Postmarketing Period Research Articles

Fingolimod effects on left ventricular function in multiple sclerosis

Background: Cardiovascular side effects such as bradycardia and atrioventricular block were observed during the early clinical trials of fingolimod in multiple sclerosis, and one cardiovascular- linked death has been reported in the post-marketing period. Objective: To investigate the medium-term effects of fingolimod on heart function in order to obtain further insights into its cardiac safety profile. Methods: The study involved 53 patients starting treatment with fingolimod 0.5 mg daily and 25 patients treated with natalizumab 300 mg monthly. Cardiac function was assessed by means of echocardiography at baseline (T0), and after one (T1), six (T6), and (in the case of the fingolimod group) 12 months (T12). Results: Mean left ventricular ejection fraction significantly decreased and end-systolic volume increased from T0 to T1 (p=0.005) and T6 (p=0.0001) in the fingolimod but not the natalizumab group, although a slight increase was observed at T12. A similar decrease in ejection fraction was also observed after six months in nine patients switched from natalizumab to fingolimod. Conclusion: Fingolimod significantly reduces left ventricular systolic function in MS patients. This effect has no clinical consequences in subjects without previous cardiac disorders, but suggests that more caution is required in patients with current or previous heart failure.

Social Pharmacology: A Further Step in Public Health

Social Pharmacology is a field of health science which generates knowledge about marketed drugs in actual use; it focuses on evaluation of the consequences of an individual's exposure to any marketed drug and factors related to its utilization.. The goal of this discipline is to gain knowledge still needed after a drug is marketed. The dossier of a new medicine following regulatory approval contains only the beginning of information needed to be gathered. The postmarketing period represents the most extensive opportunity to study medications in their social life cycle The post- approval environment is complex: strict drug development process controls are no longer in place and operational and management actions by industrial sponsors, health delivery agencies and regulators are unpredictable. We review the impact of pharmacology on public health in its broadest scope. Social pharmacology is proposed as a strategic means to obtain essential data about marketed drugs by engaging the expertise of heterogeneous groups of health-related disciplines., By assessing the wide scope of potential interactions between vectors linked to the actual use of marketed drugs, population-based conclusions may be reached about risk-benefit factors, need for alert responses, proposed actions for decision-making, importance of negative drug effects, and promotion of proper and efficient use of drugs .

Drug-Induced Hepatotoxicity of Select Herbal Therapies

The use of herbal botanicals and dietary supplements to treat and alleviate disease symptoms has increased over the past decades, and as a result, more research has been done to study the potential damaging effects of herbal products on the liver and other organs. Although reporting rates vary, cases have been published describing liver damage following herbal therapy. Studies have proposed multiple mechanisms of injury for these herbal preparations, and several potential risk factors have been identified including age, gender, polypharmacy, alcohol consumption, and genetic variability. Ingredients and other constituents often differ among products, and lack of standardization in manufacturing of these formulations makes it difficult to determine causality. The potential for drug-induced liver injury is often not known until the postmarketing period due to less rigorous safety testing and regulations.

Development and evaluation of an algorithm to identify users of Prolia® during the early postmarketing period using health insurance claims data

The goal of this study is to develop and validate an algorithm to identify Prolia(®) users within a health insurance claims database. Patients with a denosumab-specific or nonspecific administration claim during the early period of Prolia availability in the USA (June 1, 2010 to March 31, 2012) were classified as definite, probable, possible, and nonusers of Prolia using an algorithm consisting of nine different components based on claims patterns consistent with Prolia use. Medical record review confirmed a sample of definite, probable, and possible users and the positive predictive value (PPV) was estimated. The PPV of the claims-based algorithm components varied (17.8-95.8%). Requiring claims for a bone or cartilage disorder or osteoporotic fracture after excluding claims for cancer prior to a denosumab-specific administration code gave the highest PPV (95.8%), followed by requiring a Prolia National Drug Code on the same claim as a denosumab-specific or nonspecific administration code (88.2%). Among the 87 confirmed Prolia users, osteoporosis diagnoses were seen more frequently in the medical record than in claims (83% vs 62%). Prolia users are most accurately identified with administration code claims in conjunction with claims for Prolia National Drug Code and bone disorder treatment and diagnosis codes. Osteoporosis diagnoses may be under-recorded in claims data. The algorithm may require reassessment as uptake for more recently approved indications increases.

