Clinical Investigation Of Medicinal Products Research Articles

New guideline of the European Medicines Agency (EMA) on the clinical investigation of medicinal products in the treatment and prevention of diabetes mellitus.

New guideline of the European Medicines Agency (EMA) on the clinical investigation of medicinal products in the treatment and prevention of diabetes mellitus.

Efficacy and Safety of Temelimab, an Antibody Antagonist of the Human Endogenous Retrovirus Type-W env Protein, in Participants with Relapsing Remitting Multiple Sclerosis: A Double-Blind, Randomised, Placebo-Controlled Phase 2b Clinical Trial

Efficacy and Safety of Temelimab, an Antibody Antagonist of the Human Endogenous Retrovirus Type-W env Protein, in Participants with Relapsing Remitting Multiple Sclerosis: A Double-Blind, Randomised, Placebo-Controlled Phase 2b Clinical Trial

New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment.

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.

The regulator’s perspective: How should new therapies and follow-on products for MS be clinically evaluated in the future?

Background: Although there is still no cure for multiple sclerosis (MS), the introduction of several innovative drugs with modes of action different from that of the existing drug arsenal and the progress in monitoring disease progression by imaging and using biomarkers are currently causing a knowledge surge. This provides opportunities for improving patient disease management. New therapies are also under development and pose challenges to the regulatory bodies regarding the optimal design of clinical trials with more patient-focused clinical endpoints. Moreover, with the upcoming patent expiry of some of the key first-line MS treatments in Europe, regulatory bodies will also face the challenge of recommending marketing authorisation for generic and abridged versions based on appropriate requirements for demonstrating equality/similarity to the innovator’s product. Objective: The goal of this article is to improve the understanding of the relevant guidance documents of the European Medicines Agency (EMA) on clinical investigation of medicinal products and to highlight the issues that the agency will need to clarify regarding follow-on products of first-line MS treatments. Conclusion: Today, it is clear that close collaboration between patients, healthcare professionals, regulatory bodies and industry is crucial for developing new safe and effective drugs, which satisfy the needs of MS patients.

Informed consent for clinical investigation in the critically ill patient. An introduction to the regulation 536/2014/EC on clinical investigation of medicinal products for human use, repealing Directive 2001/20/EC

The principle of patient information, awareness and documented consent for the participation in clinical trials is a cornerstone in the modern ethics of clinical research. However, this procedure is seldom applicable in the critically ill patient who becomes suddenly incapable of fully evaluating the risk vs benefit of the alternative therapeutic options. This issue becomes particularly problematic in those conditions where the benefit of any intervention is highly time-dependent, such as acute myocardial infarction, stroke, cardiac arrest, polytrauma and other similar conditions. The new directive 536/2014/EC defines the concept that in these cases the expert clinician and the Ethics Committees, based upon a rigorous study protocol, are in better conditions, as compared to patients' proxies and any legal representative, to take an appropriate decision. This decision should be later confirmed (deferred consent) by the patient, in case he returns competent, or by his proxies or legal tutor, in order to use experimental data. The new directive ends a long period of disparity among the Member States, some of which had taken unilateral decisions allowing the participation of incapable patients, whereas others, among which Italy, had a more conservative approach. Unfortunately, owing to technical and bureaucratic issues, the new regulation is unlikely to become active before the beginning of 2018.

PP.21.34

Objective: To develop a new single-pill combination comprising a full strategy starting first-line for non-controlled hypertensive patients and to assess its efficacy and safety. This new first-line single-pill strategy is based on three novel and optimized dosages of perindopril arginine/amlodipine: 3.5/2.5 mg, 7/5 mg, and 14/10 mg. Context: Despite the development of novel antihypertensive therapies and evolving clinical practice guidelines, blood pressure control remains suboptimal. Design and method: This single pill was developed in accordance with European Medicines Agency guidelines on clinical investigation of medicinal products in the treatment of hypertension and clinical development of fixed combination medicinal products. The clinical trial program included 4 studies in 7462 patients with documented essential hypertension. Two studies evaluated the efficacy specifically of the first and higher dosages of the single pill, in direct comparison with monotherapies. Two other studies evaluated the strategy in comparison with a classic stepped-care strategy based on angiotensin II receptor blockers. Results: The following efficacy primary end points were met across four studies: The superior efficacy of perindopril/amlodipine 3.5/2.5 mg in comparison with placebo and monocomponents amlodipine 2.5 mg, perindopril 3.5 mg and 5 mg, and non-inferiority with amlodipine 5 mg, after 8 weeks. The superiority of perindopril/amlodipine 14/10 mg in comparison with monocomponents amlodipine 10 mg and perindopril tert-butylamine 16 mg, after 6 weeks. The proportion of patients with controlled blood pressure increased significantly after each dose of the perindopril/amlodipine strategy, At 3 months, the perindopril/amlodipine strategy produced greater reduction in blood pressure and better and faster control of hypertension than the classical stepped-care valsartan ± amlodipine strategy, The data show that the single pill combination improved the benefit/risk ratio, especially considering a 67% reduction in calcium channel blocker dose-related peripheral edema at the first step (perindopril 3.5 mg / amlodipine 2.5 mg) and a 42% reduction at last step (perindopril 14 mg/amlodipine 10 mg), without unexpected adverse events or any new safety signal. Conclusions: This registration development is among the largest of the past decade in hypertension. This single-pill combination strategy was effective and safe in first-line treatment, including grade I hypertension.

