EU Pharma IMPACTS EU Pharma IMPACTS is an advanced information service designed to provide users with updates on the changing landscape of EU regulations for medicinal products (pharmaceuticals) in an expert-produced and easy to grasp one-page format with special emphasis on the implications for the pharmaceutical industry, makers, importers and distributors. EU Pharma IMPACT content is intended both for customers in the key regulatory regions like North America and Japan, and for users across the enlarging European Union EU Pharma IMPACT represents an analytical tool and a database. As analytical tool, it provides summaries of otherwise quite lengthy documents, list of the targeted professionals, and current and future legal status of each document. As a database, for fast referencing it stores the full titles of the original documents, dates of issue, links to the original sources (at EU web sites) and image representation (thumbnails) of the documents. > How to use this document > Mini-glossary and Abbreviations > Table of Contents (detailed) How to use this document Contents: The present edition of EU Pharma IMPACTS comprises the entire collection of the comments written in the period of January-June 2005 by the JKS Europe experts on most important regulatory changes, announcements and decisions made by the European Medicines Agency (EMEA) and other relevant European Union bodies. The original comments are available online at the dedicated subscription site of EU Pharma IMPACTS and have been posted within two days after information or documents were released by EU authorities. While the online EU Pharma IMPACTS alert users and delivers an instant update, the present off-line edition has the value of a summary and provides a perspective of the most important changes in the pharmaceutical regulations in EU. The selection of the topics and documents for comments is made on the basis of three criteria: only pharmaceuticals for human use, almost exclusively medicinal products (not medical devices) and documents and changes affecting directly the pharmaceutical makers (vs. patients, healthcare providers and payers). Structure: This edition of EU Pharma IMPACTS contains 34 comments each having identical structure. Immediately following the title is the key part - Impact, titles of the original documents, targeted professionals, thumbnail, summary, legal status and links. Links: Two types of links are available for the readers of this document: internal and external. Internal links allow easy navigation from the Table of Contents and between key terms in the text. External links lead to the online addresses (URLs) of all 44 original documents commented here. Readers can access the original documents online by clicking either on the thumbnails of the documents (at the left side of Summary part) or on the "Link to the original document" at the end of each comment. For inquiries: email to regulatory@jouhoukoukai.com Mini-Glossary and Abbreviations * Authorization for Marketing - equivalent to Marketing Authorization (MA): permission granted by competent authority for medicinal product to be placed on a territory market * Committee for Human Medicinal Products (CHMP) - formerly the Committee for Proprietary Medicinal Products (CPMP): assists EMEA to evaluate scientifically the MA filed via the centralized procedure * European Medicines Agency (EMEA): coordinates evaluation and supervision of medicinal products throughout the EU * European Union (EU): ate present, an autonomous organization of 25 independent states in Western and Central Europe * Guideline / Note for Guidance / Guidance: several terms used intermittently and with no particular distinction for designating a major type of EMEA documents. The confusion stemming from the different terms is addressed in a recent EMEA document, as the term "guideline" shall become prevalent from September 1, 2005 * Medicinal Product: any substance or combination of substances presented as having properties for treating or preventing disease in human beings or any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis * Public Statement: released by EMEA to communicate information on medicinal products marketed in the EU * Rapporteur: word of French origin and meaning a member of a given committee to EU, who is responsible for drawing up a report on matter referred to that committee * Regulation: legal act directly applicable and binding in all Member States * Summary of Product Characteristics: contains information in a strict sequence and intended to inform health professionals on how to use the medicinal product safely and effectively. Table of Contents January 2005 * First EU Guideline on Novel and Established Vaccines Adjuvants * EU Clinical Trial Guideline on Obsessive Compulsive Disorder Medicines * EU Clinical Trial Guideline on Panic Disorder Medicines * EU Clinical Trial Guideline on Generalized Anxiety Disorder Medicines * New Requirements for HRT Clinical Trials February 2005 * EU Committee for Orphan Medicinal Products Report Six New Designations * EU Guideline on Quality of Inhalation and Nasal Products * The EMEA Updated Q&A Document on COX-2 Inhibitors * Guideline on Pharmacokinetics in Patients with Impaired Hepatic Function * EU Draft Guideline on Delivery Devices for Liquid Forms * EU Clarifies what Is "Serious Risk to Public Health" March 2005 * Guidance on Grounds for Inspections at Active Substance Manufacturers * EU Is Concerned on Safe and Efficacious Co-administration of Tenofovir and Didanosine * Seven New Designations for Orphan Medicines in the EU * First Revision of Core SPC for Human Albumin in the EU * Guideline on Quality Aspects of Biosimilar Products Cont. April 2005 * The European Court of Justice Questions the Food Supplement Rules in the EU * Pfizer Suspended the Use of Bextra (Valdecoxib) in the EU * Nine New Designations for Orphan Medicines in the EU * EU Introduce Braille Requirements for Labeling and the Package Leaflet * EU Guideline on Clinical Trials in Small Populations * EU Will Review Serious Skin Reactions in All COX-2 Inhibitors * Potential Cancer Risk in Tacrolimus and Pimecrolimus * Antidepressants in children and adolescents reviewed May 2005 * CHMP Monthly Report of April 2005 * EU Guideline on Non-Clinical Investigation of the Drug Dependence Potential * Advanced Therapies Regulation under Preparation in EU * How HMPC Will Work on EU Herbal Draft List and Monographs * How HMPC Will Appoint Experts and Offer Expert Advice * EU view on Herbals Containing Capsicum / Capsaicin, Asarone, Pulegone and Menthofuran * EU View on Allergic Potency of Chamomilla and Soya or Peanut Protein * Post-menopausal Osteoporosis Guidance to Be Revised June 2005 * EMEA Finalizes New Procedure for EU Pharmaceutical Guidelines * EMEA Concludes Action on COX-2 Inhibitors Disclaimer First EU Guideline on Novel and Established Vaccines Adjuvants Impacts on pharma industry The guideline helps companies to optimally identify and better justify safety and efficacy characteristics of new and established adjuvants used in human vaccines. The issues discussed in the document however could serve the regulators as a ground for revision of some already authorized vaccines / immunological products. Commented on January 27, 2005 Published by EMEA/EC: January 20, 2005 Document: The "Guideline on Adjuvants in Vaccines for Human Use" has been adopted on January 20, 2005 by the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA). Targeted professionals: adjuvant / vaccine developers / manufacturers; managers in research and product development, scientific and medical affairs, regulatory affairs Cont. Summary - The document responds to the rapidly growing interest in vaccine adjuvants especially in new rDNA technology vaccine candidates developed in fields like cancer, fertility, infectious, allergic and autoimmune diseases. The Guideline is applicable for new (liposomes, immunostimulating complexes, cytokines etc) and established adjuvants (those already included in at least one licensed vaccine to enhance the immunogenicity of one or more antigens). It is applicable to each antigen-adjuvant combination, as appropriate. The requirements address in details quality, non-clinical and clinical issues arising from the use of new or established adjuvants in vaccines providing immunity against infectious disease. They are applicable as well to quality and non-clinical aspects of 'therapeutic vaccines' (e.g. 'anti-idiotypic vaccines' such as monoclonal antibodies used as immunogens, 'tumor vaccines', allergen specific immunotherapy and vaccines used to treat infected persons). Clinical issues of 'therapeutic vaccines' are not within the scope of this document. Sufficient safety pre-clinical data should be demonstrated for novel as well for established adjuvants. In case an adjuvant accumulates suspicion, pharmacokinetic evaluation in humans is requested. In a combination vaccine, evidence will be needed that the adjuvant improves the response to at least one of the relevant antigen(s) without exerting a clinically significant detrimental effect on immune responses to any other antigen in the vaccine. Any risk associated with the adjuvant is required to be outweighed by the potential benefits conferred by enhancement of the immune response. Status/Enforcement: The requirements addressed in this document are coming into operation from July 2005. Link to the original document Updated on January 27, 2005 EU Clinical Trial Guideline on Obsessive Compulsive Disorder Medicines Impacts on pharma industry The guideline provides an important tool for companies aiming to develop medicinal products intended for treatment of obsessive compulsive disorder (OCD). It contains numerous clarifications and detailed instructions that have practical value for clinical trials planners and performers. The document contains requirements that would complicate the process of data collection and capturing of evidence for clinical trial efficacy and safety of medicinal products in OCD. Commented on January 28, 2005 Published by EMEA/EC: January 20, 2005 Document: The "Guideline on Clinical Investigation of Medicinal Products for the Treatment of Obsessive Compulsive Disorder" has been adopted on January 20, 2005 by the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA). Targeted professionals: managers in medicinal product development, clinical trials planners, research and development officers, regulatory affairs managers, scientific and medical affairs managers Cont. Summary - The Guideline aims to provide instructions on the evaluation and development of new medicinal products intended for treatment of obsessive compulsive disorder (OCD), independent of