United States' regulatory approved pharmacotherapies for nuclear reactor explosions and anthrax-associated bioterrorism.

INTRODUCTION: Nuclear reactor incidents and bioterrorism outbreaks are concerning public health disasters. Little is known about US Food and Drug Administration (FDA)-approved agents that can mitigate consequences of these events. We review FDA data supporting regulatory approvals of these agents. AREAS COVERED: We reviewed pharmaceutical products approved to treat Hematopoietic Acute Radiation Syndrome (H-ARS) and to treat or prevent pulmonary infections following Bacillus anthracis (anthrax) exposure. Four drugs were approved for H-ARS: granulocyte-colony stimulating factor (G-CSF), granulocyte/macrophage colony stimulating factor, pegylated G-CSF, and romiplostim. For bioterrorism-associated anthrax, the FDA approved five antibiotics (doxycycline, penicillin-G, levofloxacin, moxifloxacin, and ciprofloxacin), two monoclonal antibodies (obiltoxaximab and raxibacumab), one polyclonal antitoxin (Anthrax Immune Globulin Intravenous) and two vaccines (Anthrax Vaccine Adsorbed and Anthrax Vaccine Adsorbed with an adjuvant). A national stockpile system ensures that communities have ready access to these agents. Our literature search was based on data included in drugs@FDA (2001-2023). EXPERT OPINION: Two potential mass public health disasters are aerosolized anthrax dissemination and radiological incidents. Five agents authorized for anthrax emergencies only have FDA approval for this indication, five antibiotics have FDA approvals as antibiotics for common infections and for bacillus anthrax, and four agents have regulatory approvals for supportive care for cancer and for radiological incidents.

Reimagining Cancer: Moving from the Cellular to the Tissue Level.

The current universally accepted explanation of cancer origin and behavior, the somatic mutation theory, is cell-centered and rooted in perturbation of gene function independent of the external environmental context. However, tumors consist of various epithelial and stromal cell populations temporally and spatially organized into an integrated neoplastic community, and they can have properties similar to normal tissues. Accordingly, we review specific normal cellular and tissue traits and behaviors with adaptive temporal and spatial self-organization that result in ordered patterns and structures. A few recent theories have described these tissue-level cancer behaviors, invoking a conceptual shift from the cellular level and highlighting the need for methodologic approaches based on the analysis of complex systems. We propose extending the analytical approach of regulatory networks to the tissue level and introduce the concept of "cancer attractors." These concepts require reevaluation of cancer imaging and investigational approaches and challenge the traditional reductionist approach of cancer molecular biology.

Consequences to Patients, Clinicians, and Manufacturers When Very Serious Adverse Drug Reactions Are Identified (1997-2019): A Qualitative Analysis from the Southern Network on Adverse Reactions (SONAR).

Adverse drug/device reactions (ADRs) serious enough to lead to box warnings on drug labels or drug withdrawals occur in about one fifth of all new molecular entities.

Advanced cancer patients in a randomized clinical trial of night-simulating eyeglasses observed to have a normal 24-h circadian rhythm during chemotherapy.

Objectives: Cancer patients routinely exhibit dysfunctional circadian organization. Indeed, a dysfunctional circadian organization is a hallmark of advanced cancer. A cohort of advanced cancer patients undergoing chemotherapy was recruited to investigate whether manipulating exposure to blue light could restore or ameliorate their circadian organization. Methods: Thirty advanced metastatic cancer patients participated in a randomized crossover trial to evaluate whether blue light-blocking night-simulating eyeglasses could ameliorate a disrupted circadian organization better than sham eyeglasses. Circadian organization was evaluated by actigraphy and patients' self-reports of sleep, fatigue, and quality of life. Kruskal-Wallis tests compared patients' outcomes in circadian organization with a cohort of non-cancer, disease-free individuals with normal sleep as a negative control, and with advanced cancer patients with disrupted circadian organization as a positive control. Quality-of-life outcomes of the patients were compared with population-based controls (negative controls) and with cohorts of advanced cancer patients (positive controls). Results: Actigraphy measurements, self-reported sleep, fatigue levels, and quality-of-life outcomes of trial participants were similar to those of negative controls with a normal circadian organization, in spite of the trial patients' concurrent chemotherapy. Night-simulating glasses did not improve circadian organization. The 24-h correlation of day-to-day rhythms of rest and activity was 0.455 for the experimental eyeglasses and 0.476 for the sham eyeglasses (p = 0.258). Actigraphic and patient-reported outcomes compared favorably to outcomes of positive controls. Conclusion: The circadian organization of patients in this study unexpectedly resembled that of healthy controls and was better than comparison populations with disrupted circadian organization. The study clinic implements chronomodulated chemotherapy and a systematic, supportive integrative treatment protocol. Results suggest a need for further research on interventions for circadian rhythm. Although the study intervention did not benefit the participants, this work highlights the value of supporting circadian time structure in advanced cancer patients.