Clinical Development Approaches and Statistical Methodologies to Prospectively Assess the Cardiovascular Risk of New Antidiabetic Therapies for Type 2 Diabetes.

In December 2008, the US Food and Drug Administration (FDA) issued a guidance for industry requiring sponsors to demonstrate that a new antidiabetic therapy being developed to treat type 2 diabetes does not increase cardiovascular (CV) risk to an unacceptable extent. CV events reported during phase 2 and phase 3 trials should be prospectively and independently adjudicated. Before submission of a new drug application or biologics license application, sponsors should compare the incidence of major CV events occurring with the investigational agent versus the control group to show that the upper bound of the 2-sided 95% confidence interval (CI) for the estimated risk ratio is less than 1.8. If the CI includes 1.3, a postmarketing trial will be necessary to definitively show that the upper bound of the 95% CI for the estimated risk ratio is then less than 1.3. In 2012, the European Medicines Agency (EMA) issued an updated guideline on the clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus that detailed its CV safety assessment requirements. Although similar to the FDA guidance, the EMA guideline does not prospectively define any pre- or postapproval risk margins. This expert perspective, prepared by members of the Cardiac Safety Research Consortium, discusses clinical development strategies, operational issues, and statistical methodological issues to satisfy the FDA's CV safety requirements, and, where appropriate, the EMA guideline. Actual case examples, where applicable, are presented.

Measuring clinical effectiveness of medicinal products for the treatment of Duchenne muscular dystrophy

In June 2014 TREAT-NMD organised a workshop at The Wellcome Trust head office in London to discuss issues such as natural history, outcome measures, efficacy measurements, animal models and clinical study design as part of the coordinated response to the public consultation by the European Medicines Agency (EMA) on the draft guidelines for clinical investigation of medicinal products in Duchenne and Becker muscular dystrophy (DMD/BMD). The workshop attracted over 60 participants from 9 countries representing patients, academics, and industry.

ICH E11 : développement d’un médicament pédiatrique : comparaison entre les États-Unis, l’Union Européenne et le Japon