the class of product under investigation. It deals only with OCD, but not with OCD-related disorders. The document provides details on patients characteristics, selection, inclusion and exclusion criteria (among which a list of psychiatric disorders that should preferably be excluded). The clinical trials strategy and design include pharmacodynamics, pharmacokinetics, dose / response and therapeutic confirmatory studies where short term and long-term trials as well as methodological considerations are given in details. OCD can have its onset in adolescence or early adulthood and one third to one half of patients develop the disorder during childhood. Therefore separate trials are required for OCD in children and adolescents. Adequate pharmacokinetic and dose response studies are also considered in developmentally delayed children where obsessive-compulsive symptoms are often seen. Long-term efficacy studies are estimated as optional in children and adolescents once maintenance of efficacy has been demonstrated for adults. Because of the complexity of diagnosing OCD in children and adolescents due to risk of progression and co-morbidity the diagnosis is requested to be made by a well-trained child psychiatrist. As children and adolescents are particularly likely to experience "behavioral" symptoms and psychiatric adverse events, irritability, hostility, agitation and suicide-related events (e.g. suicidal ideation, self-harm and suicide attempt) a recommendation is given to monitor closely these patients during the trial course. The clinical safety evaluation includes monitoring of central nervous system, hematological, cardiovascular and endocrinological adverse reactions Special attention is paid to specific adverse events related to eventual rebound / withdrawal / dependence phenomena. Status/Enforcement: The Guideline will come into operation in July 2005. Link to the original document Updated on January 28, 2005 EU Clinical Trial Guideline on Panic Disorder Medicines Impacts on pharma industry The Guideline provides important set of assessment criteria and data on evaluation of new medicinal products developed for treatment of panic disorders (PD). The document contains a number of not clearly defined requirements and statements. Therefore, it could be a risk of over-regulation in the context of revision of old data or completion of existing new studies under arguments based on this Guideline. Commented on January 28, 2005 Published by EMEA/EC: January 20, 2005 Document: On January 20, 2005 the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) adopted a "Guideline on Clinical Investigation of Medicinal Products Indicated for Treatment of Panic Disorder". Targeted professionals: managers in medicinal product development, clinical trials planners, research and development officers, regulatory affairs managers, scientific and medical affairs managers Cont. Summary - The Guideline is intended to assist applicants during the development of medicinal products for the treatment of panic disorder (PD) independent of the class of product under investigation. The document provides clarifications on key features important for the diagnosis and differential diagnosis of PD including evaluation of severity and burden of disease for achieving primary treatment goals. Instructions are given on records of patient's characteristics and selection based on inclusion and exclusion criteria, history of the duration of PD and further descriptive parameters, like severity (e.g. frequency of panic attacks, degree of anticipatory anxiety, and degree of phobic avoidance), degree of functional impairment and previous treatment outcome. The data collected to assess the effect of medicinal products are obtained after dose response and therapeutic confirmatory studies like short-term and long-term trials as well as studies in special populations (elderly, children and adolescents). Details on the chosen strategy and design features of clinical trials including early studies in man (pharmacodynamics, pharmacokinetics / interactions / variety of other tests) are widely discussed. The adverse events that should be carefully monitored during the clinical safety evaluation need to be characterized in relation to the duration of treatment, dose and/or plasma levels, recovery time, age and other relevant variables. Specific monitoring is needed in children/adolescents and the elderly. Rebound and/or withdrawal phenomena should be investigated in both short term and long-term study designs. Special attention should be paid to hematological, cardiovascular and endocrinological adverse reactions. Status/Enforcement: The date for coming into operation of the document is July 2005. Link to the original document Updated on January 28, 2005 EU Clinical Trial Guideline on Generalized Anxiety Disorder Medicines Impacts on pharma industry The Guideline is based on the internationally acknowledged treatment principles and latest version of disease classification system of psychiatric disorders. The numerous and some times complicated pre-conditions for fulfilling of the criteria for assessment of efficacy and safety may impose troubles to the whole development program of the medicinal product intended for treatment of Generalized Anxiety Disorder (GAD). Commented on January 28, 2005 Published by EMEA/EC: January 20, 2005 Document: On January 20, 2005 the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) adopted a "Guideline on the Clinical Investigation of Medicinal Products Indicated for Generalized Anxiety Disorder". Targeted professionals: clinical trials planners/managers, research and product development, scientific and medical affairs and regulatory affairs managers Cont. Summary - The document provides guidance on the evaluation of new medicinal products in general anxiety disorder (GAD). GAD is the most prevalent anxiety disorder in primary care. In spite GAD is almost not occurring in children and has about 1% prevalence in adolescents the guideline covers these groups as they have increased over the last years. The document assists applicants during the development of medicinal products intended for treatment of GAD, independent of the class of product under investigation. It provides inclusion and exclusion criteria for characteristics and selection of patients. Rating scales are described for assessment of the efficacy. The choice of these scales needs to be justified from point of view of test quality criteria like reliability and validity. Details on clinical trials strategy and design especially covering early studies in man (pharmacodynamics, pharmacokinetics / interactions, dose-response studies), therapeutic confirmatory studies (short-term and long-term trials), and studies in special population (elderly, children and adolescents) will be requested. General recommendations for clinical safety evaluation are given with specific emphasis on carefully monitoring of rebound / withdrawal / dependence symptoms after treatment discontinuation. Special attention is paid on gathering of central nervous system, hematological, cardiovascular and endocrinological adverse reactions. Status/Enforcement: The requirements addressed in this document are coming into operation from July 2005. Link to the original document Updated on January 28, 2005 New Requirements for HRT Clinical Trials Impacts on pharma industry The document attempts to push companies to capture more information on safety of hormone replacement therapy (HRT) by applying harmonized approach for endometrial safety evaluation and pooling of data. This would complicate the clinical trial planning and performance and will bring supplementary burden to the industry in recruiting trial subjects and collecting results. Commented on January 28, 2005 Published by EMEA/EC: January 27, 2005 Document: The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) on January 20, 2005 released for consultation a draft "Guideline on Clinical Investigation of Medicinal Products for the Treatment of Hormone Replacement Therapy (HRT)". Targeted professionals: adjuvant / vaccine developers / manufacturers; managers in research and product development, scientific and medical affairs, regulatory affairs Cont. Summary - The document focuses only on the indication "hormone replacement therapy for estrogen deficiency symptoms in post-menopausal women" by providing recommendations for the development of medicinal products containing as active substance either a) an estrogen alone; b) an estrogen in combination with a progestogen; or c) a progestogen alone, to be given with an estrogen. In view of the recent evidences for the increased risk of breast and endometrial cancer, venous thromboembolism and stroke, companies are requested to choose for the initiation and the continuation of treatment the minimum effective dose of the active substance(s) for the shortest duration. As the validation standards across EU are largely different from country to country - including progestogens added to estrogen replacement therapy, mode of treatment (continuous or sequential), dose of estrogen, route of administration (oral, transdermal), the companies are advised to check the validity of their references before conducting kinetic and / or clinical studies for HRT. It is stated that bioequivalence data are not needed for all strengths provided that the applicant demonstrates dose-proportionality for the test within the applied dose-range. The following clinical study parameters are requested to justify the 1) Efficacy: prevention of osteoporosis (bone mineral density) and treatment of symptoms related to estrogen deficiency; and 2) Safety: assessment of endometrial safety (endometrial biopsy) and vaginal bleeding. Other safety issues like venous thromboembolism monitoring, breast examination, bleeding data and local tolerance are also requested. For a new combination of estrogen / progestogen, studies of at least 12 months duration are required. The document provides also methodological recommendations and requirements on how to assess the endometrial biopsies, classify the results, determine the sample size and pool the data. Guidelines are given in two Annexes on presenting the endometrial biopsy results for each study and each treatment group, and how to specify the type or types of any polyp(s) identified in the investigation. Status/Enforcement: deadline for comments July 2005. Link to the original document Updated on January 28, 2005 EU Committee for Orphan Medicinal Products Report Six New Designations Impacts on pharma industry The detailed list of future orphan medicinal products as designated from the competent EU Committee could provide companies with indirect information on