A new standardised MedDRA query to address drug abuse-related safety signals

A new standardised MedDRA query to address drug abuse-related safety signals

Poster #T214 A SYSTEMATIC REVIEW OF FACTORS INFLUENCING ANTIPSYCHOTIC MEDICATION ADHERENCE IN SCHIZOPHRENIA

The US Food and Drug Administration (FDA) has new regulatory authorities intended to enhance drug safety monitoring in the postmarketing period. This has resulted in an increase in communication from the FDA in recent years about the safety profile of certain drugs. It is important to stay abreast of the current literature on drug risks to effectively communicate these risks to patients, other health care providers, and the general public.To summarize 4 new FDA drug safety communications by describing the evidence supporting the risks and the clinical implications for older adults.The FDA Web site was reviewed for new drug safety communications from May 2011 to April 2012 that would be relevant to older adults. Approved labeling for each drug or class was obtained from the manufacturer, and PubMed was searched for primary literature that supported the drug safety concern.FDA drug safety communications for 4 drugs were chosen because of the potential clinical importance in older adults. A warning for citalopram was made because of potential problems with QT prolongation in patients taking less than 40 mg per day. The evidence suggests minor changes in QT interval. Given the flat dose–response curve in treating depression with citalopram, the new 20-mg/d maximum dose in older adults is sensible. Another warning was made for proton pump inhibitors (PPIs) and an increased risk of Clostridium difficile infection. A dose–response relationship was found for this drug risk. With C. difficile infections on the rise in older adults, along with other safety risks of PPI therapy, PPIs should only be used in older adults indicated for therapy for the shortest duration possible. In addition, a warning about dabigatran was made. There is strong evidence from a large clinical trial, as well as case reports, of increased bleeding risk in older adults taking dabigatran, especially in older adults with decreased renal function. This medication should be used with caution in older adults. Finally, several warnings were made about statins. Routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury from statin use; thus, liver enzymes are no longer recommended to be routinely monitored. Statin-induced cognitive changes are rare, and insufficient evidence is currently available to establish causality. Statins appear to moderately increase the risk of developing diabetes (versus placebo), and regular screening for diabetes should be considered, especially for patients taking high-dose statins and patients with multiple risk factors for diabetes.FDA drug safety communications incorporate complex methodologies that investigate the risks (and relative benefits) of medication therapy. Clinicians caring for older adults need to be aware of the most current evidence behind these drug risks to effectively communicate with and care for their patients.

An Update on Zolpidem Abuse and Dependence

In 2004, the health authorities (French National Agency for Medicines and Health Products Safety—ANSM) modified the summary of zolpidem characteristics. Particularly it now includes the sentence “a pharmacodependence may materialize.” The current article aims to show that despite this modification, zolpidem continues to be associated with problematic drug use, as the official system (Center for Evaluation and Information on Pharmacodependence—Addictovigilance network) providing information on the abuse and dependence potential of drugs informs us. The authors reviewed the literature on this topic and analyzed French data from zolpidem's postmarketing period that were collected by the Addictovigilance network from 2003 to 2010. Postmarketing data and the 30 case reports yielded from the literature review highlight a significant dependence and abuse potential for zolpidem. This survey led to propose in stronger additional rules in France to try to mitigate the abuse potential of zolpidem.

