Marketing Authorization Application Research Articles

Krebs - alles ganz anders? Besonderheiten onkologischer Arzneimittel aus Sicht der Arzneimittelzulassung

For innovative oncological medicines the centralised procedure at the European Medicines Agency is mandatory for a marketing authorisation application for the European Union. As with other medical drugs, the marketing authorisation decision is based on the assessment of its efficacy, safety and pharmaceutical quality but does not consider price or reimbursement. More sophisticated diagnostic methods drive an increasing stratification of cancer into a multitude of different diseases. Regardless of their different pathogenesis and therapeutic options the most relevant clinical endpoints remain cure, overall survival and progression free survival. These endpoints include both efficacy and safety, as patient survival reflects the sum of the beneficial anti-tumour effects (increasing survival) AND the adverse effects (decreasing survival). The benefit of an anticancer medicine should be evident from both overall survival and progression free survival (e.g. used as primary and secondary endpoints). Mature data on overall survival may not be needed for marketing authorisation if a clear increase in progression free survival convincingly predicts a beneficial effect on overall survival. In these exceptional cases treatment of patients with an obviously beneficial medicine must not be delayed - possibly for years - until the exact size of the benefit has been established. The continued stratification of the disease cancer results in a lower prevalence for each of the newly distinguished disease entities and an ever increasing number of orphan designations for medicines for rare diseases. Incentives for the development of orphan medicines include market exclusivity for up to ten years. In specific circumstances, however, the orphan legislation may restrict the authorisation and marketing of competing generic products even beyond these ten years. Conditional approval and approval under exceptional circumstances may accelerate patients' access to a new medicine. Both postulate that the extent of the benefit cannot be determined with sufficient certainty at the time of marketing authorisation. This uncertainty may have a negative impact on price and reimbursement as these decisions may consider data or assessments from the marketing authorisation procedure. Therefore, marketing authorisation applications and subsequent pricing and reimbursement negotiations should not be regarded as completely independent processes, but be included in an overall strategy for the development of oncologic drugs. (As supplied by publisher).

Setting the stage for biosimilar monoclonal antibodies

With the first marketing authorization application for a biosimilar monoclonal antibody now under consideration at the European Medicines Agency, what are the critical issues for regulators?

Risk assessment of Genetically Modified Organisms (GMOs)

EFSA's remit in the risk assessment of GMOs is very broad encompassing genetically modified plants, microorganisms and animals and assessing their safety for humans, animals and the environment. The legal frame for GMOs is set by Directive 2001/18/EC on their release into the environment, and Regulation (EC) No 1829/2003 on GM food and feed. The main focus of EFSA's GMO Panel and GMO Unit lies in the evaluation of the scientific risk assessment of new applications for market authorisation of GMOs, and in the development of corresponding guidelines for the applicants. The EFSA GMO Panel has elaborated comprehensive guidance documents on GM plants, GM microorganisms and GM animals, as well as on specific aspects of risk assessment such as the selection of comparators. EFSA also provides special scientific advice upon request of the European Commission; examples are post-market environmental monitoring of GMOs, and consideration of potential risks of new plant breeding techniques. The GMO Panel regularly reviews its guidance documents in the light of experience gained with the evaluation of applications, technological progress in breeding technologies and scientific developments in the diverse areas of risk assessment.

Hybrid or Mixed Marketing Authorization Application in the European Union: Not a Trivial Decision in New Development Programs for Established Drugs

For any medicinal product Marketing Authorization Application (MAA) in the European Union, the applicant needs to indicate the legal basis for the application. This legal basis, laid down in Directive 2001/83/EC as amended, determines the dossier content, the market exclusivity, and the pediatric requirements in a significant way. For new development projects for established active substances, including new strengths, dosage forms, routes of administration, and new indications, the correct choice of legal basis is critical. This article presents the dossier requirements, data protection, and market exclusivity as well as pediatric obligations for mixed MAAs using the Article 8(3) legal basis and so-called “hybrid” applications according to Article 10(3). These legal bases in the European Union are contrasted with applications according to section 505(b)(2) in the United States. A number of case studies are presented to illustrate which factors can determine the legal basis of an MAA.