the pharma industry plans in this field. Consideration is taken on acknowledged treatment possibilities and pre-conditions for fulfilling the criteria required for designating a product as orphan medicine in the EU. The information on orphan drugs designation could influence the R&D and marketing policies of companies wishing to benefit the EU initiatives in the field. Commented on February 7, 2005 Published by EMEA/EC: February 5, 2005 Document: The Committee for Orphan Medicinal Products (COMP) at the European Medicines Agency (EMEA) announced in a press release of February 7, 2005 about the adoption of six new positive opinions on orphan medicinal product designation. The assessments lasted from 60 to 88 days. Targeted professionals: medicinal product development, clinical trials planners, regulatory affairs officers Cont. Summary - Six new orphan medicinal product designations were adopted in February by the EU COMP. Two of these products came from Pfizer Limited and were for treatment of malignant gastrointestinal stromal tumors and renal cell carcinoma. Two contained Cyclosporine (inhalation use), from Chiron Corporation Limited for prevention of graft rejection and treatment of graft rejection after lung transplantation. One was from Trophos SA, for treatment of 5q spinal muscular atrophies and one from Janssen-Cilag International NV, for treatment of acute myeloid leukemia. It was announced that the European Commission granted five positive decisions on orphan designation - for recombinant human α -mannosidase (for treatment of α-Mannosidosis), for 17-allylamino-17-demethoxygeldanamycin (for treatment of chronic myeloid leukemia), for aetylcysteine (for treatment of idiopathic pulmonary fibrosis), for L-Asparaginase (for treatment of acute lymphoblastic leukemia) and for recombinant human bile salt-stimulated lipase (for treatment of cystic fibrosis). An overview of orphan designation procedures for 2000-2004 was provided in a separate Annex to the press release. The Annex provides information on the number of application procedures for orphan medicinal product designation, positive COMP opinions, applications withdrawn, final negative COMP opinions and designations granted by the European Commission. Status/Enforcement: Effective immediately. Link to the original document Updated on February 7, 2005 EU Guideline on Quality of Inhalation and Nasal Products Impacts on pharma industry Detailed guidance and technicalities are given on quality issues related to inhalation and nasal products like administration devices, drug substance and drug product specifications, pharmacopoeial and non-pharmacopoeial excipients, stability, pharmaceutical development etc. Although this document does not outline quality aspects related to changes in existing inhalation and nasal products it is not excluded that some principles would be requested by the regulators once quality part of the existing dossier would need re-formulation or revision. Commented on January 19, 2005 Published by EMEA/EC: February 16, 2005 Document: On January 19, 2005 the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) released for consultation the "Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products". This is one of the first documents that the Agency is planning to publish in collaboration with Health Canada. Targeted professionals: medicinal product development, medical device development, active substance, excipient and device manufacturers, clinical trials planners, regulatory affairs officers Cont. Summary - The Guideline applies to products to be marketed or to be used in clinical trials as drug substance and drug product batches. The Guideline outlines only quality aspects specific to inhalation and nasal human medicinal products intended for delivery into the lungs or to the nasal mucosa. It does not cover nasal ointments, creams and gels. It includes current technologies for administration, such as pressurized metered dose and dry powder inhalers, products for mobilization, metered dose nebulizers, as well as pressurized metered dose nasal sprays and nasal powders. It is recognized that the wide diversity of inhalation and nasal products with respect to formulation and device characteristics would necessitate some flexibility in testing methodology. It presents in details and with comprehensive examples issues related to drug substance and drug product specifications, pharmacopoeial and non-pharmacopoeial excipients, container closure system, stability, pharmaceutical development and manufacture. It should be noted that some aspects like impurities and process validation are not described in the guidance. Detailed guidance on pharmaceutical development study design (e.g., priming studies) and the analytical procedures used primarily for inhalation and nasal products (e.g., cascade impactor analysis) are also not provided. A glossary is elaborated for quick understanding of terms and specific definitions used in the guidance. Region-specific appendices are envisaged to be attached to the document. They will cover specific issues related to generic products, applied devices, spacers and holding chambers (valid only for the EU) and information for users (consumers and health care professionals) Status/Enforcement: Released for consultations until July 30, 2005. Link to the original document Updated on February 19, 2005 The EMEA Updated Q&A Document on COX-2 Inhibitors Impacts on pharma industry The questions and answers document on COX-2 inhibitors addressed to the general public could be an important information tool for the industry and the prescribers dealing with these medicinal products. Some statements and detailed clarifications given in the document might be successfully used in preparing information materials and launching education campaigns on COX-2 inhibitors. Commented on February 17, 2005 Published by EMEA/EC: February 17, 2005 Document: The European Medicines Agency (EMEA) and its Committee for Medicinal Products for Human Use (CHMP) have reviewed all available data on the cardiovascular safety of COX-2 inhibitors that followed the withdrawal of rofecoxib in September 2004 and the new clinical trial data published on celecoxib in December 2004. Based on these findings EMEA published on February 17, 2005 a document entitled "Questions and Answers on COX-2 Inhibitors". Targeted professionals: experts in pharmacovigilance, regulatory affairs managers, clinical trials planners/managers, medical representatives, research and product development, scientific and medical affairs managers Cont. Summary - The document announces that the available data: * show an increased risk of cardiovascular adverse events for COX-2 inhibitors and * suggest an association between duration and dose of intake and the probability of suffering a cardiovascular event. The following interim measures pending the finalization of the class review (expected in April 2005) have been taken for COX-2 inhibitors available in the EU namely celecoxib, etoricoxib, lumiracoxib, valdecoxib and parecoxib: * A contra-indication is introduced for all COX-2 inhibitors in patients with ischemic heart disease or stroke * A contra-indication is introduced for etoricoxib in patients with hypertension whose blood pressure is not under control * Given the association between cardiovascular risk and exposure to COX-2 inhibitors, doctors are advised to exercise caution when prescribing COX-2 inhibitors for patients with risk factors for heart disease, such as hypertension, diabetes and smoking. They are advised as well as to prescribe for patients with peripheral arterial disease use the lowest effective dose for the shortest possible duration of treatment. Status/Enforcement: This is an updated version of a previous document which dated of December 2004. Link to the original document Updated on February 17, 2005 Guideline on Pharmacokinetics in Patients with Impaired Hepatic Function Impacts on pharma industry The Guideline provides valuable information on how to design, assess and present data of pharmacokinetic studies performed in patients with impaired hepatic function. There is a risk this document to be used by the regulators as a ground for asking the industry to repeat studies or revise old data. Commented on February 17, 2005 Published by EMEA/EC: February 17, 2005 Document: The European Medicines Agency (EMEA) published a "Guideline on the Evaluation of the Pharmacokinetics of Medicinal Products in Patients with Impaired Hepatic Function". The Guideline was adopted by the Committee for Medicinal Products for Human Use (CHMP). Targeted professionals: managers in medicinal product development, clinical trials planners, research and development officers, regulatory affairs managers, scientific and medical affairs managers Cont. Summary - The Guideline should assist applicants during development of medicinal products by providing recommendations regarding the design and data presentation of pharmacokinetics studies that should be performed in subjects with impaired hepatic function. It gives detailed information on the study population, drug administration design (including when a single- and / or a multiple-dose studies could be sufficient, desirable or favorable), sample collection and analysis, population pharmacokinetics, physiological based pharmacokinetic models and pharmacodynamic assessments. For correct evaluation of the pharmacokinetic results the severity of subject's hepatic impairment is categorized according to Child-Pugh classification and presented in Appendix to the Guideline. According to the document the data analysis should include estimation of pharmacokinetic parameters, evaluation of the relationship between measures of hepatic function and the pharmacokinetic parameters, assessment of whether posology adjustment is warranted in patients with impaired hepatic function and assessment of alteration of the interaction profile. The results should be reflected in the Summary of Product Characteristics (SPC) in terms of specific dosing recommendations, contraindications, special precautions and warnings for use and description of pharmacokinetic properties Status/Enforcement: The Guideline is coming into operation in August 2005. Link to the original document Updated on February 17, 2005 EU Draft Guideline on Delivery Devices for Liquid Forms Impacts on pharma industry The Guideline seeks to achieve accuracy and precision as well as suitability of the measuring devices used for liquid dosage forms. The described methods and rules could increase the costs of the industry that would be needed to meet the standards and technical requirements that a dosing device for liquid dosage form should fulfill to be in line