Prospective Cohort Studies of Newly Marketed Medications

Nonrandomized safety and effectiveness studies are often initiated immediately after the approval of a new medication, but patients prescribed the new medication during this period may be substantially different from those receiving an existing comparator treatment. Restricting the study to comparable patients after data have been collected is inefficient in prospective studies with primary collection of outcomes. We discuss design and methods for evaluating covariate data to assess the comparability of treatment groups, identify patient subgroups that are not comparable, and decide when to transition to a large-scale comparative study. We demonstrate methods in an example study comparing Cox-2 inhibitors during their postmarketing period (1999-2005) with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). Graphical checks of propensity score distributions in each treatment group showed substantial problems with overlap in the initial cohorts. In the first half of 1999, >40% of patients were in the region of nonoverlap on the propensity score, and across the study period this fraction never dropped below 10% (the a priori decision threshold for transitioning to the large-scale study). After restricting to patients with no prior NSAID use, <1% of patients were in the region of nonoverlap, indicating that a large-scale study could be initiated in this subgroup and few patients would need to be trimmed from analysis. A sequential study design that uses pilot data to evaluate treatment selection can guide the efficient design of large-scale outcome studies with primary data collection by focusing on comparable patients.

Neuropsychiatric Events with Varenicline: a Modified Prescription-Event Monitoring Study in General Practice in England

Varenicline (Champix(®)), launched in the UK in December 2006, is indicated for the treatment of smoking cessation in adults (≥18years of age). In 2008, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK issued a warning suggesting that varenicline was associated with disparate neuropsychiatric symptoms, including depression, suicidal thoughts and behaviour. In response to this regulatory warning, the Drug Safety Research Unit conducted a modified prescription-event monitoring (M-PEM) study to monitor the safety of varenicline. The aim of this study was to estimate the incidence and examine the pattern of neuropsychiatric events reported to general practitioners (GPs) in England during the immediate postmarketing period for varenicline. A postmarketing surveillance study was conducted using the observational cohort technique of M-PEM. Patients were identified from dispensed prescriptions issued by primary care physicians between December 2006 and March 2007. Data on exposure, previous history of psychiatric illness and events reported during and after treatment were collected from questionnaires. In order to determine whether hazards for neuropsychiatric events of interest (depression, anxiety, aggression, suicidal ideation, non-fatal self-harm) were non-constant over time (which could indicate a possible association with the drug), the pattern of events was examined by plotting the smoothed hazard function estimate and then fitting a Weibull model. The Weibull model shape parameter (β) and 95% confidence interval were used as a test for a non-constant hazard function (where a value of 1 indicates a constant hazard over time). In addition to this analysis, the difference in incidence densities (IDs) between month 1 and months 2-3 were calculated and compared. The cohort comprised of 12,159 patients (median age 47years [interquartile range 19]; 56.9% [n=6924 female]). The number of events reported during treatment, reason for stopping, adverse drug reactions (ADRs), and the p-value for the Weibull shape parameter were as follows: depression (n=94; 42; 19; p=0.144); anxiety (n=94; 49; 9; p=0.009); aggression (n=7; 4; 2; p=0.465); suicidal ideation (n=8; 4; 1; p=0.989) and non-fatal self-harm (n=5; 1; 0; p=0.771). No differences in the IDs between months 1 and months 2-3 were found for any of the events. Whilst between 7 and 17% of neuropsychiatric events were attributed to the drug by GPs and approximately 20-50% were given as reasons for stopping, no signal was raised using the ID differences approach, and only anxiety was flagged as a potential signal for an ADR using the Weibull model. The signal for anxiety requires further evaluation to determine whether the drug plays a part in the development of anxiety or whether it is a withdrawal symptom caused by smoking cessation. Analysis methods will lack power when the numbers of events are low even when a large number of participants are included in the study.

Abstract 334: Hypertensive Crisis Combined with Acute Myocardial Ischemic Injury after Glatiramer Acetate Subcutaneous Injection: A Case Presentation and Literature Review

