Study reveals possible conflict of interest in industry-funded basic research

CoEE Endowed Chair Bennett publishes major drug safetystudy revealing industry and academic researchers reached differentconclusions about ESAs and tumor growth; authors call for researchstandardization to protect patients.

CHARLESTON, SC – September 14, 2010 – A team of investigators led by aphysician-scientist at the South Carolina College of Pharmacy’s Centerof Economic Excellence (CoEE) for Medication Safety and Efficacy hasshown differences in methodology and results from privately- andpublicly-funded studies, indicating a need for greater collaborationbetween the sectors. The study is published in the September 13 editionof the journal Archives of Internal Medicine.

The study “Association Between Pharmaceutical Support and Basic ScienceResearch on Erythropoiesis-Stimulating Agents (ESAs)” showed researcherswithout pharmaceutical industry support are more likely than those withsupport to identify detrimental in vitro effects of ESAs, includingpotentially harmful effects on cancer patients.

“The study shows that differences in methodology and results fromprivately- and publicly-funded studies is a clarion call for greatercollaboration between the sectors,” said lead author Charles Bennett,endowed chair of the CoEE for Medication Safety and Efficacy (CMSE) atthe South Carolina College of Pharmacy (SCCP). “If good scientists inboth arenas are coming up with strikingly different results, it lowersthe return on investment in the funding for both. Ultimately, thatdecreases positive outcomes for the company, the profession, and thepatient.”

Clinicians prescribe ESAs, a form of the human protein erythopoitetinthat stimulates bone marrow to manufacture red blood cells, to treatanemia, which can result from chemotherapy or from kidney failure. Since1993, ESAs have been marketed for cancer patients. These agents,marketed as Procrit by Johnson and Johnson and Aranesp by AMGEN, nowbear “black-box” warnings on their labels stating they can increase therisk for death in cancer patients. Before a cancer patient receives anydose of an ESA, he/she must sign an informed consent document statingthat the drug can increase their risk of death. Also, earlier this year,the manufacturers now require that oncologists treating cancer patientswith ESAs must complete special training every three years and discussdrug-risk information with patients.

“This paper addresses the 800 pound gorilla for ESAs- is there basicscience data showing that these drugs can cause tumor cells to grow?”said Bennett. “The study showed there was difference in pharma–fundedand non pharma-funded studies. The study did not show who was right orwrong. The science is complicated. Essentially there are three areas –agreement on controls, agreement on the antibodies, definition of cellgrowth – about which lack of standardization leads to uncertainty.Public and private researchers need to come to a consensus so there isadjudication on the study standards.”

Bennett plans to form a public-private steering committee at the CoEEfor Medication Safety and Efficacy at the South Carolina College ofPharmacy to look at best practices in study methodology and protocols.“Hundreds of millions of dollars and thousands of lives depend on it,”he said.

Method and Results
The researchers analyzed 827 total articles and excluded 758 based on avariety of disqualifying criteria. Seventy-four studies were evaluatedin the final analysis, including 64 investigations from investigatorswithout funding from ESA manufacturers (no pharma funding), seven fromacademic investigators with pharma funding (pharma funded researchers),and three from investigators with employment by ESA manufacturers(pharma employees). The research team found investigations withoutpharma funding were more likely than pharma-funded researchers andpharma employees to report:

• EpoRs on solid tumor cells (100 percent, 60 percent, 67 percent)
• erythropoietin (Epo) induced signaling events (94 percent, 0 percent, 0 percent)
• changes in cellular function (57 percent, 0 percent, 0 percent)
Investigators without pharma funding also drew conclusions lessfavorable than others. Qualitative statements on potential clinicalrelevance were included in 42 of their studies, five from pharma- fundedresearchers’ studies and two studies reported by pharma employees.These statements were similarly at odds:
• investigations had identified potentially harmful effects of Epo on cancer cells (57 percent, 0 percent, 0 percent)
• investigations had identified potentially beneficial antitumor effects (14 percent, 60 percent, 0 percent)

Conclusions and Recommendations
The authors conclude that policies are needed to help alleviate conflictof interest concerns even in the basic science setting. Beginning in2012 and reporting in 2013, all pharmaceutical manufacturers will berequired to disclose certain physician-payment information as part ofthe 2010 Patient Protection and Affordable Care Act (PPACA). The authorssuggest it should not stop there.

