Postmarketing Period Research Articles

Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey

To show that the nonbenzodiazepine hypnotic zolpidem has a higher abuse potential than previously documented. An official enquiry was carried out by the Nantes Centre for Evaluation and Information on Pharmacodependence (CEIP). The authors made a review of literature and analysed French data corresponding to the drug's postmarketing period collected by the CEIP network from 1993 to 2002. The literature review yielded mixed results concerning the behavioural effects of zolpidem. Data from the CEIP and the 53 literature case reports highlight significant dependence and abuse potential of zolpidem. This study adds to the growing evidence that zolpidem has the potential for abuse and dependence. As a consequence, the French drug monograph has been modified by the French Health Authorities.

Addressing Safety Issues and Providing Safety Assessment to Regulatory Authorities in the Post-Marketing Period

Addressing Safety Issues and Providing Safety Assessment to Regulatory Authorities in the Post-Marketing Period

Estimating post-marketing exposure to pharmaceutical products using ex-factory distribution data

The pharmaceutical industry has an obligation to identify adverse reactions to drug products during all phases of drug development, including the post-marketing period. Estimates of population exposure to pharmaceutical products are important to the post-marketing surveillance of drugs, and provide a context for assessing the various risks and benefits, including drug safety, associated with drug treatment. This paper describes a systematic approach to estimating post-marketing drug exposure using ex-factory shipment data to estimate the quantity of medication available, and dosage information (stratified by indication or other factors as appropriate) to convert the quantity of medication to person time of exposure. Unlike the non-standardized methods often used to estimate exposure, this approach provides estimates whose calculations are explicit, documented, and consistent across products and over time. The methods can readily be carried out by an individual or small group specializing in this function, and lend themselves to automation. The present estimation approach is practical and relatively uncomplicated to implement. We believe it is a useful innovation.

Interferon beta in relapsing–remitting multiple sclerosis

Long-term observational studies may provide additional information about the behaviour of different drugs in the post-marketing period. We present the data of our cohort of relapsing-remitting multiple sclerosis (RRMS) patients treated with interferon beta (IFNbeta). We analysed RRMS patients followed for at least 2 years. From 1995, we initiated therapy with IFNbeta. As they became available, patients were allocated to one of the IFNs at standard doses (IFNbeta-1b, IFNbeta-1a i.m. or IFNbeta-1a s.c.). Each patient was included in a follow-up protocol containing demographic and baseline clinical data. Between 1995 and 2004, 382 patients have completed at least 2 years of follow-up. Significant differences at entry were observed. Patients on IFNbeta-1b had a higher disease activity and disability at baseline than those on IFNbeta-1a i.m. or IFNbeta-1a s.c. A significant reduction in the relapse rate was observed for the three drugs (70% for IFNbeta-1b, 64% for IFNbeta-1a i.m. and 74% for IFNbeta-1a s.c.). We observed a sustained progression of disability in 11% of patients on IFNbeta-1b, 17% on IFNbeta-1a i.m. and 19% on IFNbeta-1a s.c.; and at four years of follow-up in 24% of patients on IFNbeta-1b, 23% on IFNbeta-1a i.m. and 35% on IFNbeta-1a s.c. No unexpected major adverse events were observed with any of the drugs. Interferon beta is safe and well tolerated. The various registered interferon beta drugs provide a comparable efficacy in a large non-selected cohort of RRMS patients.

