Planes, cars, oil spills, and pharmaceuticals-- common lessons for preventing major safety tragedies. Charles L. Bennett MD PhD MPP. Barriers to Identifying Adverse Events. Limited size of clinical trials Undetected toxicities at time of FDA approval
Planes, cars, oil spills, and pharmaceuticals-- common lessons for preventing major safety tragedies Charles L. Bennett MD PhD MPP
Barriers to Identifying Adverse Events • Limited size of clinical trials • Undetected toxicities at time of FDA approval • Many AEs identified after several years on the market
Postmarket Pharmacovigilance Hampton, T. Postmarket “Pharmacovigilance” Program on Alert for Adverse Events from Drugs. JAMA, August 22/29 2007, 298 (8): 851-2.
Lessons Learned: The RADAR method • Detect ADR signals • Investigate possible ADR occurrence • Analyze data • Disseminate results Bennett CL, Nebeker JR, Lyons EA, et al. The Research on Adverse Drug Events and Reports (RADAR) Project. JAMA 2005, 293:17, 2131-40.
Mortality and Venous Thromboembolism Associated with Erythropoiesis Stimulating Agents (ESAs) Bennett CL, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. J Amer Med, 2008; 299(8):914-924.
Mortality Meta-analysis Meta-analysis of mortality rates for 51 phase III oncology trials with 13,613 patients for ESAs versus placebo or control HR= 1.10 (1.01, 1.20)
Updated Mortality Meta-analysis Meta-analysis of mortality rates for 53 oncology trials with 14,164 patients for ESAs versus placebo or control (updated to include BRAVE study) HR= 1.09 (95% CI, 1.01-1.18)
VTE Meta-analysis Meta-analysis of VTE rates in 38 phase III trials with 8,172 patients for ESAs versus placebo or control HR= 1.57 (1.31,1.87)
Summary of Mortality Hazard Ratios from Various Published Meta-analyses: Cancer Setting
Summary of Mortality Rates from Various Meta-analyses: Chronic Kidney Disease Setting
Conflicts of Interest in Basic Science Studies:Evaluating Erythropoietin Effects of Solid Tumor Cell Lines Bennett CL, et al. Association between pharmaceutical support and basic science research on erythropoiesis-stimulating agents. Arch Intern Med, 2009; 170(16): 1490-1498.
Prominent Conflict of Interest Cases • Senator Charles Grassley (R-IA) recently initiated conflict of interest probes against physicians at Harvard Medical School, Columbia University, and Emory University. • Physician Payments Sunshine Act: requires transparency in relationships between physicians and pharmaceutical companies.
Background • Clinical studies have demonstrated that when investigators have financial relationships with pharmaceutical manufacturers, they are less likely to criticize the safety, efficacy, or cost-effectiveness of agents supplied by the manufacturers. • No study has evaluated the effects of these financial relationships in the basic science setting.
Study Objectives We investigated the relationship between manufacturer involvement and laboratory results in studies of erythropoietin receptors (EpoRs) in cancer cells.
Erythropoietin Stimulating Agents (ESAs) • ESAs were approved in 1993 for use in the treatment of chemotherapy-associated anemia. • Concerns were raised that the off-target effects might include stimulation of erythropoietin receptors (EpoRs) on cancer cells. • Early adverse clinical evidence for ESA use: - BEST 2003 (breast cancer) - ENHANCE 2003 (head and neck cancer)
Methods • A MEDLINE database search was conducted (1988-June 2008). • Studies investigating EpoR presence and ESA-induced signaling and/or changes in cellular function, in solid tumors, were evaluated. • Conflicts of interest, laboratory results, funding sources, and affiliations were extracted.
