Product Dossier Research Articles

Considerations for Producing mRNA Vaccines for Clinical Trials.

The approval of clinical trials by the competent authorities requires comprehensive quality documentation on the new drug to be used on the clinical trial participant. In the EU quality data is summarized as Investigational Medicinal Product Dossier (IMPD), in the USA as Investigational New Drug (IND) Application. For that, several preconditions concerning production, quality control, and assurance have to be fulfilled. Here, specific requirements related to mRNA vaccines are addressed on the basis of European standards.

Impact of the Council of Europe Resolution on quality and safety assurance requirements for medicinal products prepared in pharmacies for the special needs of patients

Introduction and objectiveThe regulation of pharmacy preparations, especially for standards for quality assurance and safety, is not harmonised across Europe and falls under the national competencies of individual states. There...

Inspectorate surveillance of preparing and distributing pharmacies in The Netherlands

Introduction and objectiveThe preparation of medicines in pharmacies is essential for accommodating the individual needs and medical conditions of patients in Europe and beyond. This article describes the state of...

PCMO L01-Setting Specifications for Biological Investigational Medicinal Products.

This paper provides overall guidance and best practices for the setting of specifications for clinical biological drug substances and drug products within the framework of ICH guidelines on pharmaceutical development [Q8(R2) and Q11], quality risk management (Q9), and quality systems (Q10). A review is provided of the current regulatory expectations for the specification setting process as part of a control strategy during product development, pointing to existing challenges for the investigational new drug/investigational medicinal product dossier (IND/IMPD) sponsor. A case study illustrates how the investigational medicinal product specification revision process can be managed within a flexible quality system, and how specifications can be set and justified for early and late development stages. This paper provides an overview for the setting of product specifications for investigational medicinal products used in clinical trials. A case study illustrates how product specifications of investigational medicinal products can be justified and managed within a modern product quality system.

The administrative information of the registration of a medicinal product dossier

The administrative information of the registration of a medicinal product dossier

EANM guideline for the preparation of an Investigational Medicinal Product Dossier (IMPD).

The preparation of an Investigational Medicinal Product Dossier (IMPD) for a radiopharmaceutical to be used in a clinical trial is a challenging proposition for radiopharmaceutical scientists working in small-scale radiopharmacies. In addition to the vast quantity of information to be assembled, the structure of a standard IMPD is not well suited to the special characteristics of radiopharmaceuticals. This guideline aims to take radiopharmaceutical scientists through the practicalities of preparing an IMPD, in particular giving advice where the standard format is not suitable. Examples of generic IMPDs for three classes of radiopharmaceuticals are given: a small molecule, a kit-based diagnostic test and a therapeutic radiopharmaceutical.

Product Registration in Developing Countries: A Proposal for an Integrated Regional Licensing System Among Countries in Regional Economic Blocs.

The product pipeline for diseases that disproportionately affect the developing world has considerably expanded over the last decade. Indeed, there are about 134 products for these diseases in the pipeline, including vaccines, drugs, diagnostics, microbicides, and vector control tools, and dozens of these products are currently being evaluated in human trials in developing countries where the disease of interest exists. While these efforts are underway, the need to identify regulatory pathways for licensing these new products is becoming obvious to many manufacturers. In many developing countries, where the need of these products is greatest, the national regulatory authorities often lack the resources and regulatory capacity to review the registration dossiers to approve the use of new products. Given this challenge, new regulatory models are urgently needed to offset product registration. In this paper, we propose how regional regulatory frameworks established by regional harmonization initiatives can be used to set up an integrated regional licensing system, a system that will provide for a single product dossier application and a single review, leading to a single approval that will grant access to all the markets in the region. The proposed model aims at complementing the ongoing regional regulatory harmonization efforts by pooling the activities of different national expertise groups so as to make the best use of the available skills at a reduced cost. By sharing the various regulatory tasks in an integrated manner, the total process will be accelerated and will facilitate product registration in the region.

Orphan drugs, orphan diseases. The first decade of orphan drug legislation in the EU

To assess the methodological quality of Orphan Medicinal Product (OMP) dossiers and discuss possible reasons for the small number of products licensed. Information about orphan drug designation, approval, refusal or withdrawal was obtained from the website of the European Medicines Agency and from the European Public Assessment Reports. From 2000 up to 2010, 80.9 % of the 845 candidate orphan drug designations received a positive opinion from the European Medicines Agency (EMA)'s Committee on Orphan Medicinal Products. Of the 108 OMP marketing authorizations applied for, 63 were granted. Randomised clinical trials were done for 38 OMPs and placebo was used as comparator for nearly half the licensed drugs. One third of the OMPs were tested in trials involving fewer than 100 patients and more than half in trials with 100-200 cases. The clinical trials lasted less than one year for 42.9 % of the approved OMPs. Although there may have been some small improvements over time in the methods for developing OMPs, in our opinion, the number of patients studied, the use of placebo as control, the type of outcome measure and the follow-up have often been inadequate. The present system should be changed to find better ways of fostering the development of effective and sustainable treatments for patients with orphan diseases. Public funds supporting independent clinical research on OMPs could bridge the gap between designation and approval. More stringent criteria to assess OMPs' efficacy and cost/effectiveness would improve the clinical value and the affordability of products allowed onto the market.

