Christopher Milne

Historically, the public sector has been a major contributor to basic research for drugs and biologicals while the majority of the work in late discovery, preclinical and clinical testing, regulatory approval, manufacturing, and product distribution was carried out by the private sector. Two trends in R&D have been building the past several decades, culminating in the expansion of industry–academic partnerships for biomedical innovation.   

From academia, the commercialization of discoveries from basic research was facilitated in the United States beginning with the 

 and motivated in part by the need to broaden academia's funding base. Industry also sought externalization of innovative R&D approaches and scientific knowledge to address complex, unmet medical needs. The Tufts Center for the Study of Drug Development (Tufts CSDD) recently reported the results of a year-long study, whose goals were two-fold: to typify the kinds of research projects that industry–academic partnerships entail (i.e., "the what") and to describe and categorize the organizational nature of these partnerships (i.e., "the how").   

In terms of "the what," the Tufts CSDD reviewed primary data from more than 3000 grants to academic medical centers (AMCs) from 2008–2010 involving approximately 450 industry sponsors and 22 medical schools in 15 states and determined that they fell into three major classifications. Roughly 75% were collaborations between AMCs and industry that were by-and-large conventional clinical studies and trials focused on evaluating the safety and efficacy of new drugs or new indications.  

Another 14% were comprised of otherwise conventional clinical trials considered by Tufts researchers to represent studies of high public-health priority requiring research environments with specialized characteristics. Among these were comparative clinical studies in which two or more treatments are compared with one another in an open-science environment; oversight studies (e.g., registry studies) in which privacy concerns dictate that AMCs are the most appropriate setting; vulnerable population studies for which AMCs can provide the optimum environment for patient care (e.g., neonatal studies); and breakthrough investigations (e.g., nanotechnology) in which AMCs can provide an environment for precompetitive collaboration and cross-disciplinary fertilization 

The third category of grants (11%) entailed health research and educational projects that were not clinical trials or studies investigating a particular compound but instead involved a wide range of activities. For example, there were a number of collaborations in basic medicine (i.e., foundational studies examining the impact of diseases and drugs). Educational programs beyond basic medical school curriculum represent another example. While it is generally acknowledged that the educational process for medical practitioners and researchers is lengthy and expensive, what is sometimes less well recognized is that the process never stops. Such programs were often focused on the needs of particular physician groups, for example, Haitian orthopedic surgeons or community practitioners interested in the latest diagnostic and treatment updates in endocrinology. 

While innovative technology is essential to advancing the frontiers of biomedical R&D to create innovation that changes the way things are done or so-called disruptive innovation, there must be both technological and business innovation (1). The Tufts CSDD examined secondary data from a variety of sources to describe "the how," meaning the ways and means of the business relationships between AMCs and their industry partners. Industry–academic partnership models fall into three broad categories: commonly used, increasingly popular, and, emerging. Examples of ones commonly used are unrestricted grants and fee-for-service models that anecdotal reports indicate may be on the wane.  

Academic drug-discovery centers, which are independent centers affiliated with universities, fall into the category of increasingly popular models. These independent centers affiliated with universities  represent a type of academic spin-off in reverse (i.e., industry entrepreneurs forming academic units). Much of the leadership and staff at these centers are from industry, and support from commercial sources can be as high as 50% (2). Lastly, emerging models can be exemplified by risk-sharing partnerships in which companies and academic institutions share the control of a research project and split the contribution of resources and assets.  

Facing an increasingly challenging R&D and healthcare environment, we are likely to witness more industry–AMC partnerships in the biomedical landscape. 

 is associate director with the Tufts Center for the Study of Drug Development, 

 1. K.A. Schulman A.V. Vidal, and C.D Ackerly, 

Articles

Partnerships between industry and academic medical centers are expanding to meet R&D needs.

Innovation Boom Towns

What is a conflict of interest? Gilbert's Law Dictionary says that a conflict of interest (COI) arises when private interests clash with one's duty to serve the public interest. 

 refers to having an interest in a topic that may affect one's ability to fairly and objectively consider the subject. 

is a scientific concept by which a researcher believes in a hypothesis, yet no factual proof yet exists. Equipoise becomes conflict when medical professionals convince themselves they are right despite evidence to the contrary because of their own self-interests. When that happens, an ethical line in the sand is crossed. It can be hard to tell when that line gets crossed, no matter how rigorously a decision, affiliation, or financial arrangement is examined.   