Introduction Hypertensive crisis (HC) affects more than a half million Americans each year, and leave many with irreversible injury. Despite extensive studies on HC and its complications, there remain many unrecognized risk factors and prognosticators. Physicians should perform comprehensive evaluation, including a current medication list review of patients who present with HC to effectively identify the cause and intervene accordingly. We present a case of HC with acute myocardial damage after subcutaneous injection of glatiramer acetate Case presentation A 47 year-old Caucasian male with history of multiple sclerosis (MS) who presented to the emergency room with complaints of headache, chest discomfort, and cough with frothy bloody secretions approximately 30 minutes after subcutaneous injection of glatiramer acetate. For the past 5 years, the patient had reported occasional hot flashes, headache, and palpitations after injection of glatiramer acetate. On examination, blood pressure was 260/160mmHg and heart rate was 120bpm. Chest X-ray showed acute pulmonary edema. EKG showed significant ST elevations in leads I and AVL and ST depressions in leads II, III, and AVF. Troponin levels were elevated during first 24 hours (0.1, 3.7, and 3.5 μg/L). Echocardiography revealed an ejection fraction of 45% with left ventricular wall hypokinesis. Blood pressure was controlled with intravenous nitroprusside and labetalol and after 48hours, repeat EKG was normal, and stress test with myoview was negative for ischemic changes. Discussion Hypertensive crisis is associated with significant morbidity and mortality. Myocardial damage often results from HC and causes subsequent heart failure which leads to death of sufferers. Glatiramer acetate (Copaxone) is an immunomodulator currently used to reduce symptomatic episodes in patients with relapsing-remitting MS. During the post-marketing period, there have been reports of patients with hypertension, chest pain, and others symptoms that received emergency medical care; however, HC combined with acute myocardial damage has been never reported. Whether an immunologic or non-immunologic mechanism mediates these episodes is unknown.

Dealing with Global Safety Issues

Drug-induced torsade de pointes (TdP) is a potentially fatal iatrogenic entity. Its reporting rate in association with non-cardiac drugs increased exponentially from the early 1990s and was associated with an increasing number of new non-cardiac drugs whose proarrhythmic liability was not appreciated pre-marketing. This epidemic provoked a comprehensive global response from drug regulators, drug developers and academia, which resulted in stabilization of the reporting rate of TdP. This commentary reviews the chronology and nature of, and the reasons for, this response, examines its adequacy, and proposes future strategies for dealing with such iatrogenic epidemics more effectively. It is concluded that the response was piecemeal and lacked direction. No one entity was responsible, with the result that important contributions from regulators, industry and academia lacked coordination. While the process of dealing with QT crisis seemed to have worked reasonably well in this instance, it does not seem wise to expect the next crisis in drug development to be managed as well. Future crises will need better management and the challenge is to implement a system set up to respond globally and efficiently to a perceived drug-related hazard. In this regard, we discuss the roles of new tools the legislation has provided to the regulators and the value of an integrated expert assessment of all pre-approval data that may signal a potential safety issue in the postmarketing period. We also discuss the roles of other bodies such as the WHO Collaborating Centre for International Drug Monitoring, CIOMS and the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

An Evaluation of the THIN Database in the OMOP Common Data Model for Active Drug Safety Surveillance