Octocog alfa, Plasma/Albumin-Free Method

Octocog alfa, plasma/albumin-free method (octocog alfa-PFM) is a recombinant, human, full length, coagulation factor VIII that has been produced without the addition of human- or animal-derived plasma proteins, thereby virtually eliminating the risk of transmission of blood-borne pathogens. Octocog alfa-PFM is structurally and functionally very similar to a previously marketed, albumin-containing formulation of the same recombinant factor VIII. The haemostatic efficacy of octocog alfa-PFM was rated excellent or good in the acute treatment of most breakthrough bleeding episodes in adolescents or adults with moderately severe or severe haemophilia A who were receiving prophylaxis with octocog alfa-PFM and who had been previously treated with factor VIII. Most bleeding episodes resolved after one or two infusions of octocog alfa-PFM. Efficacy was similar regardless of the cause or site of the bleeding episode. Similar excellent or good haemostatic efficacy was observed with octocog alfa-PFM in previously treated children aged <6 years with haemophilia A and during perioperative use in patients with haemophilia A undergoing surgical or invasive dental procedures. Octocog alfa-PFM was well tolerated during clinical development and in the 15-month post-marketing period. There were very few adverse events and serious events were rare. The risk for developing inhibitors (antibodies) to factor VIII was very low.

Keiretsu Affiliation and Equity Values in Japan

This study examines the association between keiretsu affiliation and corporate equity value in Japan. We hypothesize that, ceteris paribus, keiretsu firm value, measured as Tobin's Q, is higher than non-keiretsu firm value, reflecting the improved or active monitoring role of the keiretsu arrangement. The empirical tests are supportive after controlling for other financial and ownership variables. The results also show that keiretsu firm value is positively related to the strength of the keiretsu. This is additional evidence that the monitoring provided by the keiretsu relationship does indeed increase corporate equity value, and that the source of the increase in value is not merely a result of cross-shareholding, but inherent to the keiretsu arrangement. However, the effect of keiretsu membership and influence on market equity values has apparently diminished since 1990 (the post-market crash period in Japan).

Social Pharmacology: Conceptual Remarks

Traditionally, knowledge about drug mechanism of action and clinical use was derived largely from studies conducted by clinical pharmacologists and therapeutic specialists. More recently, a broader concept of drug use, social pharmacology, has attracted growing interest and recognition. Building on the foundation provided by clinical research, this discipline encompasses the multiple dimensions associated with “real world” use of drugs during the postmarketing period. Physicians, pharmacists, nurses, biologists, epidemiologists, and economists, together with lawyers and regulators, insurance specialists, and communications specialists all contribute to this broader assessment of drug use. Thus, social pharmacology brings together a broad collection of disciplines pertaining to evaluating the efficacy, safety, effectiveness, compliance, self-medication, and consumption of economic resources associated with the use of pharmaceutical products. Application of evidence-based treatment guidelines; measures of d...

FEIBA safety profile in multiple modes of clinical and home-therapy application.

The development of neutralizing antibodies to factor VIII or IX therapeutic concentrates remains the most serious and challenging complication in the management of patients with haemophilia A and B. FEIBA, Anti-Inhibitor Coagulant Complex, is an activated prothrombin complex concentrate that has been used to treat patients with such complications for almost 30 years. The mechanism of action of FEIBA has been proposed to involve simultaneous FVIII/FIX inhibitor bypassing action in the common, intrinsic and extrinsic coagulation pathways. FEIBA is derived from human plasma that undergoes stringent viral screening followed by significant viral inactivation and removal. To date, there have been no confirmed reports of transmission of hepatitis A, B or C, or of human immunodeficiency viruses associated with the use of the current, vapour-heat-treated FEIBA concentrate. The incidence of thrombotic adverse events recorded in the Baxter pharmacovigilance database for the 10-year postmarket period (1990-99) was approximately 4 : 100,000 infusions of FEIBA. Almost all documented thrombotic events with FEIBA occurred with doses that exceeded dosing recommendations, and known risk factors for cardiovascular disease were evident in more than 80% of the patients involved. Overall, clinical data have shown FEIBA to be safe and well-tolerated for use in a wide variety of clinical settings, including treatment of bleeding episodes, management of surgical procedures, home therapy, long-term prophylaxis, and prophylaxis during immune tolerance induction, when used according to dosing guidelines.

A problem-oriented approach to safety issues in drug development and beyond.