There are a panoply of new standards, rules, and guidelines relating to COI for medical research. The Physician Payment Sunshine  provisions under the 

Patient Protection and Affordable Care Act 

mandate  medical product and device companies to report any kind of transfer of value to physicians and post it in a public database. A half dozen states, with more likely to follow, have rules governing conduct for pharmaceutical and medical-device manufacturers that require reporting, prohibit, or impose restrictions on a wide array of physician–industry activities ranging from free meals to continuing medical education courses. At the federal level, rules under the National Institutes of Health (NIH) require medical researchers receiving federal grants to disclose any industry payments over $5000 and allow a university's NIH grants to be withdrawn for egregious violations or lack of oversight.  

In the private sector, medical researchers are required by some medical publications to fill out standardized forms that enumerate payments from consulting work, honoraria, expert testimony, grants, commissioned manuscripts, intellectual property rights, royalties, stock holdings, and advisory boards. The American Medical Students Association ranks medical schools annually based on their COI polices, and the Pew Prescription Project and Yale University both have  conducted recent surveys of patient attitudes regarding physician ties to pharmaceutical companies.  

Why the brouhaha? In part, it is because of the media's attention to this type of story. A recent example reported in 

concerned Thomas Zdeblick, chair of the Department of Orthopedics at the University of Wisconsin–Madison, which according to the article, received more than $25 million in royalties since 2003 from Medtronic, a firm that sells spinal devices. Reportedly, this funding occurred while the hospital affiliated with the university spent $27 million on Medtronic spinal products from 2004–2010. Zdeblick also received more than $1 million in compensation from the university in 2010, according to the article (1). 

But is this a case of COI? In this particular case, the selection of implant devices was done by a review committee. Moreover, Zbedlick's influence on residents and fellows was mitigated by the fact that they work with multiple surgeons who have differing views and preferences for various devices, and students are told about the royalties Zdeblick receives. The entire management plan, under which he operates, is a shared  responsibility of the doctor, the department, and the dean's office.  

That brings us full circle to definitions of COI and equipoise. The foundation of medical research is the state of clinical equipoise, which is met when there is genuine uncertainty within the expert medical community—not necessarily on the part of the individual investigator—about the preferred treatment (2). It is a shared responsibility. Implementing a just and workable system of COI monitoring is not something that can be achieved by simply legislating against bad acts. Rather than developing a system that prevents bad acts, legislation often creates a chilling effect—an inhibition or discouragement of legitimate expression, such as innovation.  

Curbing innovation is the last thing  we can afford in biomedical R&D. The turnover rate of researchers who have not submitted an investigational new drug application since 2006 is 35% (3). While NIH biomedical research funding has flatlined for the last several years, the number of doctors applying for NIH grants has flatlined for the last few decades. The average age of first-time biomedical grantees has risen six years to 42 years old (4).  

Cures for cancer and  neurodegenerative disease are elusive and costly as are the solutions to the crushing debt of biomedical education. There is a strong  need for translational approaches in R&D, creation of interdisciplinary MD–PhD research teams, and cross-fertilization of private and public sector resources. These are conflicts of the public interest and that is where change should focus.  

 1. J. Fauber, "Financial Conflicts Taint 'Ivory Tower'," 

 3. B. Gwinn, presentation at the Summit for Clinical Ops Executives (Feb. 7, 2012, Miami).  

 6 (12), online, Doi:10.1371/journal.pone.0029738, Dec. 28, 2011. 

The divide between innovation and conflict of interest in medical research is not so clear.