Progressive multifocal leukoencephalopathy in patients treated with rituximab: a 20-year review from the Southern Network on Adverse Reactions.

Progressive multifocal leukoencephalopathy (PML) is a serious and usually fatal CNS infection caused by the John Cunningham virus. CD4+ and CD8+ T-cell lymphopenia, resulting from HIV infection, chemotherapy, or immunosuppressive therapy, are primary risk factors for PML. Following its introduction in 1997, the immunomodulatory anti-CD20 monoclonal antibody, rituximab, has received regulatory approval worldwide for treatment of non-Hodgkin lymphoma, rheumatoid arthritis, chronic lymphocytic leukaemia, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulagris. Rituximab leads to prolonged B-lymphocyte depletion, potentially allowing John Cunningham viral infection to occur. Six unexpected cases of PML infection developing in rituximab-treated patients were first reported in 2002. We review 20 years of information on clinical findings, pathology, epidemiology, proposed pathogenesis, and risk-management issues associated with PML infection developing after rituximab treatment. Since the first case series report of 52 cases of rituximab-associated PML among patients with non-Hodgkin lymphoma or chronic lymphocytic leukaemia in 2009, updated and diligent pharmacovigilance efforts have provided reassurance that this fatal toxicity is a rare clinical event with concurring causal factors. International harmonisation of safety warnings around rituximab-associated PML should be considered, with these notifications listing rituximab-associated PML under a section titled warnings and precautions as is the case in most countries, rather than a boxed warning as is the case in the USA.

Consequences to patients, clinicians, and manufacturers when very serious adverse drug reactions are identified (1997-2019): A qualitative analysis from the Southern Network on Adverse Reactions (SONAR).

BACKGROUND: Adverse drug/device reactions (ADRs) can result in severe patient harm. We define very serious ADRs as being associated with severe toxicity, as measured on the Common Toxicity Criteria Adverse Events (CTCAE)) scale, following use of drugs or devices with large sales, large financial settlements, and large numbers of injured persons. We report on impacts on patients, clinicians, and manufacturers following very serious ADR reporting. METHODS: We reviewed clinician identified very serious ADRs published between 1997 and 2019. Drugs and devices associated with reports of very serious ADRs were identified. Included drugs or devices had market removal discussed at Food and Drug Advisory (FDA) Advisory Committee meetings, were published by clinicians, had sales > $1 billion, were associated with CTCAE Grade 4 or 5 toxicity effects, and had either >$1 billion in settlements or >1,000 injured patients. Data sources included journals, Congressional transcripts, and news reports. We reviewed data on: 1) timing of ADR reports, Boxed warnings, and product withdrawals, and 2) patient, clinician, and manufacturer impacts. Binomial analysis was used to compare sales pre- and post-FDA Advisory Committee meetings. FINDINGS: Twenty very serious ADRs involved fifteen drugs and one device. Legal settlements totaled $38.4 billion for 753,900 injured persons. Eleven of 18 clinicians (61%) reported harms, including verbal threats from manufacturer (five) and loss of a faculty position (one). Annual sales decreased 94% from $29.1 billion pre-FDA meeting to $4.9 billion afterwards (p<0.0018). Manufacturers of four drugs paid $1.7 billion total in criminal fines for failing to inform the FDA and physicians about very serious ADRs. Following FDA approval, the median time to ADR reporting was 7.5 years (Interquartile range 3,13 years). Twelve drugs received Box warnings and one drug received a warning (median, 7.5 years following ADR reporting (IQR 5,11 years). Six drugs and 1 device were withdrawn from marketing (median, 5 years after ADR reporting (IQR 4,6 years)). INTERPRETATION: Because very serious ADRs impacts are so large, policy makers should consider developing independently funded pharmacovigilance centers of excellence to assist with clinician investigations. FUNDING: This work received support from the National Cancer Institute (1R01 CA102713 (CLB), https://www.nih.gov/about-nih/what-we-do/nih-almanac/national-cancer-institute-nci; and two Pilot Project grants from the American Cancer Society's Institutional Grant Award to the University of South Carolina (IRG-13-043-01) https://www.cancer.org/ (SH; BS).