with the Guideline. Commented on February 18, 2005 Published by EMEA/EC: February 18, 2005 Document: The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) adopted on February 16, 2005 a draft "Guideline on the Suitability of the Graduation of Delivery Devices for Liquid Dosage Forms". Targeted professionals: managers in medicinal product / medical device development, research and development officers, regulatory affairs managers Cont. Summary - The Guideline intends to provide recommendations regarding the graduation of delivery devices (such as syringes without needles, measuring cups, spoons, beakers, pipette applicators) for liquid dosage forms (such as solutions, suspensions and emulsions). The document applies to liquid preparations for parenteral or oral use and deals with products that can be suited for single - dose or multi - dose use. Detailed guidelines and requirements are given on the manner of graduation, graduated scale and suitability of dosing device. They are described in the context of device material, dosing range, overdosing risk, as well as the intended patient population. Status/Enforcement: The document is released for consultation with deadline for receiving comments August 30, 2005. Link to the original document Updated on February 18, 2005 EU Clarifies what Is "Serious Risk to Public Health" Impacts on pharma industry The draft Guideline identifies situations and circumstances in which authorities could suspect that given medicinal product might present potential serious risk to public health. Once adopted the Guideline would have a major role to play for the industry as it will provide detailed and solid arguments in limiting objections related to suspected risk to public health associated with quality, safety and efficacy of medicinal products. Commented on February 22, 2005 Published by EMEA/EC: February 22, 2005 Document: The Directorate - General "Enterprise and Industry" of the European Commission released for consultation in February 2005 a proposal for a "Guideline on the Definition of a Potential Serious Risk to Public Health". Targeted professionals: regulatory affairs, scientific and medical affairs managers, crisis managers, research and development officers, managers in medicinal product development, clinical trials planners Cont. Summary - This Guideline is expected to improve the Mutual Recognition and Decentralized Procedures in the EU by defining what it means "a potential serious risk to human or animal health or for the environment". Its scope is to set out in more detail in which exceptional cases a Member State can refuse to recognize marketing authorization or assessment issued or made by another Member State on the basis of a potential risk to public health. The Guideline states that "any objection must be scientifically justified" and not "..linked to national administrative medical practices, or national scientific requirements, going beyond the framework of rules governing medical products in the European Union...". The term "risk" is determined as 'any risk relating to the quality, safety or efficacy of the medicinal product as regards to patients' health or public health' and the term "serious" is defined as "a hazard that could result in death, could be life-threatening, could result in significant disability or incapacity, could be a congenital anomaly/birth defect, or which could result in hospitalization or permanent or prolonged signs in exposed humans." These two definitions are considered as comprehensive enough to narrow the grounds justifying that a medicinal product could presents a potential serious risk for public health. In addition, in annex, examples of issues which would not be considered as grounds for a serious risk to public health are provided. Status/Enforcement: Comments on the draft proposal are expected until March 31, 2005. The Guideline's implementation is foreseen for November 2005. Link to the original document Updated on February 22, 2005 Guidance on Grounds for Inspections at Active Substance Manufacturers Impacts on pharma industry The Guidance helps industry to better understand the decision making process as to when a company manufacturing or distributing active substances shall undergo EU inspection on GMP. Many companies in the world produce or distribute starting materials in premises that do not comply with GMP. Therefore the EU requirements shall restrict Marketing Authorization Holders in the EU to make deals with non-GMP manufacturers of active ingredients. The need of investments for complying with the EU requirements for GMP may increase the prices of some active substances on the world market. Commented on March 2, 2005 Published by EMEA/EC: March 2, 2005 Document: On March 2, 2005 the European Commission published a draft "Guidance on the Occasions when it is Appropriate for Competent Authorities to Conduct Inspections at the Premises of Manufacturers of Active Substances Used as Starting Materials". Targeted professionals: GMP managers and auditors, research and product development, scientific, medical affairs and regulatory affairs managers Cont. Summary - Directives 2001/83/EC and 2001/82/EC oblige Manufacturing Authorization Holders in EU to use active substances that have been manufactured in accordance with the GMP for starting materials. This Guidance presents the harmonized understanding as to when an EU authority inspection of a company which manufactures (in premises located inside and outside of the European Economic Area - EEA) active substances for human and veterinary medicines may be appropriate. Repackaging or re-labeling of active substances carried out by a distributor Guidance is also covered. However manufacture of substances for biological or aseptically produced medicinal products lies outside the scope of the Guidance. The document contains examples of when inspections of premises used to manufacture of starting material may be appropriate or required according to the EU legislation. These are for instance inspections performed to verify particulars submitted in support of a Marketing Authorization application, inspections made on request of manufacturers of active substances which are located in a non - EEA and non - Mutual Recognition Agreement another Member States or inspections carried out on request of the European Commission or the EMEA or on behalf of the European Directorate for the Quality of Medicinal Products (EDQM). Other types of inspections are those carried out by competent authorities when a significant non-compliance with the specification(s) is/are suspected or when the quality of the active substance is implicated in a report of a serious adverse. Detailed references to the legal texts relevant to inspections of manufacturers of active substances are listed in an Annex to the Guidance. Status/Enforcement: The document is released for consultation with deadline for comments April 4, 2005. Link to the original document Updated on March 2, 2005 EU Is Concerned on Safe and Efficacious Co-administration of Tenofovir and Didanosine Impacts on pharma industry The precise nature of the observed interactions leading to non-response following co-administration of tenofovir and didanosine with a non-nucleoside reverse transcriptase inhibitor is not known. It is not excluded that the same findings can be observed in other contexts as for example in antiretroviral experienced patients and/or in combination with protease inhibitors. Therefore the EMEA Statement may provoke the competent authorities to request industry to perform supplementary or retrospective monitoring / evaluation of efficacy and adverse events related to antiretroviral combination therapy. Commented on March 3, 2005 Published by EMEA/EC: March 3, 2005 Document: On March 3, 2005 the European Medicines Agency (EMEA) published a Public Statement entitled: Efficacy and Safety Concerns Regarding the Co-administration of Tenofovir Disoproxil Fumarate (TDF, Viread) and Didanosine (Ddi, Videx). The Committee for Medicinal Products for Human Use (CHMP) adopted a variation of the Package Leaflet of Viread (part 4.3. and 4.4. of the Summary of Product Characteristics - SPC) to include new information on special warnings and special precautions for use and interactions with this product. Targeted professionals: experts in pharmacovigilance, regulatory affairs managers, clinical trials planners/managers, research and product development, scientific and medical affairs manager Summary - New clinical studies discovered a non-response (virological failure and emergence of resistance) following co-administration of tenofovir disoproxil fumarate (TDF, Viread) and didanosine (ddI, Videx) with a non-nucleoside reverse transcriptase inhibitor in HIV-infected treatment-naive adult patients. The patients were with high baseline viral load and low CD4 cell counts. It should be noted that Viread was authorized in the EU in 2002 via the Centralized Procedure. Didanosine (ddI, Videx) was authorized via the Mutual Recognition Procedure (in 1997) with France as Concerned Member State - Concerned Member State (in 1992). Similar observations have been previously reported with this dual combination in the context of triple combination therapy with a nucleoside/nucleotide reverse transcriptase inhibitor. Based on these data CHMP decided in January 2005 to modify the Product Information (SPC) of Viread to include: * Information about rare, sometimes fatal cases of pancreatitis and lactic acidosis that have been reported with the co-administration of tenofovir and didanosine; * Advice to avoid co-administration of tenofovir disoproxil fumarate and didanosine within any antiretroviral combination therapy, and particularly in patients with high viral load and low CD4 cell count. * Recommendation on using the combination only when this is considered strictly necessary and * Request monitoring of efficacy and didanosine-related adverse events in case this combination is prescribed. Status/Enforcement: Effective immediately. Link to the original document Updated on March 3, 2005 Seven New Designations for Orphan Medicines in the EU Impacts on pharma industry The detailed list of future orphan medicinal products as designated from the competent EU Committee could provide companies with indirect information on the pharma industry plans in this field. Consideration is taken on acknowledged treatment possibilities and pre-conditions for fulfilling the criteria required for designating a product as orphan medicine in the EU. Commented on March 7, 2005 Published by EMEA/EC: March 4, 2005 Document: The European Medicines Agency (EMEA) published on March 7, 2005 a Press Release of the Committee for Orphan Medicinal Products (COMP) plenary meeting that took place on March 4, 2005. Targeted professionals: clinical trials planners/managers, research and product development, scientific and medical affairs and regulatory affairs managers Cont. Summary - COMP announced in its Press Release about the adoption of 7 positive opinions on orphan medicinal product designation. The assessments lasted from 54 to 89 days. Details on the products, the companies involved and the review time are listed below: * Ambrisentan, from Uppsala Medical Information System AB, for treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (review time: 54 days) * Autologous Tumor-Derived gp96 Heat Shock Protein-Peptide Complex, from Antigenics Therapeutics Limited, for treatment of renal cell carcinoma (review time: 54 days) * Estradiol Hemihydrate and Progesterone, from B. Braun Melsungen AG, for prevention of bronchopulmonary dysplasia in premature neonates of less than 30 weeks of gestational age (review time: 89 days) * Histamine dihydrochloride, from Maxim Pharmaceuticals Europe Ltd, for treatment of acute myeloid leukemia (review time: 89 days) * Humanized agonistic anti-CD28 monoclonal antibody, from TeGenero AG, for treatment of B-cell chronic lymphocytic leukemia (review time: 89 days) * Melatonin, from ICON Consulting, for treatment of Non-24-Hour Sleep-Wake Disorders in blind people with no light perception (review time: 54 days) * Paromomycin sulfate, from OneWorld Health, for treatment of visceral leishmaniasis (review time: 89 days. Status/Enforcement: Effective immediately. Link to the original document Updated on March 7, 2005 First Revision of Core SPC for Human Albumin in the EU Impacts on pharma industry Companies marketing in the EU medicinal products containing Human Albumin in solution are advised to introduce the changes in the harmonized (core) SPC agreed by the EU competent authorities. The changes in the SPC should be presented with identical sequence. Differences in the specific countries related to the label, the trade name, the package (patient) leaflet and the pack size-presentation as well as the authorization number, shall be accepted by the regulatory authorities. Any divergences however vis-a-vis the harmonized Summary of Product Characteristic (SPC) shall remain compatible with this (core) SPC. Commented on March 16, 2005 Published by EMEA/EC: March 16, 2005 Document: The "Core SPC for Human Albumin Solution" has been prepared by the European Medicines Agency (EMEA). Targeted professionals: managers in immunological research and product development, pharmacovigilance, scientific and medical affairs managers, regulatory affairs Cont. Summary - This is a first revision that EU undertakes of the Core Summary of Product Characteristics (SPC) for Human Albumin. It was provoked by an article of Cochrane Injuries Group published in 1998 in the British Medical Journal (BMJ 1998; 317:235). The publication has shown in a meta-analysis of clinical trials in critically ill patients that treatment with albumin increased with 7% mortality compared with patients who had received crystalloids or no treatment. The publication provoked a review of the safety of human albumin products in the EU Member States followed by a discussion at the EMEA Pharmacovigilance Working Party and Blood Products Working Group. As a consequence amendments of Sections 1 and 2 of the Core SPC for Human Albumin Solution were proposed to express the strength in g/l instead of %. The quality aspects were also updated to become in line with current European Pharmacopoeia Monograph. The indication for human albumin was amended to focus on the use of albumin to replace lost fluids. Dose recommendations were removed from the Summary of Product Characteristics (SPC) because these vary depending on the clinical situation. Due to risk of hypervolemia and cardiovascular overload an advice was given that hemodynamic parameters should be monitored in patients receiving albumin. Status/Enforcement: The date for coming into operation is October 1, 2005. Link to the original document Updated on March 16, 2005 Guideline on Quality Aspects of Biosimilar Products Impacts on pharma industry The clarifications and explanations provided in the guideline will influence the world wide decision making regulatory process concerning biosimilar medicinal products. Therefore it should be read carefully by the companies claiming that a new biological medicinal product is similar in terms of quality, safety and efficacy to an original, reference medicinal product. It should be noted that some aspects pertinent to the evaluation of biosimilarity are not described in details and could not serve adequately the industry in demonstrating / reasoning their comparability exercise. Commented on March 18, 2005 Published by EMEA/EC: March 18, 2005 Document: The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) published on March 18, 2005 a draft document entitled "Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues". Targeted professionals: biotechnology managers, quality research and product development, scientific and medical affairs and regulatory affairs managers Summary - The EU regulations require comparability exercise for a similar biological (biosimilar) medicinal product versus a reference medicinal product to be presented separately in the quality dossier. The reference medicinal product must be authorized in the EU. This Guideline addresses quality issues that are relevant in demonstrating comparability for biosimilar products containing recombinant DNA-derived proteins or other proteins and peptides, including their derivatives and products of which they are components (e.g. conjugates). Changes during development and post-authorization introduced in the manufacturing process of a given product, as described in ICH Q5E are not addressed in the document. The Guideline contains specific sections dedicated to the scientific demonstration of similarity for a biosimilar product versus that of a reference medicinal product including their impurity profiles and potential safety and efficacy implications. State of the art analytical methods are requested to demonstrate, that the active substance used in the comparability exercise is representative of the reference medicinal product's active substance. Various validated approaches are recommended to obtain representative reference active substance. Analytical considerations are given including issues related to suitability of available analytical methods and their validations. The evaluation of physicochemical parameters (i.e. determination of composition, physical properties, and primary and higher order structures of the biosimilar product's active substance) are also taken into considerations. Purity and impurity profiles of both active substance and medicinal product are requested to be assessed qualitatively and quantitatively by a combination of analytical procedures for reference and biosimilar products. The setting of specifications submitted by the applicant needs to be supported by global reasoning based on his experience in quality, safety and efficacy of the biosimilar product including own experimental results obtained by testing of the reference medicinal product. Status/Enforcement: The deadline for comments on the document is June 30, 2005. Link to the original document Updated on March 18, 2005 The European Court of Justice Questions the Food Supplement Rules in the EU Impacts on pharma industry The Directive on food supplements in the EU should be implemented into Member States law by July 31, 2003. After this date many food supplements containing nutrients and nutrient sources that are not on the positive lists (Annex I and II) should be excluded from the EU market. The opinion of the ECJ Advocate General that the Directive is not valid gives hope to the industry producing food supplements that their products could stay on the EU market after August 1, 2005. It should be noted that the opinions of Advocates General are rarely rejected by the Court. Commented on April 13, 2005 Published by EMEA/EC: April 5, 2005 Document: The European Court of Justice (ECJ) Advocate General L. Geelhoed delivered on April 5, 2005 a preliminary ruling announcing invalidity of the EU food supplement Directive 2002/46/EC on the Approximation of the Laws of the Member States Relating to Food Supplements. Targeted professionals: jurists, regulatory affairs and product development managers dealing with pharmaceuticals, food and food supplements Cont. Summary - The Directive on food supplements currently only regulates the inclusion of vitamins and minerals to food supplements. The vitamins and minerals permitted to be ingredients of the food supplements in the EU are listed in positive lists (Annex I and II) to the Directive. According to the Directive nutrients and nutrient sources that are not on the positive lists should be excluded from the EU market by August 1, 2005 at the latest. In October 2003 the National Association of Health Stores and the Health Food Manufacturers Ltd and the Alliance of Natural Health and Nutri-Link Ltd commenced each separate proceeding at the High Court of Justice of England and Wales on the fact that the EU Directive on food supplements restricts marketing of substances that are not included in the positive list. The UK Court decided to refer the question for preliminary ruling to the ECJ. In an opinion delivered on April 5, 2005 the Advocate General of the ECJ found that the legal basis of the Directive is adequate. He concluded that the Directive improves the functioning of the market and does not infringe the principle of free movement of goods. He deemed as well that the system of positive lists is valid and said that in this context the Directive does not infringe the principle of proportionality. But Advocate General stated that the Directive failed to establish provisions for minimum conditions of prudent decision-making in deciding to add nutritients to the lists and to set a procedure for new submissions. The Advocate General conclusion is that in this context the Directive infringes the principle of proportionality and it is, therefore, invalid. Status/Enforcement: The judges of the ECJ should deliberate till June 2005 a final judgment on the validity of the Directive. Link to the original document Updated on April 13, 2005 Pfizer Suspended the Use of Bextra (Valdecoxib) in the EU Impacts on pharma industry After the decision of Pfizer to withdraw Bextra from the EU and US markets the pressure on suspending the other COX-2 class of medicines used in Europe could increase. The questions addressed during the ongoing review of the COX-2 inhibitors' safety may provoke