Global Clinical Studies

By Faiz Kermani and Camille Lovell-Hoare | August 23, 2005

With great power comes great responsibilities

Encouraging sufficient numbers of patients to participate in a clinical trial is important if it is to be a success. Large numbers of subject are needed to generate high quality data that will convince regulators and clinicians, as well as future users in the general population, that a product is of clinical benefit. Companies are constantly under pressure to run additional trials to prove their claims about a particular product.

An analysis by CMR International of 23 clinical dossiers submitted between February 1995 and April 1999 to regulatory authorities in Europe, the U.S. and Japan, found that the dossiers contained on average 35 clinical trials, involving on average more than 4,000 subjects each1,2. Another analysis estimated the mean number of patients per New Drug Application (NDA) to be 3,233 between 1985 and 1988, but for the period 1998 to 2001 this mean number had risen to 5,303 patients per NDA3.

The field of clinical trials is highly competitive and companies must be prepared for a situation in which their preferred initial locations do not result in the necessary number of patients being recruited. The demands to include additional patient data and the competitive nature of clinical development have led to a more global outlook for clinical trials. The major drug development regions of the world remain North America, Europe and Japan, but markets such as those in Asia, Latin America and Africa have emerged as important locations for clinical trials being run by pharmaceutical and biotech companies. These regions have large, growing populations and there is often a sizeable group of patients affected by diseases of interest to pharmaceutical companies (Figure 1 and Figure 2). This has further significance given that these emerging regions are also becoming important markets for new products. Through clinical trials, local physicians gain experience of new products and therefore it is in a company's interest to base some clinical research in these locations. According to Centerwatch, in 1998 only 11% of total sites were in emerging market locations, but by 2002 this had increased to 30%4.

The emphasis on emerging regions is more dramatic when examined in value terms. Pharmaceutical industry data shows that clinical trial spending between 1998 and 2002 rose from $20 billion to $90 billion in Asia-Pacific, from $73 billion to $325 billion in Latin America and from $10 billion to $75 billion in the Middle East and Africa4.

These trends are also being noted at a more local level. For example, in Chile, the Institute of Public Health (Instituto de Salud Pública) noted that clinical trial activity in 2003 rose by 50% over that of the previous year. The Institute registered 45 approved clinical trials and valued this type of research at between $10 million and $15 million per year. A 2002 survey found that 800 investigators in Chile were involved in clinical research and that the therapeutic areas of greatest interest were cardiovascular, diabetes, central nervous system, cancer, osteoporosis and vaccine studies5.

Mexico has become an important center for clinical trials. In 2003, around 26,300 patients participated in clinical trials and this increased to more than 37,500 in 20046. More than 1,800 investigators were involved in carrying out these clinical studies in 20 different therapeutic areas6. More than 80% of clinical trials in Mexico are carried out in public health institutions. The Pharma industry association CANIFARMA (Cámara Nacional de la Industria Farmacéutica) recently surveyed its members to find out their reasons for carrying out clinical trials in the country7. These companies believed that clinical development provided healthcare professionals with experience in using their product7. Half of the respondents also carried out clinical trials following the marketing of their products in order to gain a better understanding of the population using the medicine7. Understanding the differences in pharmacogenomic profiles was cited by some companies as important in such studies and the issue is receiving considerable attention in Mexico6, which has recently set up the National Institute of Medical Genomics (Instituto Nacional de Medicina Genómica) to examine such factors and promote research in this area. Part of the Institute's work has been to develop clinical protocols for the prevention, diagnosis and treatment of a variety of common diseases8. As Mexico has become an important pharmaceutical market in its own right, Pharma companies may need to address pharmacogenomic issues in their clinical trials in the future in order to satisfy the authorities and gain public confidence (Figure 3).

There has also been considerable interest in carrying out clinical trials in the African states due to the large population and prevalence of disease. The development of partnerships between African scientists and research institutions in Africa have been facilitated by virtue of the formation of the European and Developing Countries Clinical Trials Partnership (EDCTP)9.

Many in the pharmaceutical industry and the investigator community have supported measures to educate patients about the benefits of being involved in clinical research and on how their participation is necessary for the development of new medicines. Political measures have even been taken to encourage patient participation in clinical trials. In June 2000, President Clinton issued a memorandum that allowed Medicare to pay for routine patient care costs associated with clinical trials10. The American Cancer Society (ACS) has highlighted the benefits of participation in clinical trials, citing that around 90% of children with cancer are participating in pediatric oncology clinical trials, compared to only about 3% of adult patients10. This trend is believed to have played an important role in the medical advances in treating childhood cancers10.

