people to help with visits to the regulatory authorities to obtain firsthand information on the progress of your application and the latest requirements. These people will also help with identifying and monitoring relevant sites.
As long as Africa is approached in the correct frame of mind and the many issues raised above are taken into account, companies should be able to achieve their clinical trial objectives. Central and Eastern Europe, Asia, and Latin America have logistical and regulatory hurdles analogous to Africa's, but through experience sponsors have gained the confidence to overcome such issues in these regions. As a result, these areas are featured to a greater extent than ever before in terms of global clinical trials, and Africa may follow a similar path in the future. There is no reason to be discouraged from working in Africa as long as the region is not utilized in an attempt to rush through a clinical trial or rapidly obtain a marketing approval. As with other areas of the world, in time, Africa will have its own positive part to play in global clinical trials.
1. M.-J.Lamberti, "The Changing Climate of Clinical Research," Presentation at the February 2004 The Association for Clinical Data Management (ACDM) Meeting, Bristol, UK.
2. S. Baily and M. Cripps, "Out of Africa," The Good Clinical Practice Journal, 10 (11) 20-23 (2003).
3. Placebo-Controlled Trials, The Department of Clinical Bioethics, Unit on Clinical Research, National Institutes of Health Clinical Center, http://www.bioethics.nih.gov/research/humanres/placebo.pdf
4. "City Pays High Price for Transport Delays," Corporation of London press release, 28 July 2003, http://www.cityoflondon.gov.uk/corporation/media_centre_archive/files/delays.htm
Sharon Rouse and Faiz Kermani,* PhD, are with Chiltern International Limited, 171 Bath Road, Slough, Berkshire, SL1 4AA, United Kingdom, +44(0) 1753 512000, fax +44(0) 1753 511116, email: Faiz.Kermani@chiltern.com. Beatriz Mosqueira is with Chiltern International Spain, S.A., Madrid, Spain.
*To whom all correspondence should be sent.