Chronic myelogenous leukemia (CML) is a rare cancer that affects the bone marrow. Until ten years ago, a diagnosis of CML was a death sentence unless you had a tissue-matched donor, usually a sibling, and underwent a bone marrow transplant. In 1996, laboratory scientists showed that a drug selectively killed CML cells in culture without harming normal cells. Two years later, the first reports of 31 patients treated with this drug were published; all had dramatic responses.
This impressive progress changed the outlook for these patients, and it could not have been made without clinical trials. And with life expectancy rising around the world, but haunted by the prospect of substantial disability, such clinical trials are likely to become more important in the years ahead. But they are not without their challenges.
Recently the OECD adopted a policy initiative on the governance of clinical trials in an attempt to define a new framework for better oversight of clinical trials, with a special emphasis on facilitating those trials that have public and charitable rather than industry funders.* Why was the instrument adopted and what can it help to achieve?
A tale of two studies
Clinical trials are rigorously designed experiments in which participants who have consented to receive a new therapy or to be assigned randomly to one of several possible treatments are carefully studied for the positive and negative effects of those therapies. The aim is to provide sufficient evidence to guide medical practice and public health policy. Clinical trials are a critical step for the production of new drugs and for the study of existing health treatments. They improve the health and quality of life of our citizens, add value to our economies, and guide policymakers responsible for laws and regulations. This benefit applies to both common and rare diseases.
Take the promising results related to CML again. Over the subsequent five years, multiple studies confirmed the efficacy of the drug, now called Gleevec™. In 2013, bone marrow transplantation is rarely required for patients with CML, whose extended survival is expected. How did this happen? University medical scientists supported by US taxpayer funds from the National Institutes of Health (NIH) worked with a pharmaceutical company, Novartis, to take this drug from the shelf to the clinic. Now patients all over the world receive Gleevec™. Its approval came about because of rigorously conducted clinical trials in which participants with CML agreed to receive an experimental, untested drug. They took significant risks because no one knew whether the drug would work or have bad side effects. Later trials have included Gleevec™ as one of multiple therapies; participants are taking much less risk because the effects of the drugs are now well-known. But because CML is rare, international studies were essential to carry out the test on enough patients to get significant results.
More common diseases also benefit from clinical trials. About the same time that Gleevec™ studies began, 3,234 healthy people at high risk of developing type 2 diabetes agreed to take part in a clinical trial to see if their diabetes could be prevented. A third of the patients had no treatment, a third received an approved marketed anti-diabetes drug called metformin, and the remaining third were put on diet and exercise programmes. Four years later, the people who changed their diet and took exercise were found to be only half as likely to develop diabetes as those with no treatment. Metformin reduced the likelihood of developing diabetes, but also provided less benefit than diet and exercise. The study was funded by US taxpayers and conducted at 27 different sites.
Worldwide, about 370 million people have type 2 diabetes; the WHO estimates that this will rise to 552 million by 2030. Could the results of the US study apply elsewhere, in Germany and the UK, or India and South Africa, for instance? Clinical trials in these countries could help us find out.
The question is, how can we harmonise approaches and better compare results for better policies? Every country has laws and regulations governing the conduct of clinical trials. Following the Second World War, all nations adopted some basic principles to guide the ethical conduct of research. International guidelines are detailed in the Nuremberg Code and the Declaration of Helsinki, while many countries have additional reports, such as the Belmont Report in the US, that outline common principles (see references). These are codified and implemented differently in different countries and regions, but the common principles apply in all countries.
While research studies may pose risks to participants, failure to conduct research poses much greater risks to citizens everywhere. Examples of treatments introduced without enough evidence include thalidomide, which caused disastrous birth defects in infants when given to pregnant women; administration of high doses of oxygen to premature infants with consequent blindness; and the use first of radical mastectomy and, later, of bone marrow transplantation for breast cancer, with major toxicity and no benefit.
Because of differences in laws and regulations, there are often barriers to conducting international research. Regulations designed to assign responsibility for protection of participants and ensure accountability may hinder collaboration. Not all clinical trials pose similar risks to participants. Treatments that are untested may create significant risks to participants and liability for sponsors. In contrast, trials of established therapies (as in the case of the diabetes study described above) pose little or no risk to participants. Existing regulatory systems often have similar administrative requirements whatever the risk, and sponsor liability may be significant.
What is the new OECD Recommendation about? Health care systems and clinical research infrastructure vary widely, especially between high income and lower income countries. Many policy barriers to conducting international trials may exist, many deriving from inconsistencies in definitions, assignment of responsibilities and requirements for oversight. The OECD initiative is a major step towards developing a harmonised framework for the governance of clinical trials. It introduces a risk-based oversight and management methodology, which combines risk categories based on the marketing authorisation status of the medical product with a trial-specific approach that considers issues such as the type of populations involved in a trial, and the informed consent of the patients.
In other words, besides facilitating the conduct of international trials, the implementation of the OECD Recommendation helps to streamline procedures for low-risk trials, while at the same time strengthening the protection of the patients, increasing the quality of the data and improving the credibility of the results. It also addresses the thorny challenge of seeking an accepted method for assessing the risk that participants face in entering a trial, and hence the responsibility borne by the study sponsor for compensation and care of participants affected by the study.
In this together
In December 2012, The Lancet published an entire issue on the Global Burden of Disease Study, demonstrating improved life expectancy with substantial disability for the last decade in most countries. Neither the quality of life nor our global economy can afford to continue these trends.
Indeed, science, health care and disease are now shared globally. Biomedical research is resource-intensive. Evidence gathered in one country is used in others, sometimes without adequate study. Especially for diseases in which large numbers of participants and locations are needed to answer scientific questions with statistical validity, international studies are essential. In rare diseases, it is impossible to do studies in single countries. An outstanding example is the development of arsenic trioxide for acute promyelocytic leukemia, a treatment discovered in China, studied worldwide and now benefiting patients on every continent. Regardless of economic resources, all countries should participate in joint scientific enterprises to ensure maximal benefit.
The OECD recommendations are designed to facilitate collaboration, leverage existing investments, and enable all nations to improve the health of their citizens and economies, enhancing technological development while prolonging healthier, more productive, lives.
The 2012 OECD Recommendation on the Governance of Clinical Trials and its explanatory memorandum can be found at www.oecd.org/sti/sci-tech/oecd-recommendation-governance-of-clinical-trials.pdf
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (NCPHSBBR) (1979), “The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research”
©OECD Observer No 294 Q1 2013