Robert M. Califf, MD

Matt Rowe did a great job of presenting the results of the TRILOGY Trial–a very complicated result.  Despite a superior ability to reliably inhibit platelet aggregation, prasugrel was not superior to clopidogrel in preventing CV events in an ACS population in whom clinicians had decided to proceed with medical treatment alone in preference to coronary revascularization. However, the event curves show separation after 12 months of followup, and counting multiple events per patient, there does appear to be a modest treatment effect.  It will be interesting to see how the clinical world digest these data.

There are two provocative articles in today’s NEJM:

Swedish investigators show a dramatic reduction in progression to Type 2 Diabetes with bariatric surgery and demonstrate no relationship between baseline BMI and treatment effect.  In other words, this treatment appears as effective in moderately overweight and very obese patients.  Before we rush to line up in the surgery clinic, we should read our own Danny Jacobs (on his way to be Dean at UT Galveston), who opines that we need to do more research to define in whom the treatment is worth it.  A second relatively unnerving finding is that followup was up to 15 years.  I had dismissed short term studies of this technology because of the other profound metabolic effects that could turn out to be detrimental in the long run.

The second article is from a team of ethicists relaying conclusions of an IOM study of the TIDE Trial.  TIDE arose out of the controversy on rosiglitazone when overviews showed excess cardiovascular events with this drug that had been touted as a super drug for diabetes.  Our friends Hertzel Gerstein and Salim Yusuf designed the trial and were conducting it when the FDA halted it on the basis of safety concerns.  I personally feel that the editorial was off base and assumed as fact findings on rosiglitazone that were unproven signals.  I wish the trial had been completed and remain unsure that the “politically correct” view on rosiglitazone is really correct.  After all, who would have thought that bariatric surgery would so profoundly reduce progression to diabetes?

I surely agree with this statement in the editorial: “Reactive policy making is tempting but problematic.  The history of regulation of human subjects research suggest that rules that are ‘born in scandal and reared in protectionism often fall short of providing meaningful protections to research participants and than, once adopted, regulations can ossify and become difficult to dislodge’.”

If GSK had commissioned proper, academically independent outcome studies early in the life cycle of rosiglitazone, the truth would be known and GSK and people with diabetes would be a lot better off.

After leaving Beijing last week, I made the pilgrimage to Singapore and wish to comment on 2 aspects:

1. Duke-NUS School of Medicine:  By all accounts this effort has been a success. It has been a team effort resulting in a first rate medical school that is breaking many barriers in the US-Asian differences in approaches to educating physicians and biomedical scientists.  With a second class graduated, there is comfort that we are in it together for the long haul.

Many people know that I’ve been frustrated by the slow progress in clinical research.  It seems to be the last frontier, when I think it should be one of the fundamental pillars of a medical school (after all, people come to doctors to help them decide what to do and to make sure the recommendations are enacted effectively—these are information-based disciplines and doctors should be educated to generate and consume evidence in their practice).  Others, of course, argue that basic biological science should be the basis and clinical research should be added later—that’s what has happened in Singapore.

Be that as it may, on this visit I’m leaving optimistic about the path forward.  In many ways, the issues in Singapore with developing a true academic medical center mirror our own issues in Durham—balancing the academic mission with the crushing need to deliver care.  With Dr. Ivy Ng now in charge as CEO of the SingHealth system, I have confidence that the building blocks will be put into place to enable a gradual evolution of a first-rate system of clinical and translational medicine.  It will still take time.  Dean Ranga Krishnan has a lot more patience than do I, which is a good thing.

2. TEMASEK: I had a chance to spend time with Temasek, the investment corporation for the country of Singapore.  This group is charged with investing Singapore’s national assets, much like the Duke Management Corporation (DUMAC) manages the Duke University’s investments.  They have done a remarkable job of investing over the years and now have a large fund.  I was impressed by the collegiality and breadth of knowledge of the staff and the joy they take in making money that then benefits the people of Singapore.  It is easy to depict the down sides of a less free and open environment, but I believe we have a lot to learn from the amazing success of Singapore and the general collegiality of their people.  A country of just over 5 million people with a huge global impact and a very high standard of living is obviously doing a lot of things right.  I am grateful for the perspective of seeing a country with such dedication to achievement, amazing tolerance for religious difference, and approaches that encourage the melting of Western and Eastern approaches.