There has been increased interest in using multiple observational databases to understand the safety profile of medical products during the postmarketing period. However, it is challenging to perform analyses across these heterogeneous data sources. The Observational Medical Outcome Partnership (OMOP) provides a Common Data Model (CDM) for organizing and standardizing databases. OMOP's work with the CDM has primarily focused on US databases. As a participant in the OMOP Extended Consortium, we implemented the OMOP CDM on the UK Electronic Healthcare Record database-The Health Improvement Network (THIN). The aim of the study was to evaluate the implementation of the THIN database in the OMOP CDM and explore its use for active drug safety surveillance. Following the OMOP CDM specification, the raw THIN database was mapped into a CDM THIN database. Ten Drugs of Interest (DOI) and nine Health Outcomes of Interest (HOI), defined and focused by the OMOP, were created using the CDM THIN database. Quantitative comparison of raw THIN to CDM THIN was performed by execution and analysis of OMOP standardized reports and additional analyses. The practical value of CDM THIN for drug safety and pharmacoepidemiological research was assessed by implementing three analysis methods: Proportional Reporting Ratio (PRR), Univariate Self-Case Control Series (USCCS) and High-Dimensional Propensity Score (HDPS). A published study using raw THIN data was selected to examine the external validity of CDM THIN. Overall demographic characteristics were the same in both databases. Mapping medical and drug codes into the OMOP terminology dictionary was incomplete: 25 % medical codes and 55 % drug codes in raw THIN were not listed in the OMOP terminology dictionary, representing 6 % condition occurrence counts, 4 % procedure occurrence counts and 7 % drug exposure counts in raw THIN. Seven DOIs had <0.3 % and three DOIs had 1 % of unmapped drug exposure counts; each HOI had at least one definition with no or minimal (≤0.2 %) issues with unmapped condition occurrence counts, except for the upper gastrointestinal (UGI) ulcer hospitalization cohort. The application of PRR, USCCS and HDPS found, respectively, a sensitivity of 67, 78 and 50 %, and a specificity of 68, 59 and 76 %, suggesting that safety issues defined as known by the OMOP could be identified in CDM THIN, with imperfect performance. Similar PRR scores were produced using both CDM THIN and raw THIN, while the execution time was twice as fast on CDM THIN. There was close replication of demographic distribution, death rate and prescription pattern and trend in the published study population and the cohort of CDM THIN. This research demonstrated that information loss due to incomplete mapping of medical and drug codes as well as data structure in the current CDM THIN limits its use for all possible epidemiological evaluation studies. Current HOIs and DOIs predefined by the OMOP were constructed with minimal loss of information and can be used for active surveillance methodological research. The OMOP CDM THIN can be a valuable tool for multiple aspects of pharmacoepidemiological research when the unique features of UK Electronic Health Records are incorporated in the OMOP library.

The A 1 chieve study: Mapping the Ibn Battuta trail

The A ₁ chieve study: Mapping the Ibn Battuta trail

Pharmacovigilance in India

New drug development is a challenging and costly process as it involves focus on quality, efficacy as well as safety. Some of the adverse drug reactions (ADRs) are predicted based upon the previous experience with the pharmacologically similar drugs and others are detected during clinical trials. For detection of ADRs, clinical trials usually provide limited information as they are conducted under strictly controlled condition and largely focus on efficacy evaluation. Some of the ADRs can be detected only after long-term use in large population and in specific patient groups due to specific concomitant medications or disease. The visual field defect of vigabatrin therapy and valve defect of fenfluramine-phenteramine therapy are few such examples. Therefore early recognition of previously unknown adverse effects of medicines during post-marketing period is the primary objective of pharmacovigilance.

The Ethics of Postmarketing Observational Studies of Drug Safety Under Section 505(o)(3) of the Food, Drug, and Cosmetic Act

In 2007, Congress granted the Food and Drug Administration (FDA) new powers to order pharmaceutical companies to conduct drug safety studies and clinical trials in the postmarketing period after drugs are approved The methodologies include observational studies that examine patients' insurance claims data and clinical records to infer whether drugs are safe in actual clinical practice. Such studies offer a valuable tool for improving drug safety, but they raise ethical and privacy concerns because they would entail widespread use of patients' health information in commercial research by drug manufacturers. This is the first article to explore the ethics of these section 505(0)(3) observational studies, so named after the section of the Food, Drug, and Cosmetic Act that authorizes them. Data access problems threaten to make the FDA's section 505(0)(3) study requirements unenforceable. Under existing federal privacy regulations, it appears highly unlikely that pharmaceutical companies will have reliable access to crucial data resources, such as insurance claims data and healthcare records, to use in these studies. State privacy laws present another potential barrier to data access. If pharmaceutical companies do manage to gain access to the needed data, this will raise serious privacy concerns because section 505(0)(3) observational studies do not appear to be covered by any of the major federal regulations that afford ethical and privacy protections to persons whose data are used in research. If the FDA's program of section 505(o)(3) observational studies fails because of the above problems, this failure will have a number of bad consequences: the public will be exposed to avoidable drug safety risks; taxpayers may be forced to bear the costs of having the FDA conduct drug safety investigations that would have been funded by drug manufacturers if data had been available; and, perhaps most troubling, the FDA may be forced to order postmarketing clinical trials to answer questions that could have been answered using observational studies. Problems with access to data for section 505(0)(3) studies thus could directly imperil human research subjects by forcing a needless over-reliance on risky postmarketing drug safety trials. This Article concludes by describing a promising new legal pathway for resolving these problems. Congress has provided the FDA a new set of powers that if skillfully exercised will allow the agency: (1) to facilitate pharmaceutical companies' appropriate access to data for use in section 505(0)(3) observational studies, (2) to impose strict ethical and privacy protections for persons whose data are used in these studies, and (3) to mobilize private-sector funding to generate much-needed evidence of the safety of FDA-approved drugs.