Study Groups • Academic studies without funding from ESA manufacturers; n=64 • Studies led by academic investigators who had received funding from ESA manufacturers; n=7 • Investigators employed by ESA manufacturers; n=3
Erythropoietin Receptors in Solid Tumors:Methods of Detection Gene Protein Signal transduction Function / Activity
Erythropoietin Receptors in Solid Tumors:Gene Level Gene • EpoR mRNA is detected in a wide variety of solid tumors. • Studies have demonstrated an increase in EpoR mRNA levels upon stimulation with Epo. Protein Signal transduction Function / Activity
Erythropoietin Receptors in Solid Tumors:Protein Level Gene • Cell surface expression of EpoR in solid tumors detected by immunohistochemistry, immunocytochemistry, immunoblot, etc. Protein Signal transduction Function / Activity
Erythropoietin Receptors in Solid Tumors:Signaling • EpoR stimulation by Epo induces the phosphorylation of signaling proteins involved in critical pathways regulating cell growth, apoptosis and angiogenesis. • Signal transduction is detected in the PI3K-AKT, JAK-STAT and/or NF-kB pathways and varies among tumor types. Gene Protein Signal transduction Function / Activity
Erythropoietin Receptors in Solid Tumors:Cellular Function and Activity • Activation of the Epo/EpoR-signaling axis by Epo administration results in changes in proliferation, apoptosis, invasion, and chemosensitivity. Gene Protein Signal transduction Function / Activity
Comparison of Scientific Conclusions in Publications According to Funding Type p= 0.009 p= 0.001 p= 0.007
Comparison of Scientific Conclusions in Publications According to Funding Type p= 0.008 p< 0.04
Comparison of Scientific Conclusions in Presentations at Two National Meetings According to Funding Type
Association between pharmaceutical support and basic science research findings on ESAs: Comparison of findings before and after an NCI workshop on this subject was convened
Background • Prior study evaluated associations between pharmaceutical-industry funding and preclinical research • Study of erythropoiesis stimulating agents (ESAs) found academic researchers without industry support were more likely than others to identify detrimental effects of ESAs on tumor cells • Concurrently, a meta-analysis identified mortality risks when cancer patients received ESAs • 2007- the National Cancer Institute convened a workshop reviewing research of preclinical effects of ESAs on tumor growth • We updated our analyses of associations between funding source and ESA research findings following the workshop
Methods • Articles identified in MEDLINE and EMBASE databases (2008-2012) investigating preclinical findings for ESAs in the cancer setting were reviewed. • Possible outcomes: • EPO receptor detection • Signaling events • Cellular function • Qualitative conclusions
Outcomes were reported for the current and the earlier time-period according to funding source • investigators without ESA manufacturer funding [27 and 64 studies, respectively] • investigators with funding from manufacturers or who held an ESA patent [5 and 7 studies, respectively] • investigators employed by ESA manufacturers [2 and 3 studies, respectively]
280 Total Articles • 251 Articles were excluded: • Hematologic malignancies • Single case reports • Investigators employed contrived systems • Investigation did not involve cancer • Experiments involved tumor types for which evidence of changes in signaling upon Epo administration was not investigated in the literature • Article was a review EpoR(s), Epo Receptor(s), OR Erythropoietin Receptor(s) Cancer, Tumor, Malignancy, OR Carcinoma + Performed all combinations and used the search with most results Erythropoietin Receptor + Cancer 280 Total Articles 29 Included Articles For each of the tumor types identified in the above searches, additional searches were run with “tumor type” + “EpoR” variant: Breast Lung Prostate Cervical Endometrial Ovarian Glioma Head and Neck Neuroblastoma Renal Pancreatic Melanoma Mesothelioma Colorectal Colon Ewing’s Sarcoma Family of Tumors EpoR(s) 33 Total Articles AND Erythropoietin Receptor(s) Erythropoietin + First OR Last Author (from prior study) 4 Included Articles The first and last author of each previous article were searched for more recent publications
Academic Investigators without conflicts of interest: 16/24and 8/24, respectively Investigative teams comprised of primarily academic investigators, one or more authors has a conflict of interest: 0/3 and 3/3, respectively Investigative teams comprised primarily of ESA manufacturer employees: 1/2 and 1/2, respectively
Presence of the EpoR: 25/26, 5/5, and 2/2, respectively Erythropoietin-induced signaling events: 19/22, 2/2, and 0/2, respectively Erythropoietin-induced chances in cellular function: 19/22, 2/3, and 0/2, respectively Qualitative conclusions that ESAs were harmful: 20/26, 2/5, and 0/2, respectively Qualitative conclusions that ESAs were beneficial: 0/26, 0/5, and 0/2, respectively Qualitative conclusions that ESAs were neutral/no statement: 6/26, 3/5, and 2/2respectively
Total Presence of the EpoR: 82/83, 8/10, and 3/5, respectively Erythropoietin-induced signaling events: 50/55, 2/4, and 0/3, respectively Erythropoietin-induced chances in cellular function: 49/61, 2/9, and 0/3, respectively Qualitative conclusions that ESAs were harmful: 44/91, 2/12, and 0/5, respectively Qualitative conclusions that ESAs were beneficial: 6/91, 3/12, and 0/5, respectively
Conclusions • Academic researchers with or without financial conflicts increasingly report detrimental effects of ESAs. • Concerns over potential financial conflicts of interest affecting basic science research are less apparent in academic versus pharmaceutical-owned laboratories.
