Outsourcing of clinical trials to contract research organisations and
offshoring to middle- and low-income countries, in a sector preoccupied
with costs and productivity, create a need for more independent
monitoring and compulsory registration to ensure ethical protections
are not being traded for speed and economy, a new report argues.
In fact, the report by Dutch non-profit SOMO (Centre for Research on Multinational Corporations), conducted in collaboration with Latin American organisation Salud y Fármacos and India’s Centre for Studies in Ethics and Rights, is long on concerns but short on concrete evidence of harm caused to clinical trial participants in developing countries by lax regulatory oversight or inadequate exercise of sponsor responsibilities.
The authors complain of the “extreme lack of transparency of CROs in particular and of the pharmaceutical sector in general”, which means that some of the report’s findings “remain anecdotal and thus any generalisations from these findings should be avoided”. As such, they suggest the report “might be interpreted more as a discussion document” than as any conclusive evidence.
Nonetheless, the concerns identified were sufficient for the report authors to recommend a number of measures aimed at improving both the transparency and the independent oversight of clinical trials in ‘non-traditional’ regions. These are:
- Setting up a worldwide, compulsory clinical trial register that discloses all parties involved in the trial, including contractors and subcontractors.
- Stepping up the number of inspections of trial sites in non-traditional regions.
- Including in marketing authorisation application (MAA) procedures independent verifications that drugs have been tested in accordance with the Declaration of Helsinki.
- Involving independent organisations that promote the interest of clinical trial participants in CRO and sponsor audits of trial sites.
- Involving clinical trial participants in inspections and audits, so that their ethical perspective is taken into account.
- Making audit and inspection results publicly available.
The SOMO report takes off from the observation that around half of all clinical trial activities are now outsourced to CROs, generating a market estimated at US$24 billion in 2010.
In parallel, cost and patient recruitment pressures are pushing more and more of these trials out to Latin America, China, Eastern Europe and Russia, which offer rapid recruitment, a broad spectrum of diseases, treatment-naïve populations, available human resources and technical skills, and differentiated ethnic responses to drugs, the authors note.
As things stand, between 40% and 50% of new drug applications submitted in the EU and US include trials conducted in these regions, which are often less regulated than Western Europe or North America, have less developed healthcare systems, and contain relatively vulnerable patient populations, the report adds.
Not only are all of the major CROs present in the popular clinical trial locations across these regions but, in large markets such as India and Brazil, the regulatory process has recently been modified to expedite the approval of clinical trials – a “decisive factor” in attracting the contract research industry, the authors point out.
CROs can operate in these markets “without registration or accreditation; a registration at the chamber of commerce is enough to start testing drugs on humans”, they claim.
Research for the report involved a preliminary study of the literature as well as country-level research in Argentina, Brazil, India and Peru, plus interviews with clinical trial experts and pharmaceutical companies.
The expectation that problems with outsourcing observed in other industries (e.g., lower labour and environmental standards due to cost/competition pressures, responsibilities fragmented among value-chain actors) “would also be present in the pharmaceutical supply chain is confirmed”, the reports says.
Interviews and secondary data revealed concerns over trade-offs between the speed and costs of clinical trials managed by CROs on the one hand, and the ethical quality of these trials on the other, it explains. “The suggestion is that sponsors expect CROs to conduct the trial as quickly as possible, which might put pressure on the CROs to be lax on the ethics.”
The interviews also pointed to subcontracting by CROs, which “fragments clinical trial-related tasks further and squeezes budgets even more”, the report adds. Accordingly, trial sponsors have developed mechanisms to select, monitor and evaluate CROs, with the objective of guaranteeing compliance with relevant laws and ethical standards.
“In fact, these mechanisms greatly increase the costs of CRO-sponsor contracts, which affect the business case for working with CROs, and makes some sponsors wary of outsourcing clinical trial management altogether,” the authors comment.
Nonetheless, interviews with CROs indicate that the stringency of monitoring mechanisms varies widely among sponsors, “which obviously creates opportunities for under-performing CROs”, they warn.
Whether these risks “actually materialise into more harm” for clinical trial participants “cannot be assessed with this study”, the authors admit. “However, since our data reveal that independent oversight of CROs and clinical trial sites by authorities and ethics committees is perceived to be insufficient in at least India, Brazil and Argentina, the concerns remain justified.”
Chain of responsibility
The report did not substantiate expectations that pharmaceutical companies “might not yet fully recognise and control their responsibility for all the actors in the research and development process”.
In fact, it notes, international regulations require these companies to remain formally responsible for the ethical conduct of any clinical trial they sponsor. Moreover, pharmaceutical companies “claim they have several mechanisms in place” to control the R&D process, the most significant of these being due diligence in CRO selection, contractual arrangements, and auditing and training of CROs, clinical investigators and trial sites.
Nonetheless, the authors remain sceptical. “At the policy level, the protection of participants in clinical trials managed by CROs in non-traditional trial regions seems to be in order, but what happens in practice is hard to verify,” they comment.
As the study suggests, independent oversight of trials by the authorities in India and Brazil and by ethics committees in India, Brazil and Argentina “leaves a lot to be desired. Furthermore, European MAA procedures for drugs that have involved testing outside Europe do not include independent verification of the ethical conduct of the trials”.
Another concern raised is the lack of clarity over how responsibility for clinical trial ethics “will shift when sponsors and CROs enter into partnerships. And since such partnerships seem to be a trend, this leaves an important area unexplored”.
The research for the report and its findings have “possibly resulted in more questions than answers”, the authors acknowledge. However, they insist, the problems encountered make it clear that “the transparency of the sector needs to be greatly improved, along with independent oversight of clinical trial conduct”.
It remains “an area of grave concern that the parties that earn most money with the trials – CROs and sponsors – seem to be the most important monitors in non-traditional trial regions”, the report says.