Given the internationalization of the work in most industries, this trend in clinical trials for the pharmaceutical sector is not surprising, but it does raise several issues concerning the patients involved. In more established markets, 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. Furthermore, when outlining the commercial benefits of operating in emerging markets and recruiting patients rapidly from large populations, extreme care must be taken in how this could be perceived. When publicized from a purely commercial standpoint, the objectives for clinical trials in emerging markets could give an erroneous indication that somehow standards will not be maintained. Everyone involved in clinical development has a duty to look after and care for patients involved in trials wherever they are and commercial objectives should not interfere with this stance.

In the major world regions for drug development, clinical trials are run to ICH GCP (International Conference on Harmonization - Good Clinical Practice) standards and, when extending beyond these areas, researchers expect to run trials at a similarly high level. As outlined by the European Medicines Agency, GCP is an international ethical and scientific quality standard to ensure that clinical trials involving human participants are designed and carried out in an ethical manner. GCP has its origins in the Declaration of Helsinki and reflects the principles of the treaty; by complying with the GCP there is an implied assurance that the rights, safety and general welfare of the trial subjects are protected11.

The World Medical Association revised the Declaration of Helsinki in October 2000; it included recommendations for trials carried out in developing countries by emphasizing the requirement for informed consent and the need to protect vulnerable groups. Other changes included that the testing of any new treatment should be tried out against the best current method as a comparator, a placebo should not be used; the implementation of this would mean that the trial subjects in developing countries would have access to the best available treatment12. This has led to some controversy in the Pharma industry, since there is a concern that these new proposals could obstruct R&D in some therapeutic areas, leading to considerable delays in the development of products addressing unmet medical requirements.

Since companies are accustomed to following ICH GCP in the major world regions, they use the same approach in emerging world regions. Yet although these standards would be desirable in order to generate data that is acceptable to both regulatory authorities in ICH regions and to national governments, developing countries were not involved in the development of ICH GCP and so its application in these countries should not be taken for granted, nor should it be expected13.

In practice, companies have tended to carefully select the centers and investigators to ensure that ICH GCP standards can be maintained and to ensure thorough training and monitoring that these standards were followed. Proactive management minimizes events that might have an effect on the smooth running of the study and that may cause delays or quality issues.

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.

Despite the ability of companies to carry out trials in emerging regions to the standards necessary for use of the clinical data in established world regions, there continue to be concerns about the ethics involved. The overriding concern is that, having served as participants in clinical trials, those in underprivileged communities may not benefit in the long-term. Emerging regions are often not a market for the drug being developed and thus when the clinical trials for a product are successful, these patients may never again have access to the product14. In more established markets there is often a mechanism in place for patients to continue to receive a product following clinical trials, but there is nothing comparable in emerging regions14,15.

There are many who believe that the industry should move towards providing patients in developing regions with drugs after a trial has ended. As this would result in considerable expense for a company — due to setting up distribution systems and training healthcare personnel to administer the drug — this is not standard procedure14. There is also the problem of how widespread such provisions should be, whether they should only involve those in the trial or the community in general14,15. Many companies have tried to introduce a better system to deal with patients in these regions, but it is the lack of binding international guidelines in preventing patient exploitation in these regions that worries ethicists14,15.

Many observers believe that, while pharmaceutical companies cannot be solely held responsible for the legislative vacuum that exists in the field of emerging market clinical research, they have an important role to play in ensuring that measures are developed. Somehow those in academia, governments and industry need to address these issues so that clinical research in emerging countries does not come across as having an edge of exploitation to it. With public criticism of Pharma companies at an all-time high, confronting these issues in a manner that at least produces honest discussion would be immensely beneficial to the industry's image. Unfortunately, the good work that Pharma companies carry out to develop new medicines is frequently lost in negative media coverage and other parties that have a role in international healthcare, such as governments, escape blame.

The last few years have seen the pharmaceutical industry address issues that are more reflective of events in developing regions of the world. The Pharma industry has had to deal with the fact that the current focus of its R&D efforts are not overtly aligned with the areas of unmet medical need in developing countries. This perceived lack of research in this field has frequently led to use of the term 'neglected diseases.' An increasingly popular approach to tackling neglected diseases has been through public-private partnerships (PPPs). There are more PPPs in operation than ever before (Figure 4).

