Postmarketing Environment Research Articles

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population. The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials. The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner. Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.

The Challenges and Opportunities of Using Large Administrative Claims Databases for Biosimilar Monitoring and Research in the United States

The number of marketed biosimilars in the USA is increasing and will require careful post-marketing monitoring. We address some of the challenges and opportunities of using administrative claims data both inside and outside the context of distributed research networks to monitor post-marketing biosimilar use, effectiveness, and safety in the USA. Three major challenges and opportunities of using administrative claims to monitor biosimilars in the post-marketing environment are presented. These include (1) having sufficient longitudinal follow-up of patients in the target population, (2) identifying biosimilar exposures at the specificity of interest, and (3) having sufficient and complete detailed information on study outcomes and potential confounders. As true for all safety surveillance and comparative effectiveness studies, biologic and biosimilar research requires a focused inquiry to determine whether administrative claims or distributed research networks are suitable data sources. Administrative data affords longitudinal follow-up on large numbers of patients and includes dispensed medications and refill information, affording exposure data based on adjudicated payment. However, data elements including biosimilar exposures, outcomes, and confounders may not be measured at the desired level of specificity. Opportunities to link multiple sources of data together and augment existing data sources to include additional information may increase the utility of using administrative claims data in the monitoring of biosimilars.

Mechanisms Underlying the Immunogenicity of Therapeutic Proteins: Risk Assessment and Management Strategies.

Antibodies to therapeutic proteins have caused serious adverse events and loss of efficacy in patients. Therefore, it is critical to manage the risk of antitherapeutic antibodies (ATA) during drug development and in the postmarketing environment. Risk assessments are an important tool for managing immunogenicity risk because they provide a format for considering the consequences and likelihood of ATA development. Because many factors influence both the severity of the consequences and likelihood of ATA development, successful risk assessments require input from all relevant disciplines, including product quality, manufacturing, nonclinical, pharmacology, and clinical. The results of risk assessments are used to develop appropriate risk reduction strategies, which may include product quality and manufacturing controls and elements of clinical trial design. This article discusses considerations for immunogenicity risk assessments and management.

Principles of assessment of abuse liability

Identifying the abuse potential of drug products in the premarketing and postmarketing environment has been a critical component in the implementation of drug abuse control laws worldwide. In the US, the Controlled Substances Act of 1970 (CSA) is a comprehensive federal law enacted to prevent the abuse or diversion of substances with abuse liability or addiction potential (for present purposes, these terms are used interchangeably). Under the jurisdiction of the Drug Enforcement Administration, the law applies to the manufacture and distribution of narcotics and other drug substances with potential of abuse. The CSA classifies substances with abuse potential into schedules I-V based on the substance's risk of diversion or abuse, and thus provides a legal framework for the assessment of abuse liability of New Molecular Entities. When the Food and Drug Administration reviews the safety and efficacy of a New Drug Application it also determines whether the drug has potential for abuse, and if so, will begin the process to schedule the drug under the CSA. As the assessment of abuse potential is a critical component of a marketing application, pharmaceutical companies (sponsors) bear the responsibility of generating a comprehensive preclinical and clinical data package for regulators to review and make decisions on labeling and the corresponding postmarketing surveillance. Recent regulatory guidelines adopted in the European Union (EU) (2006), Canada (2007), and USA (2010) provide recommendations to sponsors on preclinical and clinical methodologies for the assessment of abuse potential. This paper reviews the legal framework of the assessment of abuse liability and scheduling of controlled substances in the USA and describes the current global regulatory environment and the challenges that sponsors and regulators face when assessing abuse liability of New Molecular Entities, from the early stages of development through the late stages, review, and approval.

Preparing for safety issues following drug approval: pre-approval risk management considerations.

