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.

WikiLeaks and Trovan

If you thought the WikiLeaks story had nothing for you, think again.  Today's New York Times discusses a State Department cable, made available via recent the WikiLeaks dump, alleging Pfizer's attempt to disrupt the Nigerian lawsuit following several deaths after the experimental use of Trovan in Kano in 1996.  According to the Times story, the State department accused Pfizer of hiring investigators " 'to uncover corruption links' to Nigeria’s former attorney general and apply pressure to drop lawsuits against the company."  Nigeria's former attorney general, Michael K. Aondoakaa, was quoted in the piece saying he knew nothing of any Pfizer attempt to investigate him. Pfizer denied the allegations as "simply preposterous".  This is just the latest in the continuing saga of Trovan in Nigeria, which we have talked about here and here.

Happy Thanksgiving!

To all my US readers, as well as to those who have to work tomorrow, Happy Thanksgiving!  Enjoy the holiday and try not to overeat.

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

Conducting Clinical Research

Time to play catch up with the blogging as the year begins to wind down.  The fall term at UC Santa Cruz will finish next week and I have no more conferences booked till January. 

A couple of weeks ago I attended and presented at MAGI West Conference on Clinical Research in San Francisco.  The event was neatly sandwiched in between the end of baseball pennant series' and the World Series, in which my beloved San Francisco Giants prevailed for the first time in, well, my whole life.  San Francisco was a very orange place to be during these days, and as a lifelong baseball fan left heartbroken by my team twice before in my adult life, it was a glorious time to be in the city. 

But this blog is not about baseball.  The MAGI conference was well attended by over 500 people, many more than had attended the same event last year in San Diego (on the last day of the baseball 2009 regular season, in case anyone is keeping track).  MAGI (Model Agreements and Guidelines International) so far is offered on either coast - in the east in spring and the west in the fall - and I think it is rapidly becoming one of the must-attend meetings on the yearly calendar for clinical research professionals, especially as the scope of the conference gradually expands from its origins in contracts and agreements to its current goal of "establishing best practices for clinical research operations, business and regulatory compliance".  The quality of speakers that I heard was uniformly quite high with little variation, although a couple stood out in both directions.  As the conference becomes larger it is also becoming an important networking opportunity and my LinkedIn connections have expanded significantly as a result of the acquaintances I made and renewed during the two days I attended.

One of the people I reconnected with in San Francisco is Dr Judy Stone of Maryland, the author of "Conducting Clinical Research", a newly revised quite complete how-to guide primarily written for investigators and would-be investigators to help them understand their role in the clinical research enterprise, particularly as relates to pharmaceutical industry-sponsored research, which is ultimately for profit.  Dr Stone has done her homework and produced an excellent reference that, while geared toward investigators, also offers new insights to the sponsor and CRO sides of the industry for those who might have a look.  It is always a good idea to remember to see things from the investigator's perspective, and Dr Stone has done this very well.  I plan to recommend this volume to my GCP students as adjunct reading material starting in the next term.

At the conference I was fortunate to participate on a panel entitled "Are Sponsors Re-evaluating Globalization of Clinical Sites?", moderated by Joan Chambers of Centerwatch.  In my next post I will review some of the key points of the discussion with the panel and audience. 

I close this post with the acknowledgement that our world became a great deal poorer last week when our friend Kate Allen died of gastric cancer.  She was 44.  She was a good teammate, colleague and friend, and she left many friends and loved ones behind who will miss her for the rest for our lives.

Guatlemalan Syphilis Trials and the Nuremburg Code

The New York Times has a piece this week revealing that “from 1946 to 1948, American public health doctors deliberately infected nearly 700 Gautemalans – prison inmates, mental patients and soldiers – with venereal diseases in what was meant as an effort to test the effectiveness of penicillin.”

Susan M. Reverby is a professor at Wellesley College and a medical historian who has previously written two books on the Tuskegee syphilis trial, discovered records of these experiments in the archives of the University of Pittsburgh as she was preparing a research paper. The archives also revealed that NIH funds were used to pay syphilis-infected prostitutes to sleep with prisoners in order to infect them. If that method didn’t work, patients were infected by experimenters pouring live bacteria over abrasions on their scraped up body parts or injected directly into the spine.

The connection to Tuskegee is not accidental. The Guatemalan experiments were led by one John C. Cutler,  a public health service doctor who was to become instrumental in the Tuskegee experiments later on, and it was his unpublished Guatemala work that Reverby discovered at Pitt. Reverby told the Times that she had previously presented her findings at a conference last January but received no reaction. In June she submitted a manuscript for a future issue of the Journal of Policy History to Dr David J. Sencer , former director of the CDC (a body that has its own not completely benign role in the Tuskegee affair), and he requested a government investigation.

All of this was going on at the same time military and civilian lawyers at Nuremburg were mounting a vigorous prosecution of Nazi physicians in the Doctors’ Trial following WWII. From this prosecution came the Nuremburg Code from whose appearance many ethicists date the modern era of human subjects protection, a code which included such protections as voluntary consent, a favorable risk/benefit analysis, avoidance of needless suffering, appropriate prior animal data, the right to withdraw, and so on. US public health doctors were conducting VD trials on presumably unconsented (or at least not fully informed) subjects at the same time physicians were being hanged in Germany for doing the same things. The theme connecting these events is this: lack of respect for person, the unwillingness of the experimenters to see research subjects as full human beings deserving of protection and respect.

In the wake of these revelations, Secretary of State Clinton and HHS Secretary Sebelius have issued an apology to Guatemalans, the subjects and their descendents, and of course it is not their fault. We do not need to waste time looking for conspiracies in the US government. FDA regulations, the Common Rule, the Declaration of Helsinki and ICH and WHO-CIOMS guidelines for GCP are all designed to protect future human subjects. Our job is to make sure that we educate our successors so that things like this never happen again.

Should FDA split safety ops from CDER?

This is a topic that comes up early in my GCP class at UC Santa Cruz Extension, when we do an overview of the FDA's operations and PDUFA as they pertain to good clinical practice.  PDUFA has over the years enabled a a more efficient and predictable pathway through the US regulatory review process.  Improvements are not without cost, and the consequences here have been felt on the continuing review of the safety of marketed medicines as budget has shifted to meet the Congressionally mandated trigger for user fees, and one option long under study has been to move safety evaluations altogether away from the evaluation of new drugs.


Bloomberg today has looked at the data since 1995 (PDUFA was first enacted in 1992) and reports that over half of the 21 drugs approved since 1995 have since been withdrawn from the market behind cardiovascular problems.  Armed with these findings, Sen Chuck Grassley (R-Iowa) is developing a bill with Rep. Rosa DeLauro (D-CT) to create a new Office of Surveillance and Epidemiology whose function - and one presumes budget - would be completely separate from CDER and its budgetary constraints, and its heavy reliance on voluntary post-marketing adverse event reporting.  FiercePharma has it all here, along with an interesting link to a story about Sen Grassley's plans to move from the Senate Finance Committee to Judicial.  You read it here second.


Next week I will be attending and speaking at this meeting, Managing Relationships with CROs in London, and then a couple of days off.