regulatory officials and prescribers' hesitations that COX-2 drugs' benefits outweigh any risks to patients. Commented on April 7, 2005 Published by EMEA/EC: April 7, 2005 Document: The European Medicines Agency (EMEA) released a statement on the suspension of use of Bextra (Doc. Ref: EMEA/121637/2005). Targeted professionals: experts in pharmacovigilance, regulatory affairs managers, clinical trials planners/managers, medical representatives, research and product development, scientific and medical affairs managers Cont. Summary - The European Medicines Agency announced that following discussions with Pfizer the later agreed to suspend the use of Bextra (valdecoxib) in the EU. Pfizer has agreed to similar actions in the United States at the request of the Food and Drug Administration. On December 15, 2004 the EMEA had published a statement concerning safety problems in patients undergoing coronary artery bypass graft (CABG) surgery and serious skin reactions relating to the use of two COX-2 medicines, including Bextra. On February 17, 2005 the EMEA introduced contraindications and warnings in prescribers' and patients' information concerning the cardiovascular safety of all COX-2 medicines. A safety review of all COX-2 class medicines was initiated. The Agency is in process of monitoring the safety of the COX-2 class of medicines and reviewing all new data as it becomes available. Until the completion of this review, prescribers are advised to monitor carefully patients being treated with Bextra and not to initiate treatment of new patients. Patients receiving Bextra are advised to speak to their physician regarding their current treatment. Status/Enforcement: Effective immediately. Further update will be made after the Committee for Medicinal Products for Human Use (CHMP) meeting expected on April 18-21, 2005. Link to the original document Updated on April 7, 2005 Nine New Designations for Orphan Medicines in the EU Impacts on pharma industry The detailed information in the Press Release on future orphan medicinal products as designated by the COMP provide companies with indirect information on the pharma industry plans and the EU trends in this field. Consideration is taken on acknowledged treatment possibilities and pre-conditions for fulfilling the criteria required for designating a product as orphan medicine in the EU. Commented on April 13, 2005 Published by EMEA/EC: April 12, 2005 Document: The European Medicines Agency (EMEA) published on April 12, 2005 a Press Release of the Committee for Orphan Medicinal Products (COMP) plenary meeting that took place on April 6-7, 2005. Targeted professionals: clinical trials planners/managers, research and product development, scientific and medical affairs and regulatory affairs managers Cont. Summary - COMP announced in its Press Release about the adoption of 9 positive opinions on orphan medicinal product designation. The assessments lasted from 54 to 89 days. Details on the products, the companies involved and the review time are listed below: * (3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazole-3-yl]- benzoic acid, from the Matthews Consultancy Ltd, for treatment of cystic fibrosis (review time: 89 days) * (3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazole-3-yl]-benzoic acid, from the Matthews Consultancy Ltd, for treatment of Duchenne muscular dystrophy (review time: 89 days) * (E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone, from the Matthews Consultancy Ltd, for treatment of cutaneous T-cell lymphoma (review time: 54 days) * Acadesine, from Advanced In Vitro Cell Technologies, for treatment of B-cell chronic lymphocytic leukemia (review time: 54 days) * Bimosiamose, from Revotar Biopharmaceuticals AG, for treatment of acute lung injury (review time: 54 days) * Interferon gamma, from Mondobiotech Laboratories Anstalt, for treatment of idiopathic pulmonary fibrosis (review time: 54 days)Interferon gamma, from Mondobiotech Laboratories Anstalt, for treatment of idiopathic pulmonary fibrosis (review time: 54 days) * Miltefosine, from Obwaller Forschungs- und Entwicklungs GmbH, for treatment of acanthamoeba keratitis (review time: 54 days) * Recombinant megakaryopoiesis-stimulating protein, from Amgen Europe BV, for treatment of idiopathic thrombocytopenic purpura (review time: 54 days) * Sodium butyrate (rectal use), from Promefarm srl, for prevention of radiation proctitis (review time: 54 days). Three oral explanations took place during the meeting and three applications were withdrawn by sponsors. Information on number of application procedures for orphan medicinal product designation, positive COMP opinions, applications withdrawal, final negative COMP opinions for 2000-2004 and designations granted by the European Commission (since the last COMP meeting on March 2-3, 2005) are provided in separate Annexes to the Press Release.. Status/Enforcement: Effective immediately. Link to the original document Updated on April 13, 2005 EU Introduce Braille Requirements for Labeling and the Package Leaflet Impacts on pharma industry The EU Guideline requirements on the formats for blind and partially sighted people to be used in the human medicines labeling and package leaflets shall be a great burden for the industry. The companies will be demanded to invest in new packaging materials and facilities. As any introduction of new texts or applications will need consultations with representatives of organizations for blind and partially sighted people in the EU Member States the industry will be obliged to build up new alliances with them. In spite that Braille requirements will not apply immediately to products authorized before 30 October 2005 companies will be urged in most of the Member States to implement the Guideline provisions earlier to all their medicinal products authorized in the EU. Commented on April 14, 2005 Published by EMEA/EC: April 13, 2005 Document: The European Commission published on April 13, 2005 a "Guidance Concerning the Braille Requirements for Labeling and the Package Leaflet". It is based on the provision of Article 56a of Directive 2001/83/EC and will be included as part of the EU "Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for Human Use" once the revision of the latter guideline will have been finalized. Targeted professionals: packaging material designers, human medicinal products manufacturers, medicinal product development managers, parallel importers and distributors, drug information / labeling experts, regulatory affairs officers Summary - This guidance interprets the requirements for Braille (reading and writing system for blind and partially sighted people that consists of dots which make up the letters of the alphabet, numbers and punctuation marks) that should be used after October 2005 on the packaging and leaflet of the EU human medicinal products. According to the EU pharma legislation the (invented) name of the medicinal product followed by its strength should be put in Braille on the packaging of all human medicinal products. Braille will be not required on packaging of medicinal products which are intended for administration by health care professionals. Companies are encouraged to express further information (pharmaceutical form, and if appropriate, whether it is intended for babies, children or adults, etc) in Braille on bigger volume packages on a voluntary basis. For medicinal products authorized in a single strength, only the invented name in Braille shall be put on the packaging. In case of blisters, ampoules and bottles, the name in Braille has to appear only on the outer/secondary packaging, which is normally a carton. It is not recommended to affix an adhesive Braille label at the point of sale / dispensing of the medicinal product. There is no exemption for the case of multilingual packaging. Parallel importer/distributor should ensure that the same Braille text is provided in the language(s) of the Member State of destination and that the original Braille text will not cause confusion. The Guidance stipulates that on request the package leaflet should be provided for partially sighted people in a suitable print, taking into consideration all aspects determining the readability. Status/Enforcement: The Guidance requirements will concern all human medicinal products makers planning to apply for EU marketing authorization after October 30, 2005. It will not be applied immediately to human medicinal products authorized before that date. Link to the original document Updated on April 13, 2005 EU Guideline on Clinical Trials in Small Populations Impacts on pharma industry Given that, there are no special methods for designing, carrying out or analyzing clinical trials in small populations the approaches described in this guideline could be very useful for the industry. The presentation of how the need for statistical efficiency may be weighed against the need for clinically interpretable results to increase the clinical trials efficiency could serve as a very helpful tool for the industry, moreover that it addresses conditions far beyond those performed with very few available patients. Commented on April 22, 2005 Published by EMEA/EC: April 21, 2005 Document: The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) published on March 18, 2005 a draft document entitled "Guideline on Clinical Trials in Small Populations". The Guideline was released for consultations on March 17, 2005. Targeted professionals: clinical trials planners, epidemiologists, statisticians and managers involved in medicinal products research and development, regulatory affairs managers, scientific and medical affairs managers Cont. Summary - The document considers problems associated with clinical trials when there are very few patients available to study like those affected by rare diseases or involved in rapidly evolving fields (like organ transplantation, where enrolling of several hundred patients may not be practical or even not feasible). This can apply further to cases of refinement of individually targeted medicinal products, e.g. by applying pharmacogenomics. The Guideline addresses methods where the efficiency of the design or analysis may be increased and approaches for situations where such methods are not applicable. It describes levels of evidence and pharmacological considerations that may help to identify sources of patients' heterogeneity. Data from patient registers are specified as important sources of information for assessing the effectiveness and safety of the medicinal product under consideration. The Guideline provides a number of relevant and useful clinical endpoints and presents in details a range of possible approaches as well as methodological