Liraglutide withdrawal rates: ‘real world’ practice

AbstractImportant side effects and potential clinical hazards have emerged from long‐term follow up in some drug classes used in type 2 diabetes treatment. Systematic phase 4 post‐marketing data in early use of newer diabetes drugs may have a role in informing drug choice in practice and assist in pharmacoeconomic assessments of these drug choices.We carried out a comparison of the prevalence of drug withdrawals derived from both liraglutide registration trial data, and a systematic, prospective case‐note review of all new liraglutide prescriptions (n=176) from a specialist diabetes clinic over the first 12 months of drug introduction.Trial data used for the marketing authorisation application for liraglutide reported 7.0% withdrawal due to adverse events. Equal numbers of patients experienced mild, moderate and severe side effects. By contrast, data derived from a ‘real world’ clinical group describe 14.8% withdrawal due to adverse events, with withdrawal typically occurring early, by three months. Adverse events were more frequently responsible for treatment withdrawal at lower, compared to higher, doses of liraglutide therapy.Systematic observations of withdrawals in early use of new drugs in current clinical practice are higher than reported in registration trial data. These data highlight that post‐marketing surveillance should inform guideline recommendations and pharmacoeconomic evaluations. Copyright © 2012 John Wiley & Sons.

Clinical Drug Development in Thromboembolic Diseases: Regulatory and Methodological Approach

Coinciding in time with the expiration of the patent of enoxaparin and clopidogrel, a number of new antithrombotics (anticoagulants and antiplatelets with new mechanisms of action) have been developed or are still under development for both venous and arterial thromboembolic complications. The effect of antithrombotic drugs is a continuum where a fine tune assessment of the ischemic events that are intended to be prevented and bleeding complications derived naturally from the own mechanism of action of the administered agent is essential. This paper discusses relevant aspects of pivotal studies aimed to support the marketing authorisation application of new antithrombotics for the prophylaxis or treatment of venous thromboembolism on one hand, and arterial thromboembolism on the other hand (acute coronary syndromes and stroke and systemic embolic events in patients with atrial fibrillation). General methodological issues and tools to assess efficacy and safety parameters and problems encountered in the way they are measured and classified are discussed.

Recommendations on The Interpretation of The New European Medicines Agency Guideline on Bioanalytical Method Validation By Global Cro Council For Bioanalysis (Gcc)

Senior representatives of GCC member companies have thoroughly evaluated and discussed the new European Medicines Agency (EMA; July 2011 [1]) Guideline on Bioanalytical Method Validation (BMV), during the 4th GCC (23 October 2011, Washington DC, USA) and 5th GCC (14 November 2011, Barcelona, Spain) Closed Forums. These North American and European events provided a unique opportunity for CRO leaders to openly share opinions and perspectives and to agree on unified bioanalytical recommendations specifically in relation with the new EMA guideline. The Global CRO Council for Bioanalysis (GCC) [101] is a global independent group of many Contract Research Organization (CRO) leaders. The GCC was formed in September 2010 to meet regularly and discuss bioanalytical issues and regulatory challenges, many of them unique to the outsourcing industry. The outcome of the discussions held as part of these GCC closed forum meetings are shared with the global bioanalytical community via pertinent publications [2–6] and appropriate conference presentations. Prior to the issue of this new guideline, the November 2009 Draft EMA Guideline on BMV defined the proposed guideline and criteria of the EMA on validation of bioanalytical methods and their application in the analysis of study samples from animal and human studies [7]. The EMA Guideline states that the validation of the bioanalytical methods to be used on non-clinical pharmacotoxicological studies to be submitted in a marketing authorization application should be performed following the Recommendations on the interpretation of the new European Medicines Agency Guideline on Bioanalytical Method Validation by Global CRO Council for Bioanalysis (GCC)

Clinical Development of Advanced Therapy Medicinal Products in Europe: Evidence That Regulators Must Be Proactive