Positron emission tomography radiopharmaceutical studies in humans

All clinical trials are covered by a series of regulations that seek to protect the rights, safety and welfare of participating patients. The regulations covering PET studies are especially complex to interpret because of the specialized nature of the language of the regulations and of PET studies themselves. It is often unclear whether the application demands that the radiotracer used be treated as an investigational medical product. This paper is intended to act as a general guide for UK researchers planning to perform PET research in humans by clarifying key aspects of the regulations that may affect the study and/or the radiopharmaceutical manufacturing process, providing links to useful information sources, introducing the concept of a UK Medicines and Healthcare products Regulatory Agency (MHRA) PET expert panel and outlining the value of sharing investigational medical product dossiers.

Lurasidone: An Atypical Antipsychotic for Schizophrenia

To provide a clinical overview of the antipsychotic lurasidone. Articles were identified by searching the MEDLINE, PubMed, Cochrane Library, and EBSCO databases (through February 2012) using the key word lurasidone. The manufacturer provided information on unpublished Phase 2 and 3 trials. The Clinicaltrials.gov database was reviewed for the status of ongoing and upcoming trials. All clinical trials lasting longer than 3 weeks and published in the English language were selected for review. Additional documentation, including the product dossier, package insert, and poster presentations supplied by the publisher, was also evaluated. Lurasidone hydrochloride is an atypical antipsychotic that is approved for the treatment of schizophrenia. It is under investigation for treatment of bipolar I disorder. It should be administered with food, is pregnancy category B, is contraindicated for coadministration with strong CYP3A4 inducers and inhibitors, and requires dose adjustments with certain medications and in renal and hepatic impairment. Like other atypical antipsychotics, lurasidone possesses dopamine D(2) and serotonin 5-HT(2A) antagonism but exhibits little affinity for histamine H(1), α(1)-adrenergic, or cholinergic M1 receptors. Additionally, it is a potent 5-HT(7) antagonist, which may impact depression and cognition. Phase 3 trial results revealed that 40-80 mg administered once daily resulted in statistically significant improvements in schizophrenia symptomatology compared with placebo. Lurasidone's rate of metabolic adverse events is low relative to other atypical antipsychotics; however, this is offset by dose-dependent increases in somnolence, akathisia, and parkinsonism. Lurasidone has shown efficacy when compared to placebo in acute schizophrenia. Full characterization of the adverse effect profile and cognitive and affective benefits requires publication of trials with longer durations.

Deficiencies in generic product dossiers as submitted to the WHO Prequalification of Medicines Programme

This study was undertaken to determine the type and extent of deficiencies in generic product dossiers in the therapeutic areas of HIV/AIDS, tuberculosis, malaria and reproductive health, as submitted to the WHO Prequalification of Medicines Programme. There were considerably more quality-related deficiencies in tuberculosis, malaria and reproductive health dossiers compared to HIV dossiers, especially in the category specification of active pharmaceutical ingredients, development pharmaceutics, manufacturing method and finished pharmaceutical product specifications. The deficiencies related to the efficacy/safety portion of the dossiers displayed a trend similar to that observed in the quality portion in that the most critical deficiencies such as an incorrect study design, the use of an unacceptable comparator or the failure to include a study occurred considerably more frequently in the tuberculosis, malaria and reproductive health dossiers than in the HIV dossiers. The frequency of dossier-related deficiencies as determined on screening and assessment of the dossiers seemed to be inversely related to the number of product dossiers that had been prequalified by the end of 2010. The results of this study stress the need for continued capacity building of local generic manufacturers, further development of pharmacopoeial monographs by WHO (PhInt) and other pharmacopoeial commissions, not least to promote development of generic products, as well as development of new guidelines (WHO guidelines for development of generic and paediatric products and a technology transfer guidance document are currently being finalized). To our knowledge, this is the first comprehensive review of the quality and efficacy/safety portions of generic product dossiers, originating from pharmaceutical companies in emerging markets, and comparison of dossier deficiencies across four critically important therapeutic areas.