and statistical considerations used in particular situations. Issues related to the design stage and data analyses are covered. The criteria of Bradford-Hill for determining causality in observational studies are recommended when interpreting results from small studies. The Appendix to the Guideline gives many specific examples of evidence that seems acceptable when authorizing medicinal products for which very few patients are available to study in clinical trials. Status/Enforcement: The deadline for comments given to the parties concerned is the end of September 2005. Link to the original document Updated on April 23, 2005 EU Will Review Serious Skin Reactions in All COX-2 Inhibitors Impacts on pharma industry The intention of the CHMP to include in the ongoing COX-2 class review an assessment of serious skin reactions, in addition to the cardiovascular safety aspects will complicate the further development of COX-2 inhibitors by the industry. This process might increase regulatory officials and prescribers hesitations that COX-2 drugs' benefits outweigh any risks to patients. Commented on April 22, 2005 Published by EMEA/EC: April 21, 2005 Document: Press Release of the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) on the results of its meeting held on April 18-25, 2005. Targeted professionals: experts in pharmacovigilance, regulatory affairs managers, clinical trials planners/managers, medical representatives, research and product development, scientific and medical affairs managers Cont. Summary - The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) announced in the Press Release that after a hearing with Pfizer the data on serious skin reactions occurring with valdecoxib and its parent compound parecoxib (Dynastat) will be reviewed. This followed the statement on the suspension of use of Bextra (valdecoxib) published on April 07, 2005 by EMEA. At its April meeting the CHMP agreed that it was important to analyze the occurrence of skin reactions in all COX-2 inhibitors in order to arrive at a conclusion on the benefit-risk balance of the COX-2 class of medicines. On the formal request of the European Commission, the CHMP will include the assessment of serious skin reactions in the ongoing class review, in addition to the cardiovascular safety aspects. Further hearings will be held with the concerned companies at the May 23 - 26, 2005 CHMP meeting, with the review expected to be concluded in June 2005. As already reported before, pending the finalization of the review, Bextra would not be reintroduced on the market in the European Union. Status/Enforcement: Effective immediately. Link to the original document Updated on April 28, 2005 Potential Cancer Risk in Tacrolimus and Pimecrolimus Impacts on pharma industry To exclude that the use of pimecrolimus and tacrolimus is linked to cancer would request the industry to invest in human studies of ten years or longer. It might be expected that the EU will restrict the usage of the medicinal products containing these immunomodulators only for patients who have failed treatment with other therapies. Commented on April 22, 2005 Published by EMEA/EC: April 21, 2005 Document: Press Release of the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) on the results of its meeting held on April 18-25, 2005. Targeted professionals: experts in pharmacovigilance, regulatory affairs managers, clinical trials planners/managers, medical representatives, research and product development, scientific and medical affairs managers Cont. Summary - In the Press Release the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) announced that reviews were initiated by the European Commission and by Denmark on pimecrolimus from Novartis Healthcare, and tacrolimus from Fujisawa GmbH (dermatological medicinal products containing skin selective inflammatory cytokine inhibitors). This initiative was provoked by concerns of potential cancer risks to patients. Both drugs are used in the treatment of atopic dermatitis. Tacrolimus is authorized throughout the European Union under the names Protopic and Protopy. Pimecrolimus is authorized in a number of Member States under different trade names. It should be noted that in March 2005 the FDA issued a Public Health Advisory to inform healthcare providers and patients about a potential cancer risk from use of Elidel (pimecrolimus) and Protopic (tacrolimus). Status/Enforcement: Effective immediately. Link to the original document Updated on April 28, 2005 Antidepressants in children and adolescents reviewed Impacts on pharma industry The fact that suicide-related behavior and hostility were more frequently observed among children and adolescents treated with serotonin-selective reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) would provoke concerns on the use of antidepressants in children and adolescents. This could provoke the regulators to ask the industry to provide supplementary safety data on other classes of medicines used in children psychiatry. Doctors will be strongly advised to prescribe medicines in children and adolescents only in their approved indications. Commented on April 26, 2005 Published by EMEA/EC: April 25, 2005 Document: The European Medicines Agency (EMEA) published a Press Release entitled European Medicines Agency finalizes review of antidepressants in children and adolescents containing the results on the review of two classes antidepressants. Targeted professionals: clinical trials planners/managers, pharmacovigilance experts, research and product development, scientific and medical affairs and regulatory affairs managers Cont. Summary - The review of two classes of antidepressants (serotonin-selective reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) was initiated at the request of the European Commission on December 17, 2004 and was performed by the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA). The CHMP looked at the medicinal products containing the following substances: atomoxatine, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mianserine, milnacepran, mirtazapine, paroxetine, reboxetine, sertraline and venlafaxine. Most of these products are approved in the European Union for the treatment of depression and anxiety in adults, but are not licensed for the treatment of these conditions in children or adolescents. Some of these antidepressants are licensed for treatment of obsessive-compulsive and attention deficit/hyperactivity disorders in children and adolescents. CHMP found that suicide-related behavior (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behavior and anger) were more frequently observed in clinical trials among children and adolescents treated with these antidepressants compared to those treated with placebo. The conclusion was that SSRI and SNRI should not be used in children and adolescents except in their approved indications. The CHMP recommended inclusion of strong warnings across the whole of the European Union to doctors and parents about the increased risks of side effects of these products such as suicide attempt, suicidal thoughts, and hostility. When treatment is being stopped, doctors should gradually reduce the dose over several weeks or months. A question and answer document is annexed to the press release. It should be noted that on December 9, 2004 the EMEA issued a statement to advise the practitioners to not prescribe antidepressants for children under eighteen due to the heightened potential risk of suicidal or aggressive behavior. On September 14, 2004, the FDA had already decided to introduce severe warnings against the use of any serotoninergic antidepressants. Status/Enforcement: Effective immediately. Link to the original document Updated on April 26, 2005 CHMP Monthly Report of April 2005 Impacts on pharma industry The CHMP monthly report represents minutes of the Committee Plenary Session taken place normally each month at the EMEA. They contain decisions and initiatives approved by the CHMP that have/will have serious impact on the companies' regulatory and marketing policies and plans. The monthly report gives a detailed overview of the whole EU marketing authorization system. Some conclusions taken on specific cases or issues could influence both the EU Member State and world wide regulatory and legislative practice. Commented on May 4, 2005 Published by EMEA/EC: May 3, 2005 Document: The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) released its "Committee for Medicinal Products for Human Use. April 2005 Plenary Meeting. Monthly Report". Targeted professionals: scientific and medical affairs and regulatory affairs managers, clinical trials planners/managers, pharmacovigilance experts, research and product development manage Cont. Summary - The European Medicines Agency (EMEA) published on May 3, 2005 the Committee for Medicinal Products for Human Use (CHMP) Monthly Report for April 2005. Among the issues reported in the document the following should be noted: 1. The indications of Temodal (temozolomide), from SP Europe, were extended. Since January 26, 1999 the product has been used in the EU for treatment of malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy. Now the product could be used in patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment. 2. The CHMP also recommended Xigris [drotrecogin alfa (activated)], from Ely Lilly Nederland B.V., to be used by experienced doctors only in institutions skilled in the care of high-risk patients i.e. with severe sepsis, mainly in situations when therapy can be started within 24 hours of the onset of organ failure. Xigris should not be used in patients with single organ dysfunction, especially if they have had recent surgery (within 30 days). Xigris is approved in the EU for the treatment of adult patients with severe sepsis with multiple organ failure, when added to best standard care. 3. The CHMP concluded that the benefit-risk ratio is favorable for either Crestor (rosuvastatin) from AstraZeneca 5 mg or 10 mg as alternative starting doses. The choice in individual patients should take into account aspects of efficacy and safety, as detailed in the prescribing information. The Crestor is authorized in a number of EU Member States in dosages ranging from 5 to 40 mg. The recommended start dose for patients with predisposing factors for myopathy, patients of Chinese and Japanese ancestry, and elderly patients (>70 years) was determined as 5 mg. An overview of the applications, approvals and outcomes related to medicinal products that went thought the centralized procedures could be seen in the series of Annexes attached to the monthly report. Status/Enforcement: Effective immediately. Link to the original document Updated