Advanced therapy medicinal products (ATMPs), defined as gene therapy medicinal products (GTMPs), somatic cell therapy medicinal products, and tissue-engineered products (TEPs),1,2 constitute a major class of innovative therapeutics that are being investigated as treatments for several diseases. Despite the success of many such products in animal studies, few have reached more advanced regulatory milestones in Europe (Figure 1), such as ATMP Certification from the Committee for Advanced Therapies (CAT) of the European Medicines Agency (EMA),3 regulatory scientific advice from the EMA,4 or a marketing authorization application at the EMA.5 Therefore, there is a need to identify the major stakeholders in the development of such products and to investigate why they have been unable to move these products farther down the development pipeline. As members of the CAT and EMA, we analyzed the data in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database (https://eudract.ema.europa.eu). Analysis of 318 ATMP trials performed between 2004 and 2010 revealed that the main sponsors are academia, charities, and small companies. This may have implications for the further evolution of the regulatory framework for ATMPs given that such stakeholders often have limited financial resources or regulatory expertise, leading to a “translational gap” that must be proactively closed by regulators.

Role of Modelling and Simulation

Modelling and simulation (M&S) of clinical data, e.g. pharmacokinetic, pharmacodynamic and clinical endpoints, is a useful approach for more efficient interpretation of collected data and for extrapolation of knowledge to the entire target population. This type of documentation is included in the majority of marketing authorization applications for new medicinal products. This article summarizes the current status of regulatory review with respect to the role of M&S in Europe from the perspective of the Swedish Medical Products Agency. At present, regulatory bodies in Europe encourage the application of the M&S approach during drug development. However, there is a lack of consensus and transparent guidance documents. The main regulatory usage is in the evaluation of dose choices in sub-populations and as support for the dosing regimen in general. The regulatory review of conestat alfa illustrates how the dose recommendation was revised during the approval procedure based on M&S information. A survey of marketing authorization applications for new medicinal products approved in 2010 revealed that the use of the information gained from M&S documentation varies with respect to both regulatory review and the applicants' presentation of the data in the submitted dossier. Increased utilization and broadened application of M&S is anticipated in pharmaceutical development, where one area of focus is medicines for paediatric patients. Accordingly, the regulatory agencies will need to increase their capability to assess and utilize this type of information, and an interactive process among regulatory agencies is warranted to provide more unified regulatory assessment and guidance. Moreover, applicants are encouraged to expand on the usage of exposure-response models to map the systemic exposure range that yields safe and efficacious treatment and to improve the presentation of the gained knowledge in summary documents of the marketing authorization applications.

De-convoluting the European Commission Cosmos

The centralized registration procedure allows medicinal products to be prescribed and sold in all 27 Member States of the European Community. The aim of this article is to shed light on the complex rules governing the grant of marketing authorization at the European Commission level. The ‘Decision Making Process’ surrounding the Commission is not well understood because during the review of a new marketing authorization application the focus is on the scientific evaluation carried out by the European Medicines Agency (EMA). However, after receipt of a positive opinion by the EMA the subsequent approval process is not purely an administrative act. Knowledge of the scope, sequence of procedural steps and associated timelines at the Commission is key for accurate project planning which in turn is a prerequisite for timely product launch.

Handling Worker and Third-Party Exposures to Nanotherapeutics During Clinical Trials

The article focuses on issues relating to occupational exposures of researchers and lab workers, and exposures of bystanders such as health care workers and family members during HSR using nanomaterials. Such third-party exposures give rise to unique challenges relating to oversight as well as exposures to worker groups not previously studied. Given the current state of knowledge regarding health risks from such exposures, a more precautionary approach to oversight seems advisable.