Risk management plans and risk minimization plans as well as postapproval commitment studies are based on risks identified pre-approval that need to be further characterized or minimized in the postmarketing environment. Although the implementation of these activities are conducted in the postapproval arena, the design of the plans and studies as well as the development of effective postapproval tools and mitigation strategies should be carried out pre-approval. The pre-approval period also provides the opportunity to fully understand the treatment population that is included in the clinical trial program and to determine how the target population for the drug after approval may differ from the clinical trial patient population. When regulators or sponsors have expressed concerns about safety issues identified during clinical development, the result may be a postapproval commitment in the form of a registry or an observational safety study or, in the US, a Risk Evaluation and Mitigation Strategy (REMS) as a condition of approval. Specific examples are given for risk mitigation activities that can be conducted pre-approval.

Monitoring product safety in the postmarketing environment.

The safety profile of a medicinal product may change in the postmarketing environment. Safety issues not identified in clinical development may be seen and need to be evaluated. Methods of evaluating spontaneous adverse experience reports and identifying new safety risks include a review of individual reports, a review of a frequency distribution of a list of the adverse experiences, the development and analysis of a case series, and various ways of examining the database for signals of disproportionality, which may suggest a possible association. Regulatory agencies monitor product safety through a variety of mechanisms including signal detection of the adverse experience safety reports in databases and by requiring and monitoring risk management plans, periodic safety update reports and postauthorization safety studies. The United States Food and Drug Administration is working with public, academic and private entities to develop methods for using large electronic databases to actively monitor product safety. Important identified risks will have to be evaluated through observational studies and registries.

Testing Men Who Have Sex With Men for Urethral Infection With Chlamydia trachomatis and Neisseria gonorrhoeae Is Only Half the Job, and We Need the Right Tools

Standard operating procedure in STD clinics commonly has been to test urethral specimens when evaluating males, whether they are heterosexual or men who have sex with men (MSM). Rectal or oropharyngeal specimens may be tested in MSM with symptoms, or in some clinics as screening tests if individuals report sexual practices that would indicate risk of infection at these sites. In a report in this issue of Sexually Transmitted Diseases, Marcus and colleagues studied the prevalence of infection with Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) in the urethra, the oropharynx, and rectum in asymptomatic MSM visiting the San Francisco STD clinic.1 A retrospective analysis of 3398 patient visits found CT or GC at 549 (16.2%) of those visits. The prevalence of infections among these asymptomatic men ranged from a high of 7.8% for rectal CT to a low of 0.4% for urethral GC. Strikingly, 83.8% of CT and GC infections would have been missed if only urethral screening was performed. What was found in the Marcus study, and in others, as well, is that the majority of infections with CT/GC in MSM are not in the urethra. The first major study to make this point was performed by Kent and colleagues, in 2 clinics in San Francisco, where they found that 50% of chlamydial and gonococcal infections were extraurethral.2 That finding has been confirmed by a number of approaches, including retrospective chart reviews and prospectively designed studies (Table 1). While these studies have focused on rectal and pharyngeal CT/GC infections in MSM, it must be noted that such infections are far from rare in women.12,13 In many clinical settings, the infections in women will be seen more often than those in men. These extragenital infections should not be ignored now, and we need more research to better define their potential consequences. Both CT and GC are recognized as causes of proctitis, and even asymptomatic infections have been associated with HIV transmission. 14 Current CDC recommendations call for routine screening of the oropharynx and rectum in MSM who may be exposed to GC or CT at those sites. It is not clear whether pharyngeal infections have a major direct impact on health. But evidence is emerging that infection can be transmitted from the oropharynx to the urethra of sex partners, thus continuing chains of infection.15 All of the cited studies have been made possible by the introduction and application of highly sensitive and specific nucleic acid amplification tests (NAATs) for the diagnosis of CT and GC infections. NAATs are recommended for routine diagnosis of CT/GC infections.15 Where direct comparisons have been done, it has been shown that the increment in sensitivity for NAATs as compared to culture is greater with pharyngeal and rectal specimens than it is with cervical and urethral specimens. An approximate doubling of the number of infections detected has been obtained with NAATs. 4,11 Alas, there remains a gap wherein the best tests are not readily available to the patients and providers who need them. Several NAATs are commercially available and have received FDA clearance for male and female urine specimens, urethral swabs from men, and cervical and vaginal swabs from women. Unfortunately, none have been cleared by the FDA for pharyngeal or rectal specimens. But the CDC, recognizing the superior performance of these tests used on these specimens, has taken an unusual step and recommended the use of NAATs for diagnosis of CT/GC in oropharyngeal and rectal specimens, even though such use has not received FDA clearance. 16 The

Securing the supply chain

Summary Medicines are distributed through a complex supply chain which may be disrupted anywhere from manufacturing to dispensing. Factors that contribute to unanticipated shortages of medicines include manufacturing causes, logistical failures and unexpected or unpredictable disease outbreaks. Additionally, in the postmarketing environment unexpected safety signals may require recall of batches, with a consequential scarcity of remaining supplies at short notice. early identification of potential stock shortages and early engagement with the Therapeutic Goods Administration will facilitate a coordinated response in managing interruptions or changes to patient care. Pharmaceutical companies and the Therapeutic Goods

The Identification of Benefit in Medical Intervention: An Overview and Suggestions for Process

Benefit and risk assessments are not only important to regulatory authorities but also important to the providers, patients, pharmaceutical industry, and payers. In order for patients and providers to continue to have access to new innovative medicines, which have some level of inherent risk, it is critical to have a systematic and balanced focus on understanding the safety risks and benefits to the patient during drug development, at the time of approval and postmarketing. There has been a significant amount of activity around efforts to improve the ability to assess risks in the postmarketing environment. However, there is no widely accepted, systematic approach or process for the ongoing evaluation of benefit. This article introduces 4 critical components in the process of identifying and assessing benefit with a goal of providing a framework that is transparent, comprehensive, applicable to various perspectives, and simple to communicate and implement. We propose the development of a catalog applied to a particular disease to identify the optimal data sources and methods to address the interests of a given perspective. Two key resources will need to be developed to support the catalog development: (1) a summary of benefit measures and preferences by disease and from various perspectives and (2) an investment in a simple visual communication mechanism with minimal statistical language. As the emphasis is on transparency, relevance, applicability, and communication, this approach to assessing benefit should maximize the impact of these data to all stakeholders and decision makers.

Using the internet to enhance drug safety monitoring from phase 1 to phase 4 in dermatology clinical trials

The monitoring of drug safety is one of the key events in pre- and postmarketing clinical trials. Often, safety signals are missed due to delays in gathering and interpreting safety data. It is not uncommon for there to be delays of weeks or more until case report form (CRF) data are collected from the field and entered into the database. When safety signals are missed, it may be too late to implement the corrective actions to maintain a drug in development and/or prevent product recalls and withdrawals. The use of Internet-based clinical trials in single-center studies, such as a 200-subject sensitization/irritation study, and in multicenter studies such as acne, psoriasis and atopic dermatitis, can provide rapid access to clinical trial data as well as improved quality and dramatic cost savings. The FDA has set up MedWatch to allow for the centralized reporting of adverse events over the Internet for the postmarketing environment. Now that the Internet and Web technology are being used to collect clinical trial data during the drug development process from Phase 1 to Phase 4, this same technology is probably the most cost-effective and time-effective ways that a company can monitor drug safety. The presentation will include a demonstration of this new technology, hints on implementing new programs, examples on how to gather and interpret data, and how to make FDA a partner in the process.

Drug safety, pharmacoepidemiology, and regulatory decision making.

The safety or risk assessment of a pharmacotherapeutic agent begins early in its development and continues throughout its use cycle. The practice of pharmacoepidemiology is the art of using the sciences and the tools of science to generate information about pharmaceutical outcomes, including associated risks, in the postmarketing environment. A pharmacoepidemiologist must be capable of functioning with a matrix constructed of three components: a knowledge base, a conceptual framework, and an interpretive framework. From this perspective one can establish surveillance schemes, or understand a posed research question, select strategies, apply methodologies, and interpret the results of purposeful investigations. When conveyed to the risk manager, appropriately interpreted results of a properly conducted risk assessment can be used in regulatory decision making. Seven case studies are presented as examples of this approach.