Human safety issues arise throughout the life cycle of pharmaceutical products and relevant information comes from a multitude of sources. Assessment and management of risks to humans requires a problem-based analysis to bring together relevant information regardless of source. The Safety Evaluation Plan (SEP) is a tool to support problem-oriented safety analysis. Safety issues are specified and the evaluation and management of each problem is based on a status summary that integrates the most current information from all relevant sources. The status summary is updated regularly during the course of clinical development to reflect the results of new studies and new clinical trials. In the postmarketing period, relevant postmarketing data is incorporated. Recent regulatory initiatives emphasise early identification of product safety risks so that appropriate risk-management measures can be instituted at the time of approval. A problem-oriented approach supports growing regulatory expectations regarding risk assessment and risk management. The problem-oriented approach facilitates early identification of safety issues and an evidence-based approach to their evaluation. Proactive management of safety problems leads to prompt assessment of risks and timely and appropriate steps aimed at risk reduction. The SEP provides a single global assessment for each safety issue. Regulatory submissions for pharmaceutical and biological products are organised by type of information. International Conference of Harmonisation documents covering clinical safety issues structure and analyse information separately by type, for example, adverse events, serious adverse events, laboratory data, vital signs, etc. A problem-oriented analysis would need to find a place in the regulatory process. A problem-oriented approach to safety cuts across typical structures in the pharmaceutical industry where different groups handle preclinical, clinical and postmarketing safety information. The SEP can improve communication within the company and externally. Nonetheless, supporting structures need to be adapted to support such an interdisciplinary process. Overall, the problem-oriented approach, supported by a SEP, contributes to realistic expectations and sustained credibility when dealing with safety issues.

重要な安全性情報を早期に検出する仕組み―シグナル検出の最近の手法について―

It is very important to provide safety information of new drugs to physicians and patients as soon as possible after the early postmarketing period. For that purpose, it is important to appropriately collect and analyze the spontaneous reports accumulated in databases of companies and regulatory agencies. This paper reviews the analytical methods to assess spontaneous reports. Bate et al. (1998) presented Bayesian Confidence Propagation Neural Network (BCPNN) Method used by Uppsala Monitoring Centre (UMC) of the World Health Organization (WHO). DuMouchel (1999) presented Gamma-Poisson Shrinker (GPS) Program of U. S. Food and Drug Administration (FDA), and Evans et al. (2001) presented Proportional Reporting Ratios (PRR) of the Medicines Control Agency (MCA). Furthermore, DuMouchel and Pregibon (2001) extended the GPS Program, proposing the Multi-Item Gamma Poisson Shrinker (MGPS) Program, which then became the standard method for the FDA. This report also reviews the practical problems (e.g. database, duplication cases, code of Medical Dictionary for Regulatory Activities (MedDRA)) encountered in Japan.

Oligohydrosis and fever in pediatric patients treated with zonisamide

Zonisamide is an antiepileptic drug developed and first marketed in Japan in 1989. Cases of oligohydrosis, characterized by deficient production and secretion of sweat, were reported in children treated with zonisamide in Japan during development and in the postmarketing period. Zonisamide was approved in the United States in March 2000 for adjunctive treatment of partial seizures in adults. Searching the Food and Drug Administration’s Adverse Events Reporting System, we identified six domestic cases of zonisamide-associated oligohydrosis and/or fever, all in patients ≤ 18 years of age. The calculated reporting rate was 13 cases per 10,000 pediatric-years of exposure, approximately 10–fold the reporting rate in Japan. A possible risk factor for the development of oligohydrosis in these cases was pediatric age, leading to exposure to elevated zonisamide blood levels relative to patient size. Although the mechanism for zonisamide-associated oligohydrosis has not been fully elucidated, the drug may mediate its effect on eccrine sweat glands by inhibiting carbonic anhydrase, thereby influencing pH dynamics, hydrogen ion concentration, and available calcium transients. Awareness of zonisamide-associated oligohydrosis may prevent morbidity, especially in the pediatric population.

Principles from clinical trials relevant to clinical practice: Part II.