Defining Conflict of Interest

Sometimes Congress actually gets it right, but keeping it that way is another matter. In late 1997, the FDA Modernization Act was passed and among its many provisions was an incentive for pediatric exclusivity. Under the law, FDA requested that the pharmaceutical industry conduct pediatric studies in exchange for an additional six months of market protection against generic-drug competition for all the products containing the active ingredient for which the studies applied. A year later, a complementary and mandatory provision was added in a carrot-and-stick approach to ensure the broadest coverage for an estimated 75% of drugs that were being used off-label for children. This incentive package was reauthorized in 2002 and 2007, and  reauthorization looms again in 2012. The debate already is taking shape, and the arguments and adversaries are lining up in a now predictable array.  

There is little debate about the success of the program, which has been publicly lauded by regulators, industry, pediatric healthcare professionals, and public-health advocates. Its record after nearly 15 years is still noteworthy: more than 400 drugs have been labeled for pediatric use by hundreds of companies (1). Granted, there are still some challenges to be addressed, especially with neonates and formulations, but the US program has been emulated worldwide. Europe, for example, adopted a similar approach in 2004, and Japan has been holding high-level discussions on proposals for such a program as well.   

Nor is there much debate about the difficulty of doing pediatric studies despite a report by the Tufts Center for the Study of Drug Development that showed that the scope of work, the length of time required to do pediatric studies, and the related costs have increased significantly during the life of the program (2). Nor was there any concern that more than 40% of pediatric-study programs fail, which increases overall industry spending on pediatric studies by about two-fold. Even if pediatric studies are accepted in time to garner the extension of market exclusivity, many sponsors experience events, such as court challenges by generic-drug companies, product withdrawals or prescription-to-over-the-counter switches that dramatically decrease sales during the exclusivity period. 

Ironically, the debate always is about whether the industry is receiving too much benefit from the program despite  that, nominally at least, Congressional intent was to incentivize the industry. Every five years, tired banners are waved about a profits cap, tying the length of the award to projected profits or reducing the exclusivity period to three months. All of this grandstanding starts anew even though neutral parties have considered these proposals in past debates and have rejected them.  

For example, the European Commission affirmed that a fixed six-month award is optimal both in terms of practicality and fairness (3). FDA testified in the last round of reauthorization hearings held in May 2001 that it does not really bring expertise in business matters to the table, but relies on reports from independent certified accountants or accepts a manufacturer's certification when cost recovery data is required (4). FDA added that it faces risk of litigation, especially if there is any ambiguity in the language tying length of exclusivity to sales data. The agency is also troubled that using vital resources to analyze financial data or police the sales of drugs would compromise FDA's primary mission. Congress, too, has previously weighed the trade-off implicit in marketing exclusivity in the Orphan Drug Act and determined that the benefits exceeded the dangers (5).  

Why does the pediatric studies incentive work? Because it does what an incentive program is supposed to do. It incites the intended audience to take action. Unlike many alternative incentive proposals,  it is not too speculative or unsustainable, such as those dependent on the vagaries of government grant programs or prizes from charitable foundations nor is it too limited for the risks being taken, such as tax credits. A few other incentive programs have worked, but none are as effective as the carrot-and-stick approach used in pediatric exclusivity. It has withstood the test of time and is being emulated by other countries at a time when laws passed by Congress are considered good models for little else. Now and through 2012, we have and will continue to have debates on the presidential election, healthcare reform, and the national debt. Do we really need another divisive debate on something that actually works?  

 1. FDA, "Pediatric Labeling Changes through July 18, 2011" (Rockville, MD), 

www.fda.gov/downloads/ScienceResearch/SpecialTopics/PediatricTherapeuticResearch/UCM163159.pdf

 3. EC, "Proposal for a Regulation of the European Parliament and of the Council on Medicinal Products for Paediatric Use and Amending Council Regulation (EEC) No1768/92, Directive 2001/83/EC and Regulation (EC) No 726/2004. Extended Impact Statement Final" (Brussels, Sept. 3, 2004), 

http://ec.europa.eu/health/files/paediatrics/docs/extended_impact_assessment_final_3_september_en.pdf

 4. J. Woodcock, Statement, Senate Health, Education, Labor, and Pension Committee Hearing, May 8, 2001.  

, Title 21, Food and Drugs(Government Printing Office, Washington DC. Part 316.  

Reauthorization of pediatric exclusivity provisions looms in 2012 and debates begin anew.