Difficult issues in pharma going global (part II)

Dr. Faiz Kermani

(continued from “Difficult issues in pharma trials going global (part I)”)

In the first part of this article I looked at the growth of clinical development activity in the emerging pharma markets, discussed the cost savings this presented to the industry but also raised the question of managing appropriate ethics of such activity. In this piece, I will look at some of the measures being put in place to steer pharma in the right direction and protect the local populace as more companies direct their trials to these regions.

Shaping the regulations in emerging markets

In more established markets, the regulatory, ethical and clinical research environments have become well defined over a long period of time and are enforceable by law. Furthermore, even if changes are occasionally unwelcome, companies have sufficient previous experience to help them adapt to new standards. An example of this was the 2004 introduction of the The European Clinical Trials directive (2001/20/EC), which aimed to standardize the way in which clinical trials were run across the EU.

With emerging regions of the world the clinical trials environment is 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 Harmonisation-Good Clinical Practice) standards and when extending beyond these areas researchers expect to run trials to a similarly high level. As outlined by the EMEA, 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 protected10.

 

“Everyone involved in clinical development has a duty to look after and care for patients…commercial objectives should not interfere with this stance.”

 

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 treatment11. This has led to some controversy in the pharmaceutical industry since there is a concern that these new proposals could obstruct research and development in some therapeutic areas leading to considerable delays in the development of products addressing unmet medical requirements.

Since companies follow ICG GCP in the major world regions, they use the same approach in emerging world regions. Yet although 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, other 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 expected12. This is extremely important since in many countries use a local GCP that is not equivalent to ICH GCP.

In practice, companies have tended to carefully select the centers and investigators to ensure that ICH GCP standards can be maintained and ensure thorough training and monitoring to ensure that these standards are followed. Proactive management minimises 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.

 

“It is imperative that adequate attention is paid to informed consent procedures so that potential patients understand their involvement in a clinical trial.”

 

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 product. 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 regions.

Another problem in emerging regions is that ethics committees (ECs) or institutional review boards (IRBs) may not operate in the same way as in the US, Europe or Japan. Historical abuses of human subjects in medical experiments led to the development of strict procedures in these countries, with heavy penalties for anyone caught breaking the law. Even now, these systems are not considered perfect, as was seen with the 2006 Tegenero TGN1412 trial in the UK.

In a number of emerging markets, ECs/IRBs are still a relatively new concept for that region. Given the volume of clinical development in these new areas, it is worth asking whether these committees really have the right structure and independence to make decisions concerning complex trials. Furthermore, do the people involved on the committees have the right experience and do they have adequate training? There have been instances where committee members work for the very institution conducting the research they are reviewing, thereby representing a clear conflict of interest13.

Can pharma be more proactive?

Although companies wish to maintain high standards for their clinical trials around the world and many personnel have the best of intentions, it does not take much to provoke very negative media coverage for the industry as a whole. An example of this is Pfizer Trovan case in Nigeria, which has been continuing since 2007. In 2009, a high profile article appeared in the New England Journal of Medicine that was highly critical of the trend in outsourced clinical trials. It expressed concerns that lower income countries were being used for trials for the benefit of those in higher income countries. In addition there have been television documentaries in both the US and Europe citing examples of patient exploitation.

Although the pharmaceutical industry may detest such negative coverage there is no shortage of public criticism on the back of these stories. At the moment, the pharmaceutical industry is struggling to get its views across in the media and convince a sceptical public that the research carried out by companies is always in the best interests of patients.

Advances in medicine depend to a large extent on clinical trials and without public participation these cannot proceed. Companies must become more assertive in how they discuss the outsourcing of clinical trials and other activities and be able to communicate how they are maintaining high standards. Since clinical trials depend on patient participation, volunteers must feel they can trust the company running trials in their country. Just because a potential subject is poor and illiterate this must not be mistaken for a lack of intelligence and common sense15.

Similarly, if the public in a more established market feels moral indignation at the way in which a company is perceived as operating elsewhere, they may refuse to participate in trials in their country. Recruitment in clinical trials is already difficult and so companies must do more to tackle these difficult issues. There is much evidence that the pharmaceutical industry could be helped in terms of patient recruitment for clinical trials if the public better understood the value of clinical trials and their role in the development of new medicines.

 

“Companies must become more assertive in how they discuss the outsourcing of clinical trials…”

 

In many cases, local systems in emerging markets are standing in the way of progress. It would be refreshing to see the international pharmaceutical industry showcasing these shortcomings and lobbying for improvements, otherwise they may unfairly get blamed. This may necessitate liaising with regulatory agencies and other government bodies in their home markets to drive advances. For example, the regulators in both India and China have sought discussions with the FDA in how best to develop expertise at their agencies for new demands from multinational companies. The FDA is now running a number of international programs and opening offices in different countries.

Conclusion

As business entities, the pharmaceutical industry has legitimate reasons to become more international. Developing a drug is a complex and expensive process and it makes sense to leverage benefits from other parts of the world. Furthermore, since there is a strong demand for modern medicines in these countries it is logical that clinical trials need to be carried out in local populations to demonstrate a drug’s efficacy and safety. However, this does necessitate tackling some difficult questions about how best to operate in newer markets and being more open about intentions.

There are numerous examples of clinical trials having contributed to the advances in medicine seen in more established markets, even when this has led to commercial benefits for the companies that developed the drugs involved. It is up to companies to make sure that they can demonstrate similar benefits for those in emerging markets. Commercial objectives must always be balanced with an ethical approach and companies will not lose out by discussing some of the trickier angles to working abroad. In fact, by generating better public support, they have everything to gain.

References (continued from part I):

10. Anon (2005). Good Clinical Practice – Human Medicinal Products. European Medicines Agency (EMEA).

11. Christie B (2000). Doctors revise declaration of Helsinki. British Medical Journal. http://bmj.bmjjournals.com/cgi/content/full/321/7266/913

12. Baily S and Cripps M (2003. Out of Africa. The Good Clinical Practice Journal. Volume 10 (11): 20-23.

13. Jim. O-J (2003). Current status of institutional review boards in Korea. J Korean Med Sci. 18:3-10.

14. Singer N. (2009). Outsourcing of Drug Trials Is Faulted. New York Times. http://www.nytimes.com/2009/02/19/business/19clinic.html?_r=2&amp,hp

15. Sahoo U et al. (2006). Subject recruitment: An Indian perspective. Applied Clinical Trials. 15(2): 54-62.

About the author:

Faiz Kermani is an independent consultant with experience in the US and UK. At some time or another he has found himself in discovery R&amp,D, international clinical trials, pharmaceutical pricing and reimbursement, and medical communications. This jack of all trades history causes him to attempt articles that look at the big picture for the global pharmaceutical industry. He can be contacted at faiz@doctors.net.uk.

Is pharma being proactive enough in managing emerging market trial ethics?