Principles from clinical trials relevant to clinical practice: Part II.

Principles from clinical trials relevant to clinical practice: Part I.

This last installment of a 4-part series discusses the final 5 of 11 principles derived from clinical trials during the last 2 decades of cardiovascular clinical research and the need to apply them to the care of individual patients with heart diseases. As therapies have become more biologically potent, it has become increasingly clear that every treatment can be harmful in some patients while being beneficial in others, and often both good and bad effects occur in the same patient. With many therapies, clinical characteristics can identify patients with greater expected benefit or risk, and pharmacogenetics may offer further insight into predicting which patients will achieve the greatest benefit and which will have the greatest risk of harm. For example, we know that women are at higher risk for torsades de pointes when they are treated with QT-interval-prolonging drugs, and it is likely that a genetic predisposition may be important.1 Unfortunately, however, the relative power of these findings is limited, and we are left with broad treatment guidelines that will leave patients at risk of harm that cannot be predicted in absolute terms. The recognition that therapeutics are not commonly either “good” or “bad,” but carry a mixture of good and bad effects, has spawned the concept of risk-management in therapeutics. Each clinician has the responsibility of helping the patient place these risks and benefits in perspective when making decisions about therapeutics. Inevitably, this approach will require an improved grasp of probabilities and quantitative outcome estimates by clinicians and patients. Furthermore, there is an implied responsibility, both to participate in the generation of knowledge about risks and benefits through clinical trials and to report adverse events observed in the post-marketing period. Such adverse event reporting played the critical role in identifying cisapride as a cause of sudden death2 …

Signal generation in the New Zealand Intensive Medicines Monitoring Programme: a combined clinical and statistical approach.

The New Zealand Intensive Medicines Monitoring Programme (IMMP) undertakes prospective observational cohort studies on selected new drugs in the early postmarketing period using prescription-event monitoring (PEM) methodology with the purpose of identifying signals of previously unrecognised ADRs and establishing risk profiles for each drug. Events are reviewed by a physician and a relationship is established between each event and the drug. The events are then sorted into reactions and incidents. The latter are used to assist signal detection and control for bias. Rates for reports, reactions and incidents are used to assess the adequacy of reporting, signal detection and identification of confounders. Most signals are identified by clinical evaluation of the reports at a stage when statistical analyses are unlikely to have the power to detect them with confidence. The incident group is used for signal detection and controlling for bias. A low reporting rate indicates that certain types of event are unlikely to be reported. A systematic review of the original case reports at the site of collection provides the best opportunity for early signal detection. More resources need to be invested in the training and support of clinical evaluators. Categorising events into reactions and incidents gives added value to the data. Rates of reporting should be quoted with the results of cohort studies to facilitate assessment of their power to detect new signals.

Aspartame: Scientific Evaluation in the Postmarketing Period

Prior to marketing, the safety of the high-intensity sweetener aspartame for its intended uses as a sweetener and flavor enhancer was demonstrated by the results of over 100 scientific studies in animals and humans. In the postmarketing period, the safety of aspartame was further evaluated through extensive monitoring of intake, postmarketing surveillance of anecdotal reports of alleged health effects, and additional research to evaluate these anecdotal reports and other scientific issues. The results of the extensive intake evaluation in the United States, which was done over an 8-year period, and the results of studies done in other countries demonstrated intakes which were well below the acceptable daily intakes set by the FDA and regulatory bodies in other countries, as well as the Joint FAO/WHO Expert Committee on Food Additives. Evaluation of the anecdotal reports of adverse health effects, the first such system for a food additive, revealed that the reported effects were generally mild and also common in the general population and that there was no consistent or unique pattern of symptoms that could be causally linked to consumption of aspartame. Finally, the results of the extensive scientific research done to evaluate these allegations did not show a causal relationship between aspartame and adverse effects. Thus, the weight of scientific evidence confirms that, even in amounts many times what people typically consume, aspartame is safe for its intended uses as a sweetener and flavor enhancer.