To address the lack of appropriate pediatric drugs available on the global market, in 2000 the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) issued the ICH E11 guideline regarding the Clinical Investigation of Medicinal Products in the Pediatric Population. This guideline considerably changes the environment of drug development for children. It has been written specifically to harmonize, promote, and facilitate high-quality and ethical clinical research for children within the ICH regions, i.e., the United States of America (USA), the European Union (EU), and Japan. This article details the various regulations applicable in each ICH region following the publication of the guideline. The framework of rewards, incentives, and obligations for pharmaceutical companies established for the development of pediatric drugs are compared. It appears that the USA and the EU have both developed specific regulations for pediatric drug development while Japan has not. However, in Japan, pharmaceutical companies (PCs) are encouraged to develop pediatric drugs voluntarily, and they may be granted additional months of market exclusivity or the postponement of the drug re-examination deadline. In both the USA and the EU, regulations aimed to increase the number of clinical studies conducted in children, in order to ensure that the necessary data are generated, determining the conditions in which a drug may be authorized to treat the pediatric population. PCs are encouraged to develop pediatric assessment, including pediatric clinical trials, which is described in a pediatric plan submitted to the relevant authorities. A system of rewards for PCs submitting an application for marketing authorization containing pediatric use information has been put in place to cover the additional investment for testing drugs in children. Subject to conditions, these rewards consist in a 6-month extension of the patent or supplementary protection. Regarding the approval for new medicinal products in these two regions, regulations require PCs to include, when it is relevant, a pediatric assessment in their drug research and development plan, which must be approved. Although these regions have implemented the ICH guideline, the regulation differs with respect to the timing of studies in children relative to adults and approval of a pediatric drug development plan. Except for special cases, the pediatric investigation plan in the EU is required to be prepared and submitted to the competent authorities upon availability of adult pharmacokinetic studies (after phase I), which means at an early phase of a new drug development plan. In the USA, the pediatric plan is requested later during the phase II or III trials. In practice, it has become difficult for pharmaceutical industries to develop a practicable clinical program for pediatrics including timelines for studies in children that satisfy both EU and USA authorities. Nevertheless, at an early stage of the development strategy, direct support and advice from competent authorities can be obtained. For the ICH regions, pediatric committees are well-established albeit less structured in Japan. Their roles are to review and assess pediatric plans, to issue recommendations, to advise pharmaceutical companies on the content and format of pediatric data to be methodically collected and analyzed, and to avoid exposing children to unnecessary or redundant clinical trials. This regulatory framework encourages the study and the development of pediatric drugs, but it is still quite difficult to actually measure the impact of the ICH E11 on increasing the number of drugs for pediatric use.

SP0055 Licensing New Drugs in SLE: The EMA Draft Guideline

The European Medicines Agency has released the draft Guideline on clinical investigation of medicinal products for the treatment of systemic lupus erythematosus, cutaneous lupus and lupus nephritis. A request for...

Drug Development

Drug Development

Guidelines and methods for clinical investigation of drugs for treatment of stable angina pectoris

To prove the antianginal efficacy of drugs in patients with stable angina pectoris the notice of certain criteria is necessary for the planning and performance for the clinical investigation of medicinal products. They consist of the study design, the randomization, blinding, inclusion and exclusion criteria, definition of endpoints, the performance of the study, the doses and dosing scheme, the methods of investigation, the sample size estimation and the evaluation of the results. If there will be not paid enough attention to these criteria and conditions false positive but also false negative results can arise. The criteria necessary for proving the antianginal efficacy in patients with stable angina pectoris will be presented.

Anleitung und Methodik zur klinischen Prüfung von Arzneimitteln für die Therapie der chronischen systolischen Herzinsuffizienz

To prove the efficacy of drugs in patients with chronic systolic heart failure, taking into consideration certain criteria is necessary for the planning and performance of the clinical investigation of medicinal products. For the different stages and the collective of patients those criteria include the definition of the corresponding endpoints, adequate study design, appropriate randomisation, blinding, the choice of an appropriate dose, valid methods of examination, the correct sample size estimation and analysis. If these criteria will b e used, the besttherapy for the different stages can be ascertained.

Safety of pandemic H1N1 vaccines in children and adolescents

During the 2009 influenza A (H1N1) pandemic several pandemic H1N1 vaccines were licensed using fast track procedures, with relatively limited data on the safety in children and adolescents. Different extensive safety monitoring efforts were put in place to ensure timely detection of adverse events following immunization. These combined efforts have generated large amounts of data on the safety of the different pandemic H1N1 vaccines, also in children and adolescents. In this overview we shortly summarize the safety experience with seasonal influenza vaccines as a background and focus on the clinical and post marketing safety data of the pandemic H1N1 vaccines in children.We identified 25 different clinical studies including 10,505 children and adolescents, both healthy and with underlying medical conditions, between the ages of 6 months and 23 years. In addition, large monitoring efforts have resulted in large amounts of data, with almost 13,000 individual case reports in children and adolescents to the WHO. However, the diversity in methods and data presentation in clinical study publications and publications of spontaneous reports hampered the analysis of safety of the different vaccines.As a result, relatively little has been learned on the comparative safety of these pandemic H1N1 vaccines – particularly in children. It should be a collective effort to give added value to the enormous work going into the individual studies by adhering to available guidelines for the collection, analysis, and presentation of vaccine safety data in clinical studies and to guidance for the clinical investigation of medicinal products in the pediatric population. Importantly the pandemic has brought us the beginning of an infrastructure for collaborative vaccine safety studies in the EU, USA and globally.