The First 2 Years of Biosimilar Epoetin for Cancer and Chemotherapy-Induced Anemia in the U.S.: A Review from the Southern Network on Adverse Reactions.

Biosimilars are biologic drug products that are highly similar to reference products in analytic features, pharmacokinetics and pharmacodynamics, immunogenicity, safety, and efficacy. Biosimilar epoetin received Food and Drug Administration (FDA) approval in 2018. The manufacturer received an FDA nonapproval letter in 2017, despite receiving a favorable review by FDA's Oncologic Drugs Advisory Committee (ODAC) and an FDA nonapproval letter in 2015 for an earlier formulation. We discuss the 2018 FDA approval, the 2017 FDA ODAC Committee review, and the FDA complete response letters in 2015 and 2017; review concepts of litigation, naming, labeling, substitution, interchangeability, and pharmacovigilance; review European and U.S. oncology experiences with biosimilar epoetin; and review the safety of erythropoiesis-stimulating agents. In 2020, policy statements from AETNA, United Health Care, and Humana indicated that new epoetin oncology starts must be for biosimilar epoetin unless medical need for other epoetins is documented. Empirical studies report that as of 2012, reference epoetin use decreased from 40%-60% of all patients with cancer with chemotherapy-induced anemia to <5% of such patients because of safety concerns. Between 2018 and 2020, biosimilar epoetin use varied, increasing to 81% among one private insurer's patients covered by Medicare whose cancer care is administered with Oncology Analytics and to 41% with the same private insurer's patients with cancer covered by commercial health insurance and administered by the private insurer, to 0% in several Veterans Administration Hospitals, increasing to 100% in one large county hospital in California, and with yet-to-be-reported data from most oncology settings. We conclude that biosimilar epoetin appears to have overcome some barriers since 2015, although current uptake in the U.S. is variable. Pricing and safety considerations for all erythropoiesis-stimulating agents are primary determinants of biosimilar epoetin oncology uptake. IMPLICATIONS FOR PRACTICE: Few oncologists understand substitution and interchangeability of biosimilars with reference drugs. Epoetin biosimilar is new to the market, and physician and patient understanding is limited. The development of epoetin biosimilar is not familiar to oncologists.

Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions.

The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 [11%] with the EMA, seven of 16 [44%] with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.

Interpreting Breast Cancer Survival Data by the Hazard Function: Remarkable Findings from Event Dynamics.