European Regulatory Authorities and Pediatric Labeling

### The Need for Medicinal Product Testing in Children #### Ethical Considerations Children should not be given medicines that have not been evaluated adequately for use in that age group. There is a responsibility, shared by applicants and the appropriate authorities, to ensure that children have timely access to safe and effective medicines that have accurate, scientifically justified prescribing information. Applicants are encouraged to investigate the safety and efficacy of a product in children, if it is likely to be of therapeutic benefit in this age-group, and to develop suitable formulation, even if use is likely to be small. However important a clinical trial may be to prove or disprove the value of a treatment, individual members of one or both of the groups—subject or control—can suffer injury as a result of inclusion in the trial, even if the whole community benefits. As with adults who participate in clinical trials and who understand the issues involved in giving their informed consent, consent should be obtained from the legal guardian of children in accordance with national legislation. Children should be fully informed about the trial in language and terms they understand and, if able, should personally sign and date the written informed consent. The child should be made aware of his/her rights to decline to participate. The child's wish to be withdrawn from a study must be respected. These measures should be applied in conjunction with 1) part 4 of Directive 75/318/EEC, as amended, which requires “… details concerning patients who may be at increased risk”; the CPMP/ICH guideline for good clinical practice; and 3) the CPMP guideline on biostatistical methodology in clinical trials in applications for marketing authorizations for medicinal products. These measures are intended to assist applicants with specific problems presented by medicinal product testing in children. The child should stand to obtain some direct benefit from the clinical trial, except … Address correspondence to Elisabeth Autret, MD, Hopital Bretonneau, Pharmacologie Clinique, Boulevard Tonnele, 37044 Tours, France.

The treatment of depression with paroxetine in psychiatric practice in Germany: the possibilities and current limitations of drug monitoring.

A drug monitoring of the antidepressant paroxetine was carried out in Germany from August 1992 to November 1993. The principal aim of this study was to collect demographic, diagnostic, efficacy, and medical-safety data regarding patients who were treated for up to 12 weeks with this SSRI. A secondary goal was the investigation of differences between patients who left treatment after 6 weeks or earlier and those who continued treatment. Evaluable data were obtained from 507 psychiatrists for 2817 patients, 1301 of whom extended treatment beyond 6 weeks. 64% of the patients had been pretreated for the current episode of depression. 50% were considered by their doctors to have either chronic or recurrent illness and 92% to possess moderate to severe symptomatology. Concomitant psychotropic medication was reported in 43% of cases, the most frequent medications being benzodiazepines, neuroleptics, and/or tricyclic antidepressants. Clear or complete improvement was noted for 63% of assessable patients by the end of week 6 and for 79% of the patients who extended treatment to 12 weeks. There were significantly more patients with DSM major depression and severe symptoms in the treatment-extender than in the 6-week treatment group. Paroxetine was tolerated well by most patients: of the 1009 adverse events reported, only 17 were considered "serious". There were no suicides or cases of overdose attributable to paroxetine. The discussion of these results is the basis for a critical appraisal of postmarketing-surveillance methodology. It is concluded that, despite its present structural weaknesses as compared to controlled investigations, drug monitoring of a new medication in the immediate postmarketing period can give insights into the treatment of large numbers of patients under private-practice conditions. However, drug monitoring as it is conducted in Germany can have different and perhaps conflicting functions which may limit its effectiveness. The authors recommend that all interested parties (physicians, the pharmaceutical industry, regulatory bodies) engage in a continuous dialog aimed at clearly formulating the goals and improving the methodology of drug monitoring.

