Wednesday, November 24, 2010
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.
Wednesday, November 17, 2010
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
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.
photo credit: J. Mardell, 2010
Tuesday, November 9, 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.
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.
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.
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