EMA’s reflection on placebo does not reflect patients’ interests

The European Medicine Agency (EMA) is preparing a reflection paper on the need for an active control in pivotal trials supporting marketing authorization applications [1]. The paper takes for granted the presence of a placebo arm, while “the need for an active control must be considered on a case-by-case basis”. The EMA’s reflection stems from the consideration that “the most common primary objectives for pivotal clinical trials are to demonstrate superiority to placebo control, or to demonstrate non-inferiority or equivalence to an active control”. Though preferred by prospective marketing authorization holders developing new drugs, these approaches are not in the best interest of patients or those paying for the public healthcare system. Both the criteria of superiority over placebo and non-inferiority to active comparators may allow drugs onto the market that are in fact less effective or less safe than those already available, and do not help define the place in therapy and respective values of new and available treatments [2]. Extended use of placebo overlooks possible added value

Critical Assessment of Belgian Reimbursement Dossiers of Orphan Drugs

Orphan medicinal products are designed to diagnose or treat rare diseases that are serious, life threatening or chronically debilitating and that affect 50 or fewer people in every 100 000 in the EU. In Belgium, the Drug Reimbursement Committee (DRC) evaluates reimbursement requests for orphan drugs based on multiple criteria: the therapeutic value, price and proposed reimbursement tariff; the importance of the drug in clinical practice; and the budget impact of the drug. This study aimed to assess reimbursement dossiers of orphan drugs in Belgium and to compare them with the clinical evidence submitted to the European Medicines Agency (EMA). A qualitative analysis examined all reimbursement dossiers of orphan drugs that were submitted in Belgium between January 2002 and June 2008. The following information was extracted from each dossier: description of the orphan drug; indication; reimbursement status; therapeutic value and needs; budget impact; and number of registered indications. For selected orphan drugs, an in-depth analysis extracted and compared information about the clinical trials, their primary endpoints and results from EMA documents (i.e. the marketing authorization application file, European public assessment report and summary of product characteristics) and the Belgian reimbursement dossiers. Reimbursement was awarded to the majority of orphan drugs. In addition to the official criteria, other negotiable factors, such as price adjustments, employment incentives, patient population restrictions and funding of diagnostic tests by the company, seemed to play a role in the reimbursement decision. Despite the low number of patients, randomized controlled trials were conducted for many orphan drugs. Budget-impact analyses were simplistic and did not consider the impact across multiple indications. Some differences were also observed between the clinical evidence submitted to the EMA and that submitted to the Belgian DRC. In addition to the official criteria, other negotiable factors, such as price adjustments and employment incentives, may play a role in Belgian reimbursement decisions of orphan drugs. Some differences have also been noted between the clinical evidence reported in EMA documents and the evidence included in Belgian reimbursement dossiers of orphan drugs. There appears to be a need for further standardization of Belgian reimbursement applications and for European cooperation in sharing clinical evidence of orphan drugs.

Current european regulatory perspectives on insulin analogues

Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions.

News & Views Ethical Standards For Clinical Trials Conducted In Third Countries: The New Strategy of the European Medicines Agency

Clinical trials increasingly occur on a global scale as industry and government sponsors in wealthy countries move trials to low- and middle-income countries. The globalization of clinical research raises important questions about the economical and ethical aspects of clinical research and the translation of trial results to clinical practice: which ethical standards are applied? Are trials results accurate and valid, and can they be extrapolated to other settings? This article provides an overview of the strategy approved by the European Medicines Agency (EMA) to clarify ethical standards for clinical research conducted outside the European Economic Area (EEA) and included in Marketing Authorization Applications. Reference to the EMA Reflection paper is made.

Clinical Translation of Stem Cell Therapies: A Bridgeable Gap

Stem cell scientists trying to reach patients often lack the multidisciplinary skills needed to overcome complex regulatory barriers and may feel deterred from pursuing clinical implementation. In order to help bridge this gap, we offer a European perspective based on our hands-on experience at the Andalusian Initiative for Advanced Therapies.