I am not an expert on China, but my several visits there have left distinct impressions about policies, activities and collaborations.  If we think broadly about 3 areas of translation: bench to bedside and back, knowledge generation to determine what works and implementation of what works into effective healthcare delivery public health practices, there is merit in focusing on implementation because both countries have major gaps.  The Duke Global Health Institute (DGHI) has done an amazing job in a short period of time in putting Duke on the global implementation science map.

Our Chancellor has caught the implementation science “bug”.  In particular, leveraging his role in the World Economic Forum, he and Krishna Udayakumar have developed the Institute for International Partnership for Innovative Healthcare Delivery (IPIHD).  Led by Duke, McKinsey and the World Economic Forum, the vision is to “Support innovators to scale, replicate successful innovative delivery solutions around the world, improving access to quality care at affordable cost”.  The group is identifying not only what works, but studying models of successful delivery with a view that includes entrepreneurial development of delivery systems and business and financial models.

Until recently, I would have thought this is just a matter of the US “teaching China how to do it”.  After all, we have many of the world’s most prestigious academic centers and public health efforts.  However, an evaluation of the state of health of the 2 countries reveals that China is catching up quickly with the US in health statistics and that parts of the US are far below the national averages for China in measures like longevity and freedom from disability.  IPIHD gives us a chance to see the world’s efforts and to adapt successful practices to the local cultural, financial, business and environmental landscape.

China has amassed massive financial resources, but it has major gaps in health status, as does the US.  I hope we can find common ground to better understand how to solve these implementation issues.

Many faculty have asked me why I’m spending time in China and whether its just a distraction from the everyday business of running an academic enterprise in North Carolina. Other than the fact that 1.4 billion people live there, I believe the time is right for collaboration for the benefit of both countries.

Like most major clinical research coordinating centers, we are conducting multiple clinical research projects in China.  Most of our global trials have significant participation of Chinese sites.  We have evolved through a period in which the efforts were considered novel into one in which much has been learned and new, more effective strategies can be developed in 4 key domains.

Over the past half-century, public health projects involving US collaborators or funders have been a part of the Chinese research landscape.  Until recently, these efforts have been put forward as a chance for knowledge transfer from US (or Western European) universities into China.   Now there is mutual transfer of information about public health, gene-environment interactions, and effective interventions.  Linking of public health entities, such as our Global Health Institute with Schools of Public Health in China, can broaden our mutual knowledge base.

More recently, clinical trials funded by US industry or major academic centers were moved into China.  Initially this approach represented arbitrage in which the sponsors could achieve substantial improvements in recruitment at much lower costs to “test” drugs and devices, often in the setting more “treatment naïve” patients.  Over time, this situation has become much more complex and positive, as the Asian market is rapidly expanding and the Chinese themselves are developing drugs and devices for use in their own population and for expert to the West.   Globalization, with the recognition that we all need to do relevant clinical trials for our populations and practice patterns, is replacing offshoring, which has a much more negative connotation.

Recently, China has been investing heavily in fundamental technologies for translational medicine.  As capital has moved East and China has become a more significant direct participant in the global knowledge network, it is moving to become a leader.  The scale of some of these investments is now unimaginable in the current environment in the US and Western Europe.  By developing collaborations, we can enhance the degree to which we unravel the biological basis of health and disease.

Finally, we have a mutual interest in implementation science.  Given an understanding of what works, both the US and China have enormous disparities in health outcomes and failure to deploy knowledge in the most effective manner.  In many ways the US has been locked into a system which limits our ability to innovate, while the Chinese have an opportunity to create new systems with their rapidly changing society.

In my view we have 2 choices: 1) ignore China and hope it doesn’t overtake us or 2) collaborate wholeheartedly, always reflecting on what we are learning and what strategies will optimize our chances of both countries doing well.  I think Option 2 is best, and its the chance to accelerate knowledge that makes the jet lag worth it!