The report addresses the role of the hazard function in the analysis of disease-free survival data in breast cancer. An investigation on local recurrences after mastectomy provided evidence that uninterrupted growth is inconsistent with clinical findings and that tumor dormancy could be assumed as working hypothesis to understand the clinical course of the disease. Additionally, it was deemed that the lag-time between primary tumor removal and tumor recurrence is dynamically dependent on the subclinical metastasis development within the host-tumor system and, therefore, may be informative about the biology of the disease. Accordingly, the hazard function, which estimates the event risk pattern through the time, was adopted to analyze survival data. The multipeak pattern of the hazard function suggested that the process metastasis development has discontinuous features. A new paradigm of breast cancer metastatic development was proposed, involving the notions of tumor homeostasis, tumor quiescence in specific metastatic microscopic phases and surgery-related acceleration of the metastatic process. All analyses by prognostic factors (e.g., by menopausal status) or treatment modalities (e.g., by adjuvant chemotherapy) or other parameters (e.g., site of metastasis), provided coherent data in agreement with the model. The hazard rate function allowed addressing several clinical questions including meaning of ipsilateral breast tumor recurrence (IBTR), oncologic effect of delayed breast reconstruction, surgery related metastasis acceleration, possible role of anti-inflammatory drugs and body mass index (BMI) to modulate the recurrence risk. We conclude that the hazard function is a powerful tool to investigate the post-surgical course of early breast cancer and other operable tumors and to make inferences on their biology.

Breast cancer and the black swan.

Most current research in cancer is attempting to find ways of preventing patients from dying after metastatic relapse. Driven by data and analysis, this project is an approach to solve the problem upstream, i.e., to prevent relapse. This project started with the unexpected observation of bimodal relapse patterns in breast and a number of other cancers. This was not explainable with the current cancer paradigm that has guided cancer therapy and early detection for many years. After much analysis using computer simulation and input from a number of medical specialties, we eventually came to the conclusion that the surgery to remove the primary tumour produced systemic inflammation for a week after surgery. This systemic inflammation apparently caused exits of cancer cells and micrometastases from dormant states and resulted in relapses in the first 3 years post-surgery. It was determined in a retrospective study that the common inexpensive perioperative non-steroidal anti-inflammatory drug (NSAID) ketorolac could curtail the early relapse events after breast cancer surgery. A second retrospective study strongly confirmed this but an apparently underpowered prospective study showed no advantage. We are analysing these data and are now proposing to test the perioperative NSAID at Beth Israel Deaconess Medical Centre with triple-negative breast cancer (TNBC) patients, the category that could respond best to the perioperative NSAID. If this works as well as we expect, we would then transfer this technology to low- and/or middle-incomes countries (LMICs), starting with Nigeria where early onset type of TNBC is common. There is an unmet need in LMICs, especially in countries like Nigeria (190 million population), for a means to prevent surgery induced relapse that we are attempting to resolve. This work aims, thus, to describe eventual mechanisms, and ways to test a solution addressing an unmet need. But first, we consider the context, including within an historical perspective, important to explain how and why a Kuhnian paradigm shift may be considered.

End of an era of administering erythropoiesis stimulating agents among Veterans Administration cancer patients with chemotherapy-induced anemia.

Erythropoisis stimulating agent (ESA) use was addressed in Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC) meetings between 2004 and 2008. FDA safety-focused regulatory actions occurred in 2007 and 2008. In 2007, black box warnings advised of early death and venous thromboembolism (VTE) risks with ESAs in oncology. In 2010, a Risk Evaluation Strategies (REMS) was initiated, with cancer patient consent that mortality and VTE risks were noted with ESAs. We report warnings and REMS impacts on ESA utilization among Veterans Administration (VA) cancer patients with chemotherapy-induced anemia (CIA). Data were from Veterans Affairs database (2003-2012). Epoetin and darbepoetin use were primary outcomes. Segmented linear regression was used to estimate changes in ESA use levels and trends, clinical appropriateness, and adverse events (VTEs) among chemotherapy-treated cancer patients. To estimate changes in level of drug prescription rate after policy actions, model-specific indicator variables as covariates based on specific actions were included. ESA use fell by 95% and 90% from 2005, for epoetin and darbepoetin, from 22% and 11%, respectively, to 1% and 1%, respectively, among cancer patients with CIA, respectively (p<0.01). Following REMS in 2010, mean hematocrit levels at ESA initiation decreased from 30% to 21% (p<0.01). Black box warnings preceded decreased ESA use among VA cancer patients with CIA. REMS was followed by reduced hematocrit levels at ESA initiation. Our findings contrast with privately- insured and Medicaid insured cancer patient data on chemotherapy-induced anemia where ESA use decreased to 3% to 7% by 2010-2012. By 2012, the era of ESA administration to VA to cancer patients had ended but the warnings remain relevant and significant. In 2019, oncology/hematology national guidelines (ASCO/ASH) recommend that cancer patients with chemotherapy-induced anemia should receive ESAs or red blood cell transfusions after risk-benefit evaluation.