Registration trials for specific immunotherapy in Europe: advanced guidance from the new European Medical Agency guideline

Marketing authorization of medicinal products is granted based on results of registration trials. The European Medical Agency (EMA) has issued general and disease state-specific guidelines for the conduct of such trials. In the area of allergic diseases, there are basically two general therapeutic approaches: Drugs that mitigate the symptoms and an approach that is targeted to the root cause of the disease, the allergen-specific immunotherapy (SIT). While the 'Guideline on the Clinical Development of Medicinal Products for the Treatment of Allergic Rhino-Conjunctivitis' (CHMP/EWP/2455/02) and the 'Note for Guidance on the Clinical Investigation of Medicinal Products in the Treatment of Asthma' (CPMP/EWP/2922/01) focuses exclusively on the development of medicinal products to treat allergic symptoms, there was no guideline for SIT in the past. In consequence, the conduct of clinical trials for SIT was widely lacking a standardized approach. This created difficulties when comparing drugs and outcomes and also uncertainty to predict marketing authorization. In 2009, the EMA has issued a new guideline on the clinical development of products for SIT. Despite some white spots in some areas, the new guideline constitutes a breakthrough with regard to guidance, harmonization and transparency in the conduct of clinical trials in SIT.

Better medicines for children: clinical investigation of medicinal products in the paediatric population ‐ a QA perspective

AbstractCurrently the number of medicinal products labelled for paediatric use is limited. Clinical trials involving children are surely amongst the most challenging types of studies performed from a scientific, ethical and medical perspective. The article provides an outline of critical issues to be considered when developing drugs in this population. Copyright © 2008 John Wiley & Sons, Ltd.

Onercept for Moderate-to-Severe Crohn’s Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

Onercept is a recombinant, soluble human p55 receptor to tumor necrosis factor-alpha. A randomized, double-blind, placebo-controlled, dose-ranging trial was performed to evaluate the efficacy of onercept induction therapy in patients with Crohn's disease (CD). Patients (n = 207) with moderate-to-severe acute or chronic active CD were randomized to receive subcutaneous onercept (10, 25, 35, or 50 mg) or placebo 3 times weekly for 8 weeks. Primary analysis was induction of remission (defined as a CD activity index score < or = 150) at week 8. A total of 104 patients had acute active CD. Remission rates at week 8 were 23.5% for placebo (n = 17), and 34.8%, 20.0%, 26.1%, and 28.6% for onercept 10 mg (n = 23), 25 mg (n = 20), 35 mg (n = 23), and 50 mg (n = 21), respectively (P = .98). A total of 103 patients had chronic active CD. Remission rates at week 8 were 23.8% for placebo (n = 21), and 23.8%, 9.1%, 35.3%, and 13.6% for onercept 10 mg (n = 21), 25 mg (n = 22), 35 mg (n = 17), and 50 mg (n = 22), respectively (P = .66). There were no differences between treatment groups in the incidence of adverse events. However, mild-to-moderate injection-site reactions occurred in up to 12% of onercept-treated patients. Onercept was well tolerated but was not effective at the doses studied in patients with active CD.

More on: venous thromboembolism and mortality after hip fracture: the ESCORTE study

More on: venous thromboembolism and mortality after hip fracture: the ESCORTE study

Clinical development, registration and off-label-use with regard to psychopharmacotherapy in rehabilitation

The presentation intends to broach the issue of clinical development and formal registration for psychiatric drugs which are also used in rehabilitation medicine. Due to the historical shift from national to European registration procedures in the EU, new compounds for major psychiatric disorders (e.g. Major Depression) are centrally evaluated by the EMEA (European Agency for the Evaluation of Medicinal Products; United States: FDA). Clinical development programs of the pharmaceutical industry follow the CPMP (Committee for Proprietary Medicinal Products) guidelines (Note For Guidance On Clinical Investigation Of Medicinal Products), and refer mainly to syndromal diagnostic criteria of major psychiatric disorders according to ICD and DSM. Furthermore, they refer primarily to the proof of efficacy and safety in acute disease states. Instead, psychopharmacotherapy in the field of rehabilitation is frequently driven by different and more symptomatic indications. Long-term outcomes and other specific aspects of rehabilitation medicine (e.g. work- and driving ability) are important for psychopharmacotherapy in rehabilitation. Thus, there is a need to consider those issues in particular with regard to off-label-use and to generate evidence by non-registration trials in the field of rehabilitation.

The physician's role and responsibility in reporting adverse drug events in children

The physician's role and responsibility in reporting adverse drug events in children