Last week, I had the privilege of presenting a view of the role Duke could play as a collaborator in the annual Sino-American Science of Clinical and Translational Medicine (SAS-CTM) meeting in Shanghai.  In this 3^rd year of the meeting, it was really clear that China is continuing to make a huge investment in both technology and human capital in this area.  We heard about 75 new translation medicine centers that have been funded by the government, massive biobanks, and significant investment in omics technology.   The Ministry of Health, the Chinese Academy of Medicine, (its NIH equivalent) and its universities are applying major energy to the effort.

Almost all major American universities are developing collaboration with institutions and investigators in China, but few have an entire campus underway as we have with Duke-Kunshan University.  Although this project has been controversial, I found our Chinese colleagues to be enthusiastic about what can be accomplished there.

I presented 5 key areas in CTM where Duke can play a role that will provide mutual benefit for Duke and for China:

1. Participate in and coordinate global clinical and translational research projects
2. Work with Chinese collaborators on sharing knowledge and developing policy on implementation science for health improvement
3. Develop a physical presence as a university
4. Disseminate fundamental knowledge about clinical research through internet based training and education
5. Mutually develop the new workforce needed to drive translation, focusing on the quantitative discipline (biostatistics, informatics, clinical research, global health/epidemiology and health sector management)

I was heartened by the positive response at the meeting and the excitement about the potential for expanding our joint knowledge base.

I continue to be impressed by the creative ideas coming from people inside and outside of the “DTMI family” with regard to the future.  Please continue to send messages with insights and concerns.

There is obvious tension between the desire to maintain what is special about DTMI and its major engine, DCRI, and the obvious importance of better integrating its efforts with the University and Duke Medicine.  The name “DCRI” has tremendous recognition now around the world and stands for excellence in collaborative clinical research.  We need to understand how to extend the support systems in DCRI to a wider group of faculty on the Duke campus.

In addition, we now have a rapidly expanding network of collaborators in many countries and a university that is dedicated to globalization as a key part of its educational mission.  With “bricks and mortar” in Singapore and soon in Kunshan, in addition to a joint venture in Delhi, we have a presence in Asia that will need to be developed with an effective strategy for bringing our talents to the region in a manner that fosters networking and collaboration.   This was the topic of an interesting conversation with President Brodhead yesterday, and I see our efforts as completely aligned with where the university is going.

The next several months should be a fertile time to revise our plans. Dr. Harrington will be with us and free to think without the constraints of operationalizing ideas and the leadership groups of our various entities will be charged with thinking through our best organizational approach and strategy for our research and education missions.

Don Berry from MD Anderson has this excellent post on biostatistical/clinical interactions.
http://magazine.amstat.org/blog/2012/02/01/collaborationpolic/

Its worth the read for researchers trying to understand how to operate in a collaborative world.

We are now meeting under the auspices of a new School of Medicine Committee on Clinical Research, chaired by Dean Andrews and including myself, Scott Gibson (Exec Vice Dean for Admin,), Mark Stacy (Vice Dean for Clinical Research), Jeff Ferranti (CMIO for Duke Medicine), the DCRI Director and Sally Kornbluth (Vice Dean for Basic Science). Becky Moen MBA has taken on the job of administration for the TMQF effort and the implementation  is really taking shape with her involvement.

We are struggling with a number of difficult issues where the right balance is not entirely clear, including:

1.  How do we define accountability of the quality of translational research?

2.  In the basic science labs, is documentation of data provenance (“reproducible research”) a requirement or is it optional?

3.  In human research, how far do we go in mandating reproducible data systems and significant input/collaboration/oversight by biostatistics?

4.  How do we structure a system to oversee management of conflict of interest in translational research (we’re confident that we have a system for identifying COI and designing plans for management; its the execution that needs work)?

There is an interesting set of issues around the economy of site based research that will be the topic of serious discussion involving the SBR directors.

I hope that people will join in a vigorous debate about the topics so that we can go forward with a plan that has the support of the faculty and staff because the development of the plan has been inclusive.

Interest in this issue will be heightened when the case of Anil Potti airs on 60 Minutes, which I’m told likely to happen on Feb 12th, although decisions on airing are held tightly by CBS for obvious reasons.