A Reappraisal of Quinolone Tolerability The Experience of their Musculoskeletal Adverse Effects

The experience of the rheumatological adverse effects of fluoroquinolones should be helpful for both toxicologists and epidemiologists. In the case of fluoroquinolone-related arthropathy, the paediatric clinical experience seems to support the possible use of newer derivatives like ciprofloxacin in children who really need it. This therapeutic attitude is still contradictory to the labelling of fluoroquinolones. Inversely, there has been an important time-lag between the first reports of fluoroquinolone-related tendinopathies and the official recognition of this unusual toxic phenomenon. This delay, along with the widespread use of fluoroquinolones, makes it difficult to return to more reasonable prescribing guidelines for these very useful and effective anti-microbial compounds. The reasons why potentially serious adverse effects of fluoroquinolones were not anticipated before their commercialisation may be related to the lack of adequate in vitro and in vivo models, and the unexpectedness of the events. When it occurs, fluoroquinolone-induced arthropathy is most frequently benign, and heals without sequelae. The prognosis is not so favourable in the case of fluoroquinolone-related tendinopathy, which carries an important risk of immediate or secondary tendon rupture. Increasingly, fluoroquinolones are being prescribed for benign infections of the urinary or bronchopulmonary tracts. Sometimes, they are even used for antimicrobial prophylaxis before surgical or endoscopic procedures. We believe that for any prescription, the risk/benefit ratio of the fluoroquinolones should be carefully considered, since better tolerated, less expensive drugs can usually be prescribed. Clear information dedicated both to physicians and patients regarding the cautions for use and possible adverse effects of fluoroquinolones would help reduce the risk and severity of adverse reactions. This is especially important for phototoxicity, tendinopathy and cardiovascular adverse effects. As underlined by Ball and Tillotson in this issue, the future clinical use of the fluoroquinolones will be determined by the balance between the antibacterial efficacy and adverse effects of these agents. The adverse reactions affecting the musculoskeletal system provide a good example of this dilemma. Given the absence of an adequate model of tendinopathy and the poor predictivity of animal manifestations in arthropathy and cartilage lesions in humans, careful monitoring of patients during phase II and III trials and, more importantly, long term pharmacovigilance during the postmarketing period, are still strongly warranted.

Postmarketing Surveillance of Food Additives

Postmarketing surveillance of consumption and of anecdotal reports of adverse health effects has been recognized by a number of regulatory authorities as a potentially useful method to provide further assurance of the safety of new food additives. Surveillance of consumption is used to estimate more reliably actual consumption levels relative to the acceptable daily intake of a food additive. Surveillance of anecdotal reports of adverse health effects is used to determine the presence of infrequent idiosyncratic responses that may not be predictable from premarket evaluations. The high-intensity sweetener, aspartame, is a food additive that has been the subject of extensive evaluation during the postmarketing period and is thus used as an example to discuss postmarketing surveillance.

Prescriber profile and postmarketing surveillance

The response rate to requests to general practitioners (GPs) to supply post-marketing data on new drugs has been falling within the prescription-event monitoring (PEM) system organised by the Drug Safety Research Unit in Southampton, UK. To find out why, we looked at the characteristics of prescribers and the pattern of their prescribing for twenty seven PEM drugs and 543,788 treatments dispensed in England between September, 1984, and June, 1991. 28,402 GPs identified during PEM studies were divided into six groups according to the largest number of prescriptions for one or more of the drugs, ranging from group 1 (none of the drugs prescribed) to group 6 (one or more drugs for over 60 patients). From group 1 to group 6 the proportion of the GPs who were women decreased from 46% to 9%, and the proportion of overseas-qualified doctors increased from 13% to 47%. 10% of doctors who had prescribed most heavily accounted for 42% of total prescribing. 19 doctors had each prescribed a drug for more than 120 patients during the early post-marketing period. There was a consistent inverse relation between the number of prescriptions and the response to requests for post-marketing information. The overall response was 53% but the heaviest 10% of prescribers returned only 44% and the heaviest 1% returned only 34% of questionnaires. No differences in medical need can account for such variations in prescribing practice. Heavy prescribing by a minority of doctors during the period immediately following licensing for marketing may be placing patients at unnecessary risk. These doctors also affect the success of attempts to monitor the safety of new drugs.