Toward a European harmonisation of the requirements for the first clinical use of Advanced Therapy Medicinal Products (ATMPs): Preclinical requirements for cell based medicinal products

The necessity of a consistent approach and a regulatory “memory” was addressed by the EU with the promulgation of the Regulation 1394/2007/EC and the creation of a new committee for the evaluation of the Marketing Authorisation Application (MAA) of ATMPs, the Committee for Advanced Therapies (CAT). However, the scientific background of the ATMPs is rapidly changing due to a high rate of innovation. In fact, often the time frame required to perform the clinical development, usually of at least 5 years, is such that the product or some of its assumption might be obsolete at the moment of the Marketing Application. To favour the Small and Medium Enterprises (SMEs) and academic sponsors, the Regulation contains provisions which are intended to help this transition and to smooth the regulatory hurdles.

Tolvaptan for the treatment of hyponatremia and congestive heart failure

Vasopressin plays a central role in regulating body fluid homeostasis, serum osmolality and vascular tone. In response to elevated serum osmolality, vasopressin acts on V2 renal receptors increasing water reabsorption and causing serum sodium to decrease. Pathological conditions characterized by abnormally elevated vasopressin levels such as heart failure (HF) or syndrome of inappropriate antidiuretic hormone (SIADH) can result in hyponatremia. Tolvaptan is a new selective nonpeptide vasopressin V2 receptor antagonist that has shown to rapidly normalize serum sodium concentrations in hyponatremic patients. In patients with congestive heart failure (CHF) and symptoms of volume overload, tolvaptan prompted rapid free water elimination and improved short-term signs and symptoms of HF, although no effect on long-term mortality or HF-related morbidity was observed. Data from phase III studies including over 5,000 patients have demonstrated that tolvaptan is a safe and well tolerated vasopressin receptor antagonist, whose long-term use is not associated with adverse outcomes. Tolvaptan has been recently approved for the treatment of hyponatremia and a marketing authorization application has been filed for the treatment of CHF.

The role of the Orphan Drugs initiative

The Orphan Regulation (EC) No 141/2000 has been successful in stimulating RD reduction in fees payable to EMA for review of the marketing authorisation and subsequent license maintenance fees, market protection in terms of market exclusivity in addition to a range of European and national incentives. This has favoured an increase in the number of applications submitted and, subsequently, granted. So far over 850 applications for orphan designation have been submitted and, to date, these have translated into more than 50 products being approved in Europe for the treatment of rare conditions. Today orphan drugs constitute a solid reality. However, barriers to the development of orphan medicinal products still exist because of the small number of patients affected, the wide geographical widespread, the non-rewarding markets and the insufficient incentives. Additional difficulties arise from the consideration that orphan diseases are heterogeneous, with low prevalence and with often poor or relatively short survival rate. To this regard, the scientific advice/protocol assistance procedure represents a valuable tool to guide the drug development process in rare diseases. In particular, there are issues which are specific for orphan drugs and can be scope for the advice. It is a free of charge procedure and can be requested at any stage of the development by a sponsor who can be either a company or an individual. Currently, there are many Companies that apply for scientific advice around issues involving: a) the patient population (high unmet medical needs), b) clinical practice (comparator), c) rarity (limitation of sample size, multiple subtypes), d) statistical methods (study power, interim analysis), and e) study design (primary endpoints, homogeneous population, randomisation, cross-over). To date, 192 marketing authorisation (MA) applications have been filed: 140 received positive opinion, 10 received negative opinion and 42 were withdrawn. Out of 51 orphan drugs which are on the market, 21 asked for PA. The rarity of these diseases often leads to an inability to investigate and provide comprehensive evidence on the product quality, clinical safety and efficacy during the registration evaluation process which may mean that approval has to occur via

CAT – The new committee for advanced therapies at the European Medicines Agency

The Regulation on Advanced Therapies (Regulation (EC) 1394/2007) establishes a new scientific committee, the Committee for Advanced Therapies (CAT), at the European Medicines Agency. The CAT is composed of experts in the field of Advanced Therapy Medicinal Products (ATMPs)--gene and cell therapy and tissue engineered products--and is responsible for the evaluation of the marketing authorisation applications for this novel class of products. The CAT is also involved in all scientific advice on ATMPs and in two new regulatory procedures for ATMPs, the classification and the certification procedures. The CAT will also play a key role in early contacts with developers of ATMPs.