Patient Participation in Clinical Trials: Is There a Country Difference?

In the December 2010 issue of PLoS One, a diverse group of authors from Brazil, Singapore, India and the US published a paper entitled:  So Different, yet So Similar: Meta-Analysis and Policy Modeling of Willingness to Participate in Clinical Trials among Brazilians and Indians.  Their objective was to conduct a systematic review and meta analysis (SRMA) of the literature to determine a model for predicting willingness of Brazilian patients to participate in clinical trials,and then compare the findings regarding Indian patients' willingness to participate in clinical trials.  The results if validated could be useful for sponsors and CROs planning studies to avoid wasting time and money in the wrong country and to better design protections for vulnerable patients.

The findings are based on a rather small sample of only five papers, narrowed down via various factors from 28119 (that's the systematic review part), and the authors grouped their results into two broad groups: factors favoring participation in clinical trials and factors presenting a barrier to that same end.  Interestingly, and again based on a relatively small sample, the researchers found that the most commonly cited reason for participating in clinical trials among Brazilian patients was altruism, at 55%.  Personal health benefits (30%), convenience (11%), and monetary reimbursement (6%) completed the list of favoring factors.  The barrier factors amongst Brazilian patients were: fear of adverse events (12%), mistrust (6%),  lack of knowledge (4%) and inconvenience (2%). 

By modeling this information to a previous systematic review of literature pertaining to Indian patients, the authors discovered a significant difference in Indian patients' motivations to participate in clinical trials.  The leading factors for Indian patients were: personal health benefits (48%), altruism (43%), monetary reimbursement (31%), and trust in their physician (8%).  Convenience did not factor at all for  Indian patients according to these findings.  The factors representing barriers to participation for Indian patients were:  fear of side effects (27%), mistrust of drug companies or researchers (26%), dependency issues (19%), loss of confidentiality (17%), and inconvenience (11%).

The authors also conclude from their research that Brazilian patients are more likely to participate in clinical trials than their Indian counterparts.  I think we can also draw from this the inherent vulnerability of clinical trial participants, especially in the developing and emerging regions,and use the factors favoring and inhibiting participation to help protect and reassure patients as they come into trials.

Has Clinical Trial Globalization Run Its Course?

A few weeks ago I had the good fortune to participate in a very interesting panel on just that topic at MAGI's Clinical Research Conference in San Francisco.  The session was chaired by Joan Chambers, COO of CenterWatch, and my panel mates were Kamran Ansari of Sanofi-Aventis and Nye Pelton of Eli Lilly.  I jumped at the chance to be on this panel because I have noticed that the recent, breathless you-heard-it-here-first pronouncements coming out of the CRO industry hearkening a great tidal wave of clinical studies to places like India, South America, Russia and Central European countries have not quite panned out.  The studies are still going to those places but not exactly in the free-for-all we were led to expect.  Does this signal that globalization has peaked, and if not, what adjustments should we make in our expectations, especially those of us with a strong international expertise component in our business models?

My view is that we are experiencing a pause in the marketplace, if not quite a correction, and we will start to see increased movement again quite soon.  I think the pause occurred for a couple of reasons: one) performance did not quite measure up to the claims of some providers, and two) the worldwide financial meltdown took an awful lot of business with it in the form of reigned in development programs and planned studies that never got started to save precious cash.  Let's look at the first reason, since this is not an economics blog.

In the first half of the 'aughts' or the decade just ended, I attended a lot of informational meetings and conferences on emerging markets and heard many vendors explain how they had so harmonized their processes, so locked in the regulatory pathways in each country that sponsors could entrust their studies to these vendors safe in the knowledge that the conduct and resulting data would be of the highest quality and the entire experience would be as painless as if the study were being run in the US or EU.  Which is many things but painless is not one of them.  And which inevitably turns out not to be true anyway.  Sponsors experienced some significant buyer's remorse when they discovered that their project manager was not the person who came to do the bid defense; that the data, ethics, and medical practice standards could be very different in actual countries of conduct and required an experienced hand in the design phase of the protocol, not just the conduct and reporting phases; that their data were being collected many time zones away by people who the sponsor had never clapped eyes on.  Instead of finding the experience painless, many sponsors felt unease with the entire process even when the data and trial results proved to be of high quality - they didn't quite trust what they saw because they didn't know who was running the trial - there was no relationship.  Vendors who were paying attention have now retooled their presentations to highlight the relationship side of the business.

Even the FDA has got on the bandwagon of mistrust.  A recent Pink Sheet ($) dated October 4, 2010 published findings by CDER's Office of Biostatistics that showed in 13 of 16 large multinational cardiovascular outcome trials, the measured drug efficacy was lower in the US than outside.  Four drugs studied in these trials were not approved specifically because of this 'regional heterogeneity' and nine of the drugs were deemed approvable but required more data.  Anecdotally I have seen this type of regional difference myself and have always interpreted it as proof of the quality of the conduct, the high acceptability of the data.  FDA says not so fast.  Some regional differences in treatment effect may be expected, but too much can arouse concern.  The Pink Sheet report cites examples such as the extended release version of metaprolol (AstraZeneca) whose 'effect on mortality was virtually all outside the US"; AZ's ticagralor which demonstrated no effect in US patients, only exUS; and whether anti-epilepsy drugs bring an increased risk of suicidality, where studies showed that outside the US, suicidality was higher.  Bridging studies, even PK/PD or surrogate studies may be indicated to explain regional differences that are not entirely due to chance.

In discussion amongst our panel and with the attendees, it seemed that at least based on the interest in the room, globalization is not dead yet. We all agreed that training, relationship, close monitoring, realistic expectations and appropriate study design are all important factors in running successful, evaluable international clinical trials.




photo credit: J. Mardell, 2010