Criticisms of Findings Suggesting Harmful Effects of ESAs • Antibody specificity • Choice of controls; proprietary versus non-proprietary carrier protein • Differences in biological threshold for identifying changes in cellular function of erythropoietin-exposed cancer cells
Summary of Results In these basic science studies, pharmaceutical sponsorship is associated with a decreased likelihood of identifying: • Presence of EpoR on solid cancer cell lines • Unfavorable signaling events upon ESA administration • Unfavorable changes in cellular function upon ESA administration
Future Implications of COI Study • These findings are counter to the belief that basic science studies are not subject to variable interpretation. • The observed relationship may extend to other basic science research studies. • Only further analyses can confirm or deny these preliminary findings, but the implications are significant and additional studies in this area are warranted.
Rituximab-associated Progressive multifocal leukoencephalopathy (PML) Carson KR, Bennett CL, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood, 2009; 113(20). 4834-4840.
Progressive Multifocal Leukoencephalopathy (PML) • Etiology • JC polyomavirus infection • >80% of cases seen in patients with HIV • Latent JC virus in up to 80% of population • Reactivation of JC virus not well understood • Non-HIV PML • Hematologic malignancy • B-cell lymphoproliferative disorders • Possible association with stem cell transplant and purine analog therapy • Chronic inflammatory diseases, solid organ transplant, sarcoidosis, advanced age
Rituximab and viral reactivation(United States) • June 2004 • Warning about Hepatitis B reactivation added to package insert • February 2006 • Warning about other viral infections added to package insert • December 2006 • Letter to health professionals from manufacturer and FDA warning: PML seen in two patients with lupus • February 2007 • Black box warning added to package insert
Case Reports, Inclusion/Exclusion • Cases were identified among rituximab-treated patients by clinicians from 12 cancer centers or academic hospitals (22 cases) or by reviewing FDA reports (11 cases), the manufacturer’s database (30 cases), and publications (18 cases; MeSH search terms: leukoencephalopathy, rituximab, immunosuppressed, lymphoma, and leukemia) • Unique data sources • Clinical observation (n=7) • Medical literature (n=14) • FDA MEDWatch (n=14) • Manufacturer (n= 23) • Inclusion criteria: Rituximab treatment AND • Brain biopsy confirmation of PML OR • Autopsy confirmation OR • MRI evidence AND JC virus in CSF by PCR • Exclusion • Diagnosis of HIV
15 excluded for inadequate evidence of PML, 2 for diagnosis of HIV Patient Information (n=57) Findings Carson, Blood 2009
Additional Findings • Median time course (All patients, n=57) Carson, Blood 2009
Symptoms at diagnosis • Mental status changes or confusion 54.4% • Focal motor weakness 33.3% • Loss of coordination 24.6% • Difficulty speaking 21.2% • Vision changes 17.5% Carson, Blood 2009
MRI Findings Carson, Lancet Oncology 2009 (In press)
Inhibition of T-lymphocyte Trafficking by natalizumab and efalizumab Carson, Lancet Oncology 2009 (In press)
T-Lymphocyte count at PML diagnosis Carson, Blood 2009