Industry-sponsored clinical trials in emerging markets should be more sensitive to local conditions across parameters ranging from research misconduct to disease profiles and access to medicines, an opinion piece in the latest issue of JAMA argues.
According to Stephen MacMahon and colleagues at the George Institute for Global Health in Sydney, Australia, there is a “real risk” that the “enormous health benefits and corporate profits” flowing from clinical research over the last few decades will not be sustained “unless there is adaptation to the new circumstances in which trials are conducted and recognition of the rights and expectations of communities in which trial participants live”.
Noting that in China, for example, the number of pharmaceutical company-sponsored clinical trials doubled between 2005 and 2010, MacMahon et al point out that the rapid expansion of offshoring in clinical research has “raised concerns, including questions about the quality of data generated and the relevance of the products being tested to local healthcare priorities”.
While there is no evidence that the quality of clinical-trial data from emerging markets is any different from data generated in established markets, there have been several high-profile cases of research misconduct in Asia, Africa, and Latin America, the authors observe.
In addition, “recent accusations of widespread bribery and research misconduct by pharmaceutical companies in these markets have heightened concerns about the capacity of the industry to self-regulate”.
The priority here, MacMahon et al suggest, is to ensure that effective, affordable, and practical strategies are implemented to detect serious misconduct in clinical trials. Regulatory agencies in emerging markets are “often weak and largely depend on established market regulators to detect fraud or misconduct”.
Many of the recommendations in the International Conference on Harmonization’s Technical Requirements for Registration of Pharmaceuticals for Human Use–Good Clinical Practice (ICH-GCP) do not meet these needs, though, the authors claim.
For example, ICH-GCP calls for “detailed and expensive on-site monitoring of all patient records by representatives of the product manufacturer (effectively self-monitoring)”.
Moreover, the GCP requirements assign “much of the responsibility for protocol compliance to institutional review boards, which, in emerging markets, are often underresourced and inexperienced”.
One alternative strategy, MacMahon et al propose, is comprehensive central statistical monitoring – ideally by an independent body – for real-time assessment of data quality from clinical trials in both emerging and established markets.
There is a good deal of ongoing methodological research around, for example, algorithms to detect fabricated or missing data, fraud-risk estimation models, and machine-learning techniques to identify unusual data patterns.
In the meantime, though, the routine establishment of central statistical monitoring to uncover site-level fraud “is a practical strategy that could have an immediate effect on how trials are conducted today”, the authors believe.
For one thing, they explain, “it would seem reasonable to expect that in the presence of continuous real-time central statistical monitoring, the need for routine monitoring and source document verification could be reduced to a random sample of participants or sites”.
This holds the potential to render clinical trials less expensive, more practical and more reliable – “benefits that would apply to both emerging and established markets”.
Another issue raised by the rapid expansion of clinical trials in emerging markets is the relevance of investigatory products to the regions in which they are studied.
There are ethical issues around patients taking part in clinical trials of drugs that may well be “unaffordable for all but the most affluent in their community”, at least until patent expiry, MacMahon et al write.
Brazil has tackled this issue by stipulating that research involving human subjects “must ensure benefits from the research project, in terms of social return, access to procedures, products or research agents”, they note.
The challenge, though, “lies in the actual enforcement of such a policy. For instance, a survey found that one-third of US investigators and half of in-country investigators did not believe that interventions being tested in emerging economies would be accessible to the majority of eligible people in those regions”.
One approach pioneered in HIV/AIDS research involves emerging-market regulators and pharmaceutical companies negotiating appropriate pricing agreements before clinical trials are conducted in these regions, MacMahon and colleagues point out.
These agreements define a strategy whereby effective interventions will be made affordable to the communities in which the research is conducted – for example, post-registration access to therapy for participants and community members over a defined period at an affordable cost; technology transfer through low-cost licensing for local manufacture and dissemination; or subsidised bulk purchasing by governments or healthcare organisations.
Qualms have also been expressed about the degree of alignment between products being tested in emerging markets and the disease burden of the same communities, the authors observe.
Given the increasing prevalence of chronic conditions, such as cardiovascular, respiratory, and neoplastic diseases, in emerging markets, this type of misalignment “is likely to decline”, they suggest.
All the same, emerging markets still have a substantial burden of infectious disease including tuberculosis, malaria and diarrhoea, and these conditions “are not prominent targets in the pipelines of most pharmaceutical companies”.
There could be a role here for agreements between emerging-market regulators and pharmaceutical companies on the development or joint development of appropriate products “as one of the conditions of approval of other agents that are company priorities”, MacMahon et al propose.
Market sizes in countries such as China and India “could provide the required leverage to achieve this mutually beneficial goal”, they add.
The rapidly increasing value of emerging markets to global pharmaceutical companies, MacMahon and colleagues conclude, will “hopefully provide the incentive for change” in the way these companies approach offshoring of clinical trials.
Otherwise, the authors warn, “it will be up to emerging markets to insist on it”.