IOM calls for consistent, rigorous approach to drug safety

FDA needs to implement a rigorous, consistent approach to overseeing the safety of drugs after they enter the U.S. market, according to a report from the Institute of Medicine (IOM). The report, “Ethical and Scientific Issues in Studying the Safety of Approved Drugs,” was released online May 1. FDA had commissioned the report to seek guidance on the types of studies needed to address safety issues during the postmarketing period and how to ensure the ethical treatment of study participants. The report recommends that FDA adopt a patient-centered, three-stage framework for making regulatory decisions about a marketed drug’s risk–benefit profile. First, according to IOM, FDA should define the public health question that prompted the agency to consider making a regulatory decision. Such questions may arise when FDA learns new information about a drug’s risks or benefits from surveillance data, published reports, or other sources. The second stage requires FDA to evaluate the scientific quality of all available risk–benefit information about the drug, including any new information that prompted the regulatory review. The evaluation should include an assessment of the level of uncertainty associated with the available evidence.

Severe sustained cholestatic hepatitis following temozolomide in a patient with glioblastoma multiforme: case study and review of data from the FDA adverse event reporting system

Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults. Its established first-line adjuvant treatment is radiotherapy in combination with temozolomide (TZM). Hematotoxicity is listed as a frequent adverse drug reaction in the US prescribing information and hepatotoxicity has been reported infrequently in the postmarketing period. We here present the case of a patient diagnosed with GBM who developed severe sustained cholestatic hepatitis following treatment with TZM. The cholestasis was not reversible after withdrawal of TZM during 6 months before the patient's death. Another 2 published case reports of sustained cholestasis following TZM treatment were identified; however, the sustained nature of cholestasis was not emphasized in these reports. Sixteen cases of cholestatic hepatitis/cholestasis associated with TZM were identified in the FDA spontaneous reporting system between 2007 and 2010. Information on the course of the cholestasis in these cases could not be retrieved. In the literature there are other published reports of hepatotoxicity associated with TZM that have reported reversibility upon withdrawal of the drug. Thus, TZM appears to cause different types of hepatotoxicity. Particular attention should be paid to sustained cholestasis as a very serious type of TZM-associated liver toxicity.

The US Food and Drug Administration's Sentinel Initiative: Expanding the horizons of medical product safety

The US Food and Drug Administration's Sentinel Initiative: Expanding the horizons of medical product safety

The Front Line of Genomic Translation

The Front Line of Genomic Translation

Long-term treatment of osteoporosis: safety and efficacy appraisal of denosumab

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), a member of the tumor necrosis factor receptor superfamily essential for osteoclastogenesis. Denosumab treatment is associated with a rapid, sustained, and reversible reduction in bone turnover markers, a continuous marked increase in bone mineral density at all sites, and a marked decrease in the risk of vertebral, hip, and nonvertebral fractures in women with postmenopausal osteoporosis. Therefore, it could be considered as an effective alternative to previous bisphosphonate treatment as well as first-line treatment of severe osteoporosis. Cost-effectiveness studies support this suggestion. In addition, denosumab seems to be the safest treatment option in patients with impaired renal function. Denosumab is characterized by reversibility of its effect after treatment discontinuation, in contrast with bisphosphonates. Large-scale clinical trials, including the extension of FREEDOM trial for up to 5 years, are reassuring for its safety. However, given its brief post-market period, vigilance regarding adverse events related to putative RANKL inhibition in tissues other than bone, as well as those related to bone turnover oversuppression, is advised.