End of an era for erythropoiesis-stimulating agents in oncology.

Erythropoiesis-stimulating agents (ESAs) are available to treat chemotherapy-induced anemia (CIA). In 2007-2008, regulatory notifications advised of venous thromboembolism and mortality risks while the Center for Medicare and Medicaid Services' restricted ESA initiation to patients with hemoglobin <10 g/dl. In 2010, a Risk Evaluation and Mitigation Strategies required consent prior to administration. We evaluated ESA utilization from 2003 to 2012 and obtained private health insurer claims data for persons with lung, colorectal, or breast cancer from 2001 to 2012. ESA use for CIA was determined by an ESA claim after chemotherapy, up to 6 months after treatment. We identified 839,948 commercially insured patients, including 24,785 patients with ESA-treated CIA (3.2%). Darbepoetin use increased 3.9-fold from 2003 to 2007 (12.3% to 48.7%) and then decreased 95% to 2.6% by 2012. Epoetin use decreased 90% from 2003 to 2012 (30.3% to 3.1%). Between 2003 and 2012, mean epoetin dosing decreased 0.8-fold (244,979 in 2003 vs. 196,216 units in 2012), but increased 1.8-fold for darbepoetin-treated CIA (262 in 2003 to 467 µg in 2012). Among CIA patients, transfusions were low (4.5%) in 2002-2007, then increased 2.2-fold between 2008 and 2012. Safety initiatives between 2007 and 2010 facilitated reductions in ESA use combined with changes in coverage. These data show the efficacy of regulatory efforts, publication of adverse events and changes in reimbursement in reducing use of ESAs. Future studies are warranted to optimize deimplementation strategies to improve patient safety.

Caveat Medicus: Clinician experiences in publishing reports of serious oncology-associated adverse drug reactions.

Oncology-associated adverse drug/device reactions can be fatal. Some clinicians who treat single patients with severe oncology-associated toxicities have researched case series and published this information. We investigated motivations and experiences of select individuals leading such efforts. Clinicians treating individual patients who developed oncology-associated serious adverse drug events were asked to participate. Inclusion criteria included having index patient information, reporting case series, and being collaborative with investigators from two National Institutes of Health funded pharmacovigilance networks. Thirty-minute interviews addressed investigational motivation, feedback from pharmaceutical manufacturers, FDA personnel, and academic leadership, and recommendations for improving pharmacovigilance. Responses were analyzed using constant comparative methods of qualitative analysis. Overall, 18 clinicians met inclusion criteria and 14 interviewees are included. Primary motivations were scientific curiosity, expressed by six clinicians. A less common theme was public health related (three clinicians). Six clinicians received feedback characterized as supportive from academic leaders, while four clinicians received feedback characterized as negative. Three clinicians reported that following the case series publication they were invited to speak at academic institutions worldwide. Responses from pharmaceutical manufacturers were characterized as negative by 12 clinicians. One clinician's wife called the post-reporting time the "Maalox month," while another clinician reported that the manufacturer collaboratively offered to identify additional cases of the toxicity. Responses from FDA employees were characterized as collaborative for two clinicians, neutral for five clinicians, unresponsive for negative by six clinicians. Three clinicians endorsed developing improved reporting mechanisms for individual physicians, while 11 clinicians endorsed safety activities that should be undertaken by persons other than a motivated clinician who personally treats a patient with a severe adverse drug/device reaction. Our study provides some of the first reports of clinician motivations and experiences with reporting serious or potentially fatal oncology-associated adverse drug or device reactions. Overall, it appears that negative feedback from pharmaceutical manufacturers and mixed feedback from the academic community and/or the FDA were reported. Big data, registries, Data Safety Monitoring Boards, and pharmacogenetic studies may facilitate improved pharmacovigilance efforts for oncology-associated adverse drug reactions. These initiatives overcome concerns related to complacency, indifference, ignorance, and system-level problems as barriers to documenting and reporting adverse drug events- barriers that have been previously reported for clinician reporting of serious adverse drug reactions.

Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada.

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%-40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the "rebate trap" with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. IMPLICATIONS FOR PRACTICE: We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing "rebate traps" where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR).

A 43-year-old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against α4 integrins. To investigate the risk-exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab-associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) (2004-2014), a FDA Advisory Committee Meeting Report, and peer-reviewed publications. In the United States, the manufacturer maintains an FDA-mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab-treated patients. We statistically compared reporting completeness for natalizumab-associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab-associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21-74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab-treated MS patients who developed biopsy-confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38-48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1-77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8-possible items, P < 0.0007). Clinicians should monitor existing nevi and maintain suspicion for melanoma developing in natalizumab-treated patients. The TOUCH Safety Surveillance Program, currently focused on progressive multifocal leukoencephalopathy, should be expanded to include information on other serious complications including malignancies, particularly if they are immunologic in nature.

Tale of Two Erythropoiesis-Stimulating Agents: Utilization, Dosing, Litigation, and Costs of Darbepoetin and Epoetin Among South Carolina Medicaid-Covered Patients With Cancer and Chemotherapy-Induced Anemia.

PURPOSE: The US Food and Drug Administration (FDA) has approved epoetin and darbepoetin for chemotherapy-induced anemia (CIA). Approved epoetin and darbepoetin dosing schedules were three times per week and weekly, respectively, although off-label, less frequent scheduling was common. In 2004, 2007, and 2008, a US Food and Drug Administration Advisory Committees warned of risks associated with erythropoiesis-stimulating agents. During this period, lawsuits alleging illegal darbepoetin marketing practices have concluded, resulting in $1.1 billion in fines and settlements and one criminal conviction. No prior study, to our knowledge, has reported on the use of darbepoetin versus epoetin for CIA. METHODS: We evaluated the dosing, utilization, and costs of erythropoiesis-stimulating agents among 3,761 South Carolina Medicaid patients with CIA. RESULTS: Epoetin and darbepoetin utilization rates were 22% and 28% in 2003, 10% and 33% in 2007, and 3% and 7% in 2010, respectively. Mean per-patient per-administration epoetin and darbepoetin doses were 40,983 IU and 191 µg, respectively, in 2003 and 47,753 IU and 369 µg, respectively, in 2010. Mean monthly patient costs for epoetin and darbepoetin were $1,030 and $981, respectively, in 2003 and $932 and $1,352, respectively, in 2010. Epoetin use decreased steadily between 2002 and 2010; darbepoetin use increased steadily between 2003 and 2007 and then decreased steadily thereafter. Per-patient dosing of darbepoetin, but not epoetin, increased steadily between 2003 and 2010, and monthly per-patient epoetin costs decreased 3% while the per-patients costs of darbepoetin increased 30% between 2003 and 2010. CONCLUSION: To our knowledge, our findings are the first data reporting on epoetin versus darbepoetin use for CIA and support recently concluded lawsuits involving allegations of illegal marketing practices of the manufacturer of darbepoetin.

Generic oncology drugs: are they all safe?

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval.

Cancer as a changed tissue's way of life (when to treat, when to watch and when to think).

The profound scientific and commercial success of molecular biology, the progress of 'cancer gene' investigation technologies, together, pushed forward the postulate that genes explain 'everything'. Yet, during the last few years the microenvironments of solid tumors have emerged as key modulators of initiation, progression and metastasis and as essential to the therapeutic response. In the present review, we provide a synthetic examination of the main traits of cells embedded into the cancer stroma and emphasize several evidences that all components of the tumor tissue cooperate in space and time. Then we turn to discuss the epitheliocentric somatic mutational view and other new paradigms assuming that disturbed tissue interactions among cell populations are critical to cancer causation, growth and spread.