“Basic science researchers may face similar challenges with regard toconflict of interest as physicians,” said co-author Stephen Lai, M.D.,Ph.D., associate professor of Head and Neck Surgery at The University ofTexas MD Anderson Cancer Center. “Clinical researchers have certainprotocols they follow to protect against conflicts of interest and theoutcome of this study suggests that basic science research would benefitfrom those same systems.”

In addition, the conflicts of interest would benefit from policies of transparency.

“Conflicts of interest in the basic and clinical sciences may alter thereporting of results,” said co-author Oliver Sartor, C.E. and BernadineLaborde Professor of Cancer Research, Tulane University School ofMedicine, and medical director of the Tulane Cancer Center in NewOrleans. “The process of declaring conflicts of interest for basicscientists needs to be examined very carefully going forward, andpolicies should be considered to ensure that these conflicts areapparent to all.”

The authors’ recommendations include:
• extending the PPACA to include reporting by basic science researchers
• making nonclinical basic science researchers follow the same policiesthat clinical researchers follow, including disclosure of fundingsources in communications with research institutions, journal editorsand publications
• making manufacturers produce reports on certain basic sciencequestions within pre-agreed-on periods after regulatory approval for aclinical indication is granted

For the article abstract, go to http://archinte.ama-assn.org/cgi/content/abstract/170/16/1490.

About the Authors
Dr. Charles Bennett is the CoEE Endowed Chair in Medication Safety andEfficacy at the South Carolina College of Pharmacy and director of theSouthern Network on Adverse Reactions (SONAR) in Columbia, S.C. Dr.Stephen Lai is an Associate Professor of the Department of Head and NeckSurgery, University o f Texas, M. D. Anderson Cancer Center in Houston.Dr. Michael Henke is a Professor of Radiation Oncology, UniversityHospital in Freiburg, Germany and the principal investigator of thefirst clinical trial that identified increased mortality risks whencancer patients received ESAs. Sara Barnato was a post-doctoral fellowat the Center for Management of Complex Chronic Care at the Chicago VAMedical Center. Dr. James Armitage is a Professor of Hematology andOncology at the University of Nebraska School of Medicine, in Omaha, anda former president of the American Society of Clinical Oncology. Dr.Oliver Sartor is the C.E. and Bernadine Laborde Professor of CancerResearch, Tulane University School of Medicine, and Medical Director ofthe Tulane Cancer Center in New Orleans
About the Center for Medication Safety and Efficacy
The Medication Safety and Efficacy CoEE works to prevent adverse drugeffects (ADEs) and to improve drug safety. The Center was created in2005 to study the effects of prescription and over-the-countermedications, particularly on children and the elderly. The CoEE also isfocused on education and outreach to health care professionals and thegeneral public through the Doris Levkoff Meddin Medication SafetyEducation Program. Charles L. Bennett, M.D., Ph.D., M.P.P., wasrecruited in 2010 as the endowed chair and the Josie M. FletcherProfessor of Pharmacy at the University of South Carolina (USC) campusof the South Carolina College of Pharmacy. His appointment is supportedin part by Health Sciences South Carolina , the Centers of EconomicExcellence Program and the Frank P. and Josie M. Fletcher Endowment.

About the South Carolina College of Pharmacy
The South Carolina College of Pharmacy (SCCP) was formed in 2004 throughthe integration of the Colleges of Pharmacy at the University of SouthCarolina in Columbia (USC) and the Medical University of South Carolinain Charleston (MUSC). The SCCP is a statewide education, research, andservice institution that combines the nationally recognized faculty,staff, and resources of MUSC, a major academic medical center, and USC, alarge comprehensive university, to create a statewide approach topharmacy education that is on a par with some of the most highlyregarded colleges in the United States.