This is exemplified by EDCTP, which was set up to respond to the emergency caused by HIV/AIDS, malaria and tuberculosis (TB) in the developing world9. This initiative was launched in 2001 by the European Commission with the member states co-operating to develop a partnership with the developing countries in order to concentrate on the real needs of developing countries and with strong focus on the Sub-Saharan African states. These are the areas most at risk from the three communicable diseases mentioned above and therefore the goal of EDCTP is to accelerate the development of new clinical interventions to fight these disease by improving the co-operation and networking of European national programs and accelerating clinical trials of new products in developing countries. It also aims to ensure that any research carried out in the developing countries addresses their needs and is aware of their priorities; it additionally seeks to promote the transfer of technology. The EDCTP has a budget of $803 million for the period 2003-2007, one third is directly from Community funding, $268 million from member state activities and a further $268 million from industry charities and private organizations9. This co-operation between the developing countries and Europe means research into these diseases is more effective and also has the added benefit of enhancing the clinical environment for further clinical trials focusing on new therapeutic areas.

Recently, major companies such as AstraZeneca, Glaxo SmithKline and Novartis have set up well-publicized initiatives in the field of neglected diseases. AstraZeneca opened a research facility in Bangalore, India focusing on tuberculosis and Novartis opened an Institute for Tropical Diseases in Singapore16. GlaxoSmithKline is involved in similar projects using its drug discovery unit in Tres Cantos, Spain and its vaccine research facility in Rixensart, Belgium16. These initiatives should be recognized as major steps forward by the industry as this will encourage further participation by other companies. Cooperation with governments and local agencies must also be enhanced so that the results of these initiatives will benefit local populations in the long term and will fully address issues over equal access to essential medicines (Figure 5).

The internationalization of clinical trials is inevitable and in many cases, such as Latin America, the market is already fairly mature. There are considerable benefits that companies can gain from operating in these regions, given the enormous expense of drug development and the competition they face in bringing a drug successfully to market. However, in extending their reach to these emerging regions there are difficult questions to answer in how best to involve subjects in clinical trials and yet not be seen to be exploiting them. In more established markets there have been a number of instances in which patient participation in clinical trials has been identified as contributing to advances in medical research and treatments, even when taking into account the commercial gains for the companies involved. In encompassing emerging regions into their global clinical programs, pharmaceutical companies must ensure that they can also bring similar demonstrable benefits to local communities.

is a marketing executive at Chiltern International.
is a regulatory officer at Chiltern.

  1. Kermani F and Findlay G (2000). The Pharmaceutical R&D Compendium. CMR International. http://www.cmr.org/
  2. Hynes CL, McAuslane JAN and Walker SR (2000). Issues of Concern in Clinical Development: The Growing Size of the Clinical Dossier. Proceedings of a CMR International Workshop. CMR International 2000. http://www.cmr.org/
  3. Lamberti M-J. (2004). The Changing Climate of Clinical Research. Presentation at the February 2004 The Association for Clinical Data Management (ACDM) Meeting, Bristol, UK.
  4. Lamberti M-L (2004). The Changing Climate of Clinical Research. Presentation at the Association for Clinical Data Management (ACDM) Meeting (15-17 February 2004 Bristol, UK).
  5. Urbina S (2004). Ensayos Internacionales de nuevos fármacos aumentan 50% en el país. La Tercera, 26th July 2004. Boletines Fármacos. http://www.boletinfarmacos.org/
  6. Anon (2004). La Investigación farmaceútica en México. Beneficios para los Mádicos y sus Pacientes. Asociación Mexicana de Industrias de Investigación Farmacéutica. http://www.amiif.org.mx/
  7. Anon (2004). Misión, Visión, Valores, Principios, Código de Ética, Estatutos. Cámara Nacional de la Industria Farmacéutica (CANIFARMA). http://www.canifarma.org.mx/
  8. Jiménez Sanchéz G. (2004). ¨Qué es la medicina genómica?. Instituto Nacional de Medicina Genómica. http://www.inmegen.org.mx
  9. Anon (2005). European and Developing Countries Clinical Trials Partnership (EDCTP). http://www.edctp.org/
  10. Anon (2000). Clinton Orders Medicare Coverage of Clinical Trials. American Cancer Society News Center.
  11. Anon (2005). Good Clinical Practice - Human Medicinal Products. European Medicines Agency (EMEA).
  12. Christie B (2000). Doctors revise declaration of Helsinki. British Medical Journal.
  13. Baily S and Cripps M (2003. Out of Africa. The Good Clinical Practice Journal. Volume 10 (11): 20-23.
  14. Marino IR and Cirillo C (2004). Clinical trials or exploitation. Science. 306 (5693): 54-55.
  15. Marino I and Cirillo C (2005). Is pharma reneging on its duty of care? Good Clinical Practice Journal. Volume 12 (2): 10-11.
  16. Kermani F. (2004). Neglected and Emerging Diseases: The Next R&D Challenge. Chiltern International.

Related Compliance: