In today’s globalized drug development landscape, the need for regulatory professionals to be more seamlessly integrated into strategic decisions is evident. Whereas a few companies see the benefit of involving regulatory affairs professionals in strategic business decisions, many still lag behind. Limited literature and scholarly discussion is available on whether regulatory affairs professionals are given the stature and power to make a meaningful contribution during strategy formulation across all stages of the product development, launch, and life-cycle management. This article examines the current business environment for the regulated industries; discusses why it is important that regulatory affairs play an active and strategic role in this sector; and proposes a new educational perspective to facilitate the recognition and acceptance of regulatory affairs professionals as strategic partners.
CONTEXT:Modernized approaches to multisite randomized controlled trials (RCT) include the use of electronic medical records (EMR) for recruitment, remote data capture (RDC) for multisite data collection, and strategies to reduce the need for research infrastructure. These features facilitate the conduct of pragmatic trials, or trials conducted in "real life" settings.OBJECTIVE:We describe the recruitment experience of an RCT to evaluate a clinic-based intervention targeting urban youth with asthma.MATERIALS AND METHODS:Using encounter and prescription databases, a list of potentially-eligible patients was linked to the Epic appointment scheduling system. Patients were enrolled during a scheduled visit and then electronically randomized to a tailored versus generic online intervention.RESULTS AND DISCUSSION:1146 appointments for 580 eligible patients visiting 5 clinics were identified, of which 45.9% (266/580) were randomized to reach targeted enrollment (n=250). RDC facilitated multisite enrollment. Intervention content was further personalized through real- time entry of asthma medications prescribed at the clinic visit. EMR monitoring helped with recruitment trouble-shooting. Systemic challenges included a system-wide EMR transition and a system-wide reorganization of clinic staffing.CONCLUSIONS:Modernized RCTs can accelerate translation of research findings. Electronic initiatives facilitated implementation of this RCT; however, adaptations to recruitment strategies resulted in a more "explanatory" framework. .
AbstractThe human body is now understood to exist as an ecosystem that includes an abundance of life, called the human biome. For purposes of understanding and treating disease, the biome of the human ‘superorganism’ can be divided into three parts: human, microbial, and more complex organisms such as worms and protists. This paper examines medical progress with biome restorative practices, including fecal microbiota transplants and helminthic therapy, which have proven in some cases more effective and more economical at treating a wide range of diseases than pharmaceutical-based approaches. The regulatory and policy hurdles responsible in part for this limited use of these restorative practices are examined. More importantly, new approaches are encouraged which might reverse the general lack of interest for these restorative practices seen in the medical and biomedical research communities. Such approaches include the regulation of benign helminths as dietary supplements and the establishment of an Insti...
A Risk Management Plan (RMP) is a detailed description of the activities and interventions designed to identify, characterize, prevent, or minimize risks relating to medicine’s use. The objective of this article is to assess RMP-related knowledge of community pharmacists and explore the reasons behind any potential issues with its use. This study has two focus points: (1) A cross-sectional survey within a sample of pharmacies in the area covered by the South Pharmacovigilance Center; and (2) a focus group (FG) with key-informants, in order to increase the explanatory scope of quantitative results. In total, 41.6% of the participants in the study knew what a risk management plan was, but 50% rated their knowledge as poor. According to focus group participants, this lack of knowledge seems to be related to three main factors: (i) this subject not being addressed during graduation training; (ii) professionals’ attitude; and (iii) lack of communication among different stakeholders. It is recommended that there is enhanced academic training in risk management. There is an important call for attitudinal change interventions and further investigation in monitoring RMP use and impact. A closer articulation between the regulator, the pharmaceutical society, associations, and industry is needed to promote and boost this topic among community pharmacists.
Abstract Adverse drug reactions (ADRs) are an inevitable part of medication use. During clinical trials, limited information was gained on drug safety. After marketing authorization (MA), more safety data is available as more patients use the drug. Major changes in drug regulation came after drug disasters, like with sulphanilamide elixir or thalidomide use. In recent history, withdrawal of rofecoxib has demonstrated the importance of post-marketing safety monitoring. Subsequently, legislation on drug safety changed both in the United States (US) and in the European Union (EU), becoming simplified and more comprehensive. New EU legislation was implemented in 2012 and has broadened ADR definition to medication errors and overdoses. In the EU, the Pharmacovigilance Risk Assessment Committee (PRAC) has been formed within the European Medicines Agency (EMA), regulating all aspects of drug safety. Referral procedures enable a thorough scientific analysis on all issues of medication safety. In both the US and the EU, ADRs can be reported directly by patients. All reports of suspected ADRs are kept on electronic databases and are analyzed regularly using new technologies. New safety signals are subsequently discovered and evaluated. This author expects that the new regulations will effectively safeguard healthcare consumers from major drug risks.