Off-the-Shelf Cord Blood Mesenchymal Stem Cell Bank

Abstract 4403Our hospital-based GMP facility, named Cell Factory, built in Milano (Italy) and the first one authorized by the National Drug Agency (AIFA) in 2007, has pioneered innovative manufacturing technologies in order to supply therapeutic clinical development programs.By our group and by others, cord blood (CB) mesenchymal stem cells (MSC) have been already tested both in vitro and in extensive pre-clinical disease models, demonstrating that CBMSC are safe and effective. Therefore, CBMSC are the best candidate product for several clinical trials including neurologic and renal repair (1–3).In this context, our group developed the first off-the-shelf (OTS) bank where CBMSC are expanded and banked in GMP conditions, and now they are available as “a drug”, to be distributed for patient doses, much like an off-the-shelf pharmaceutical product. From informed consent CB donations, CBMSC were grown and expanded in CellSTACK kit that includes devices for a closed-system cell culture (Macopharma) with EMEA-grade Australian FBS and they were manufactured through a multi-step controlled and well-validated process. Cell Factory established this innovative culture approach through sufficient passages to produce hundreds of thousands of potential doses from an individual donor. After culture, our quality control approach has been designed to ensure that controls are implemented and completed satisfactorily during manufacturing operations, and that developed procedures and specifications are appropriate and followed, including those performed by contract testing laboratories. In fact, at each step and at the end of the production process before cryopreservation, CBMSC were analyzed and qualified according to pre-established criteria (cell count, viability, extensive immunophenotype, CFU-F, karyotype, CGHArray, telomerase activity, sterility, mycoplasma and endotoxin assays) to ensure that a consistent, well characterized product candidate is produced. The same CBMSC batches can be provided for pre-clinical testing and for further validations to prepare the investigational medicinal product dossier (IMPD) for each clinical trial approvals.Now these GMP batches of CBMSC are cryopreserved and available in our OTS CBMSC bank in different cell doses to comply any kind of medical needs. Products are provided under specific contract conditions developed with the clinical centers. (Contact: cellfactorypoliclinico@gmail.com) Disclosures:No relevant conflicts of interest to declare.

Methods in clinical pharmacology - a tale of two worlds

Methods in clinical pharmacology - a tale of two worlds

AMCP Format dossier requests: manufacturer response and formulary implications for one large health plan.

The Academy of Managed Care Pharmacy (AMCP) Format for Formulary Submissions, a template for health plans to use in developing formulary submission guidelines, has been widely adopted since its initial release in 2000. Many health plans request a dossier (a standardized set of clinical and economic evidence prepared by pharmaceutical manufacturers) to provide information for consideration during the formulary decision-making process. While dossier quality has reportedly improved over time, there is no recent research examining the response rate to dossier requests and the quality of dossiers received. To perform an evaluation of pharmaceutical manufacturers. response to a request for a product dossier prepared using the AMCP Format, and to determine if dossier receipt was associated with a favorable formulary placement. The pharmacy and therapeutics (P&T) committee of a mid-Atlantic health plan with approximately 3 million members reviewed 43 drug products from February 2004 through December 2005. A university-based clinical evaluation subcontractor requested dossiers in the AMCP Format by telephone and e-mail from the manufacturers. drug information center about 8 weeks before the committee meeting. A retrospective evaluation of the materials received from the manufacturers was performed. A logistic regression model was developed to determine if dossier receipt increased the likelihood of second-tier copayment formulary placement for new product reviews. Dossiers were requested for 43 products. We received dossiers for 25 products (58%), other drug information (e.g., journal reprints, product labeling) for 10 products (23%), a formulary kit for 4 products (9%), and no response for the remaining 4 products (9%). Of the 25 dossiers, 21 (84%) generally followed the AMCP Format. Unlocked interactive budget impact models were included in 5 dossiers (20%), and modeling reports (without an unlocked interactive model) were included in 12 dossiers (48%). Dossiers were more likely to be received when the time between U.S. Food and Drug Administration (FDA) approval and dossier request was >/- 4 months (65% vs. 27% when <4 months; P <0.05) and when requested from a large manufacturer (top 25 in sales) compared with smaller manufacturers (75% vs. 43%; P <0.05). Dossier receipt did not improve a product.s likelihood for preferred formulary placement; none of the new products for which dossiers were received were assigned to the second copayment tier compared with 33% of the new products with no supporting dossier. The logistic regression model failed to find any correlation between dossier receipt and preferred formulary placement. Manufacturers met the request for a dossier nearly three fifths of the time. The dossiers were of high quality and generally followed the AMCP Format; the models included in dossiers varied widely in their design and utility. The product manufacturer.s size and the time between FDA approval and dossier request influenced the likelihood of dossier receipt. Receipt of a dossier did not appear to influence the likelihood of a product attaining preferred formulary status.

Safety evaluation of cosmetics in the EUReality and challenges for the toxicologist

Council Directive 76/768/EEC, its seven amendments and 30 adaptations to technical progress form the basis of the cosmetic EU legislation today. There are actually four key principles for safety in the cosmetic legislation. The full responsibility for the safety of cosmetics for human health is placed on the manufacturer, first importer in the EU or marketer. The safety evaluation of finished products is based on safety of individual ingredients, more specifically on their chemical structure, toxicological profile and their level of exposure. A compilation of information on each cosmetic product (dossier) must be kept readily available for inspection by the competent authorities of the Member State concerned. This information source, usually called a technical information file (TIF) or product information file/requirements (PIF(R)), contains, as the most important part, the safety assessment of the product undersigned by a competent safety assessor. The use of validated replacement alternative methods instead of animal testing forms the 4th key principle for safety of cosmetic products on the EU market. The 7th amendment imposes strict deadlines for the abolition of animal in vivo studies on cosmetic ingredients. These legal requirements induce a number of important challenges for the cosmetic industry and more specifically for the toxicologist involved as safety assessor.