'Nutraceuticals' are a category of substances without a legal definition, often sold as dietary supplements or components of conventional foods. Nutraceuticals are considered to impart health benefits beyond ordinary nutrition; many nutraceuticals do improve health, but for others evidence is often equivocal or based on animal and/or in vitro data. Moreover, evidence that a component of a substance in a food has a beneficial effect often does not translate into benefits of a substance that has been isolated and consumed in greater quantities. Increasing regulatory requirements from multiple government agencies complicate the design, testing, and marketing of these substances. Dietary advice also is contradictory to much of the marketing of nutraceuticals as it emphasizes using whole foods and ensuring that the overall diet is adequate, rather than focusing on individual components. How the nutraceutical industry responds to these changing conditions will determine the health and growth of the industry over the coming decade(s).
Pharmacovigilance (PV) has witnessed several advancements throughout the world over the past few decades. This review provides an overview of the PV system in India, focusing on the current scenario, its development, the challenges faced, and the interventions suggested for its improvement. The Pharmacovigilance Program of India (PvPI) is playing a major role in gathering drug safety related data and adding it to the WHO database. PvPI fulfills the minimum requirements given by the WHO for any functional national Pharmacovigilance system. The Indian Pharmacopoeia Commission (IPC) is the national coordinating center under PvPI. PV in India relies mainly upon the spontaneous reporting of adverse drug events. The major challenge for PV in India is under-reporting. However, there is an improvement in the number of submitted reports after regular training and awareness programmes, which have been conducted by the IPC. The regular and periodic circulation of the 'PvPI Newsletter' by the IPC has also been instrumental in increasing awareness about PV amongst healthcare professionals and patients. The intensification of PV activities in India demands particular attention in health science curricula. Indeed, a change in mindset is necessary for prescribers, patients, regulatory agencies, and pharmaceutical companies.
Herbal medicines have formed the basis of healthcare worldwide since the earliest times and are still widely used. Recognition of their clinical, pharmaceutical, and economic value is still growing, although this varies widely between countries. Legislative controls in respect of medicinal plants have not evolved around a structured control model. There are different ways in which countries define medicinal plants or herbs or products derived from them, and countries have adopted various approaches to licensing, dispensing, manufacturing, and trading to ensure their safety, quality, and efficacy. The legal situation regarding herbal preparations varies from country to country. A critical problem in the evaluation of herbal drug products is the fact that they are complex mixtures of constituents and the constituents responsible for the therapeutics effects are unknown, which also complicates the stability of these products. A detailed literature survey of the current regulatory challenges and approaches in the registration of herbal drugs in Europe was performed to identify recently introduced changes in regulations or newly introduced regulations compliant with the regulatory bodies.
Abstract Treatment of urothelial cancer (UC) has seen limited advances over the last three decades. As new agents become available, a critical look at trial design across the spectrum of UC is needed. Early UC trials should aim to stratify patients by risk level, defined by molecular features to reduce the heterogeneity and improve interpretation of trial results. For muscle invasive UC, the practice of neoadjuvant chemotherapy should be encouraged, especially as complete pathological response could be used as a surrogate end-point measure on trials and has the potential for garnering expedited drug approval. The neoadjuvant setting also provides a unique opportunity for evaluating biomarkers and targeted therapy given the availability of tumor tissue. For advanced disease, more emphasis should be placed on studies for patients who are cisplatin-ineligible or have poorer performance status, which represents many UC patients. Bladder-sparing therapy, incorporating agents targeting the HER2 or PI3K/AKT/mTOR pathway, or immunotherapy are potential new directions in UC. The importance of quality-of-life as an end-point in clinical trials in UC should also not be overlooked. Ultimately, multidisciplinary large-scale collaborations will be the key to move this field forwards.
CONTEXT:The context for this study was the Adaptive Designs Advancing Promising Treatments Into Trials (ADAPT-IT) project, which aimed to incorporate flexible adaptive designs into pivotal clinical trials and to conduct an assessment of the trial development process. Little research provides guidance to academic institutions in planning adaptive trials.OBJECTIVES:The purpose of this qualitative study was to explore the perspectives and experiences of stakeholders as they reflected back about the interactive ADAPT-IT adaptive design development process, and to understand their perspectives regarding lessons learned about the design of the trials and trial development.MATERIALS AND METHODS:We conducted semi-structured interviews with ten key stakeholders and observations of the process. We employed qualitative thematic text data analysis to reduce the data into themes about the ADAPT-IT project and adaptive clinical trials.RESULTS:The qualitative analysis revealed four themes: education of the project participants, how the process evolved with participant feedback, procedures that could enhance the development of other trials, and education of the broader research community.DISCUSSION AND CONCLUSIONS:While participants became more likely to consider flexible adaptive designs, additional education is needed to both understand the adaptive methodology and articulate it when planning trials.
The oversight of monitoring activities in clinical trials generally comes from the ICH GCP Guidelines and covers a wide range of responsibilities: trial progress oversight, adherence to the Study Protocol, Standard Operating Procedures, Good Clinical Practice, applicable regulatory requirement(s) and Source Data verification vs accuracy and completeness of the Case Report Form entries. Risk-based monitoring was developed and adopted by Sponsors, Investors, and CROs to decrease the costs of clinical trials and make study management more effective. Both the EMA and the FDA support such an approach with their papers. Interestingly, the review of the EMA “Annual report of the GCP Inspectors working group in 2012” has consistently shown persistence of a significant number of findings in fields/areas of monitoring that cannot be fully or partially captured with a centralized or targeted monitoring approach and cannot be identified, such as essential documents, presence and adherence to SOPs, trainings, and the quality of source documentation. Such results open up new challenges for Sponsors, CROs, and other stakeholders. As long as all current ICH GCP Guidelines are a cornerstone of clinical research, monitoring plans and risk assessments will include overseeing a significant pool of additional aspects, apart from the SDV.
Abstract Sarcomas are rare and heterogeneous mesenchymal tumors affecting connective tissue. For many years, doxorubicin-based chemotherapy has been the main systemic therapy option for patients with metastatic soft tissue sarcoma. This ‘one size fits all’ approach has led to marginal benefit, but the introduction of tyrosine kinase inhibitors in gastrointestinal stromal tumors has shown that sub-type-specific, molecularly targeted therapy can lead to significant advances. Next generation sequencing has led to the discovery of the biologic nature of many histological sub-types of sarcomas, and now an emphasis has been placed on assessment of novel therapies for each sub-group. However, the transition into the clinic is both challenging and protracted due to the rarity and heterogeneity of these tumors. The high failure rate of phase III trials in oncology has shown that clinical trials can be difficult to run, especially in rare forms of cancer like sarcomas. In this review, the authors provide an evaluation of the potential approaches toward better clinical trial design in sarcoma studies.
Special populations, including women (non-pregnant and pregnant), pediatrics, and the elderly, require additional consideration with regard to clinical research. There are very specific regulatory laws, which protect these special populations, that need to be understood and adhered to in order to perform clinical research. This review provides a broad overview of some of the physiological differences in special populations and discusses how these differences may affect study design and regulatory considerations. These various special populations, with respect to regulatory affairs, are clearly defined within the Code of Federal Regulations. The definition of "special population" exists to provide enhanced awareness of their vulnerabilities, thereby allowing the creation of regulatory guidance aimed to decrease injury or outright harm. Currently, progress is being made to be more inclusive of special populations in clinical trials. This reflects changing attitudes towards drug information, with it being more representative of those patients that will ultimately be prescribed or exposed to the therapy. However, all research undertaken in these populations should be performed in a manner that ensures all protections of each participant are upheld.
The field of transcranial electrical stimulation (tES) has experienced significant growth in the past 15 years. One of the tES techniques leading this increased interest is transcranial direct current stimulation (tDCS). Significant research efforts have been devoted to determining the clinical potential of tDCS in humans. Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity on international regulatory pathways. We therefore convened a group of research and clinician experts on tDCS to review the research and clinical use of tDCS. In this report, we review the regulatory status of tDCS, and we summarize the results according to research, off-label and compassionate use of tDCS in the following countries: Australia, Brazil, France, Germany, India, Iran, Italy, Portugal, South Korea, Taiwan and United States. Research use, off label treatment and compassionate use of tDCS are employed in most of the countries reviewed in this study. It is critical that a global or local effort is organized to pursue definite evidence to either approve and regulate or restrict the use of tDCS in clinical practice on the basis of adequate randomized controlled treatment trials.
The rising incidence of drug-resistant tuberculosis (DR-TB) in South Africa is cause for concern, with doctors having limited treatment options to offer patients who face excruciating side-effects from existing medications, and poor odds of treatment success. With several newer drugs showing efficacy against DR-TB, increased possibilities exist to stem the tide of the epidemic, shorten treatment duration, and improve outcomes. To take advantage of this potential TB treatment revolution, countries must rapidly facilitate access to existing and future drugs. This requires co-ordinated action from governments, and particularly regulatory authorities, in promoting early access to new treatments, tackling intellectual property and price barriers, expediting regulatory approval, adopting and implementing up-to-date TB management policies, and engaging with research and development processes for new regimens. Doctors Without Borders expended great effort to obtain a less expensive version of the drug, linezolid, for its DR-TB pilot program in Khayelitsha, South Africa. This piece describes that experience, and subsequently offers recommendations for policy reforms which could help South Africa more rapidly access other new TB drugs in the future. The South African experience may be of relevance to other countries seeking advice on how to facilitate access to new treatments and tackle their TB epidemics.
The FDA’s Guidance for Industry, Patient-Reported Outcomes (PRO) Measures: Use in Medical Product Development to Support Labeling Claims (i.e. “PRO Guidance”; 2009) outlines the agency’s perspectives on how PRO measures, used to support efficacy end-points in therapeutics clinical trial programs, may be evaluated by the FDA. Prior reviews have attempted to identify PRO-based statements in product labels in order to evaluate the potential impacts of the PRO guidance on the rate of approvals of PRO-based claims, but none have been enacted after 2010. An in-depth search identified drug product labels approved by the FDA from January 2006 through to December 2014, with efficacy statements supported by PRO measures. Drug product labels were sorted by chemical type and year of approval, and the differences between time periods before and after the finalization of the PRO Guidance were reviewed with statistical tests. Results showed a reduction in the overall approvals of label-based efficacy statements supported by PRO measures after 2009, which may indicate that fewer phase 3 clinical trial programs have met agency benchmarks for the inclusion of subjective assessments as primary or secondary end-points in support of therapeutic efficacy.
Adjuvants have been incorporated into vaccines for decades to improve the immune response to vaccine antigens. In developing new vaccines or simply improving existing vaccines, interest in adjuvants has been growing rapidly, with various types of adjuvant (some novel; some already incorporated into specific vaccines) used in clinical research or under development. The development of adjuvants is generally closely linked to the development of a specific vaccine. With the adjuvant being an integral constituent of the final medicinal product, current legislation does not foresee authorization being granted for an adjuvant as a stand-alone product. A dedicated EU guideline addresses the quality non-clinical and clinical development of vaccine adjuvants, and this guidance needs to be considered alongside the specific guidelines for medicinal products in general. This paper provides an overview of the requirements for developing or modifying an adjuvanted vaccine. The authors also address the experience gained for the adjuvanted 2009 H1N1 pandemic influenza vaccine and its implications.
Clinical trials are the gold-standard means to evaluate the efficacy and safety of new drugs and other medical technologies. They can provide a scientific basis for treatment decisions for patients and their caregivers as well as sound reimbursement policies for governments and insurers. There has been a spectacular shift from government and academia to industry in the organization of clinical trials in the past decade. Currently, most of the trials are funded by industry and their research does make great contributions to the biomedical innovations, although limitations are inevitable. The finding that industry sponsorship is strongly associated with results that favor the experimental therapy brings concerns of sponsorship bias and quality issues to clinical trial results. However, existing research has its own limitations, and there is no solid evidence of causality. Industry-funded clinical trials are a two-edged sword, and further research on sponsorship bias is encouraged. A stronger regulatory policy and a new model of alliance between academia and industry are also imperative.
The two key components of the pharmacology of a drug—dose–concentration (pharmacokinetic) and/or concentration–response (pharmacodynamic) relationships—are often influenced by genetic variations. These account for a substantial fraction of variability in dose–response or drug response, not only between individuals, but also between different ethnic groups. The approval of ‘BiDil’ for the treatment of cardiac failure in self-identified black patients is a spectacular example of inter-ethnic differences in drug response and regulatory awareness of ethnicity of the study population. Drug development programs are increasingly undertaken globally to reduce costs, shorten timeframes, and address issues concerning global prescribing. Regulatory authorities have responded to this globalization of drug development by promulgating guidelines that recommend sponsors of new drugs to explore the role of genetic variations, and potential differences in drug response, between different ethnic populations. They may refuse to accept an application, or require bridging studies, when such differences are anticipated but not adequately addressed. These bridging studies may include (i) pharmacokinetic studies, (ii) pharmacodynamic studies, (iii) dose–response studies, and/or (iv) in extreme cases, pivotal phase III studies in order to extrapolate efficacy and/or safety data from one population to another.
Clostridium difficile is the most common hospital-acquired pathogen in the US, and recurrent C. difficile infection (CDI) is a major public health issue. Twenty per cent of CDI patients experience recurrence, and their risk of recurrence rises with each failure to achieve clinical resolution. Fecal microbiota transplantation (FMT) is a remarkably efficacious treatment for recurrent CDI. However, national health agencies are grappling with the appropriate regulatory paradigm to apply to this innovative treatment. Current FMT regulations in the US, Canada, Western Europe, Australia, and China are in varying degrees of flux, although many regulators are choosing to apply the drug and biologic framework. FMT regulations should allow recurrent CDI patients safe access to this treatment as research continues. Regulating FMT like a drug or biologic, although most convenient from a legal perspective, overly restricts access while under-regulating the methods by which the stool is screened, processed, stored, and used. Human tissue and tissue-based products regulations could achieve the desired level and kind of oversight, but fecal microbiota for transplantation fail to meet applicable statutory definitions. A custom regulatory solution would be more appropriate, but many pathways that regulators may take to achieve this goal require time and resources for health agencies to develop.