on May 7, 2005 EU Guideline on Non-Clinical Investigation of the Drug Dependence Potential Impacts on pharma industry The non-clinical data obtained in the investigation of the drug dependence potential are part of the risk assessment phenomena associated with dependence, including discontinuation syndrome and drug dependence. These complications could emerge with clinical use of the drug and the potential that this would lead to drug abuse either in a clinical or in a non-clinical setting. In spite that this is still an area that needs further development, the guideline provided could help the industry to identify models and to choose parameters for assessing dependence potential of drug compounds. As the data obtained are part of the drug risk/benefit assessment of the drug, non-clinical data obtained early during development phase may bring relevant evidence for directing further clinical development of a compound by providing early warnings of drug dependence-related problems. Commented on May 6, 2005 Published by EMEA/EC: May 5, 2005 Document: On April 21, 2005 the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) adopted and released for consultation the "Guideline on the Non-Clinical Investigation of the Dependence Potential of Medicinal Products". Targeted professionals: managers and experts/scientists involved in medicinal product pre-clinical research and development, clinical trials planners, epidemiologists, statisticians and regulatory affairs managers, scientific and medical affairs managers Summary - The Guideline is prepared by the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA). It aims at providing guidance on the need for testing in animals of possible dependence potential of medicines and on the type of information expected to be presented in this context as part of a Marketing Authorization Application (MAA). In general, this concerns only central nerve system (CNS) active compounds and medicines with pharmacological profile that suspects that parent drug or metabolite may enter the brain and interact at central targets. Compounds from classes known to cause dependence would in principal require limited testing to characterize the dependence potential. The extent of studying these properties needs to be determined on a case-by case basis. However medicines with peripheral targets that may enter the brain and for which available data give rise to a concern should be considered to further clarify their pharmacological profile. The guideline describes possible first signals derived from in vitro and in vivo biochemical and pharmacological studies pointing dependence potential and gives clarifications on when further studies investigating dependence might not be necessary. The choice of specific behavioral pharmacology studies is given in details based on animal species responsive to the pharmacological effects of the compound and with sufficient documented experience in dependence potential testing. Concerning the reinforcing properties of compounds, the self-administration paradigm is advised to be most widely used. The document presents a number of points to consider for the types of approach with great validity. Different classes of compounds like opioids, CNS stimulants, sedatives and anxiolytics that should be investigated both for their potential to induce self-administration and for the occurrence of withdrawal phenomena are described in details. The study of the dependence potential of compounds belonging to novel pharmacological classes where no class-specific standards may be available for reference, and the dependence potential has yet to be established is also mentioned. There is a special statement saying that all safety and behavioral in vivo pharmacology studies for investigating dependence potential referred to in the document should meet the requirements of GLP. Status/Enforcement: The document is released for consultation with the concerned parties with a deadline for comments October 31, 2005. Link to the original document Updated on May 7, 2005 Advanced Therapies Regulation under Preparation in EU Impacts on pharma industry The Regulation will establish legal certainty in the emerging, fast-growing and fast-evolving field of advanced therapies in the EU and beyond. The document shall bring a broad consensus in favor of a specific, harmonized and coherent EU regulatory framework covering human tissue engineered products, as well as other cell/tissue based products. The Regulation will cover not only existing, but also future cell/tissue based products and will serve as important tool for companies in planning, developing and marketing products in advanced therapies. There are key procedural and technical aspects addressed in the draft Regulation (notably the scope, definitions, marketing authorization requirements and borderline issues) that would need careful and critical stakeholders' evaluation and opinion. Commented on May 12, 2005 Published by EMEA/EC: May 10, 2005 Document: Based on the outcome of two public consultations (performed in 2002 and 2004), the European Commission has prepared and released two draft documents: 1. "Consultation Paper on Human Tissue Engineering and Beyond: Proposal for a Community Regulatory Framework on Advanced Therapies"; 2. "Proposal for a Regulation of the European Parliament and of the Council on Advanced Therapies and amending Regulation (EC) No 726/2004". Targeted professionals: product developers, regulatory affairs managers, scientific and medical affairs managers in innovative small and medium-sized enterprises and in highly specialized divisions of larger operators; regulatory affairs managers and experts working in life science sectors (biotechnology, medical devices and pharmaceuticals) Cont. Summary - The released by the European Commission Consultation Paper and Proposal for Regulation on Advanced Therapies aim to bridge the regulatory gap existing in the EU in fields like gene therapy, somatic cell therapy, and human tissue engineering by establishing a single, integrated and tailored regulatory framework for authorization, supervision and post-authorization vigilance of medicinal products used in advanced therapies. The proposal should take into account their scientific and technical characteristics, as well as the specificities of the economic operators concerned. Advanced therapy products produced on an ad-hoc, one-off basis, according to a specific and unique manufacturing process, for the single treatment of an individual patient are excluded from the scope of the Regulation. At that stage, tissue engineered products derived exclusively from animal cells or tissues are also excluded from the proposal. Animal tissues and cells used in the manufacturing process and present, even when detected only in trace amounts and without being viable are not excluded from the Regulation. A compulsory, "centralized marketing authorization procedure" is introduced to all advanced therapy products to ensure for them direct and effective operation on the global EU biotechnology market. The scientific evaluation shall be carried out by the Committee for Advanced Therapies (CAT) in close cooperation with, and under the general supervision, of the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA). Interested parties, such as patient associations, medical practitioners, surgeons or scientists shall be represented at the CAT. It is foreseen certain type and amount of quality-related, pre-clinical and clinical data necessary to demonstrate the quality, safety and efficacy of the advanced therapy products to be modified (for human tissue engineered products), complemented (for human tissue engineered products) or drown up on ad-hoc basis (for Good Manufacturing Practice, GMP and Good Clinical Practice, GCP). In cases when advanced therapy products are integral parts of medical devices, the 'medical device' part should meet the EU essential requirements but CE-marking will be not necessary. A suitable risk management system and a system allowing complete traceability of the patient, the product and its starting materials should be in place and under essential responsibility of the Marketing Authorization Holder. Companies developing advanced therapies will gain a number of benefits like: direct access to the global EU market, harmonized data protection period (10 years), possibility to get an orphan medicinal product designation (with 10 years market exclusivity), access to an accelerated ("fast-track") assessment procedure, an option to get conditional marketing authorization, a 90% fee reduction for the provision of EMEA scientific advice. Specific provisions for small and medium-sized enterprises will allow them to get significant fee reductions for scientific advice and inspections, deferral of the fee for marketing authorization application until the end of the procedure and special administrative assistance from EMEA. Status/Enforcement: Released for consultation with the interested parties till June 20, 2005. Link to the original document 1 | Link to original document 2 Updated on May 12, 2005 How HMPC Will Work on EU Herbal Draft List and Monographs Impacts on pharma industry The documents published by the HMPC make transparent the way that the European Community herbal monographs and the draft list of herbal substances, preparations and combinations thereof will be elaborated in the EU. The documents are useful for companies intending to keep the status of their products as medicines on the EU market. They contain important information for the herbal industry in and outside Europe, planning to penetrate the EU market thought the newly adopted abridged traditional herbal medicinal products authorization procedure. Commented on May 13, 2005 Published by EMEA/EC: May 12, 2005 Document: The following documents were adopted by the Committee on Herbal Medicinal Products (HMPC) in March 2005: 1. "Consultation Paper on Human Tissue Engineering and Beyond: Proposal for a Community Regulatory Framework on Advanced Therapies" 2. "Human Tissue Engineering and Beyond: Proposal for a Community Regulatory Framework on Advanced Therapies" 3. "Structure of the List of Herbal Substances, Preparations and Combinations Thereof" 4. "Guideline on the Documentation to Be Submitted for Inclusion into the List of Herbal Substances, Preparations and Combinations Thereof". Targeted professionals: producers of herbal / traditional herbal medicinal products / homeopathic medicinal products and food supplements, regulatory affairs and product development managers dealing with pharmaceuticals and food supplements based on plants, herbalists and botanical scientists Cont. Summary - According to Article 16h (a) and (b) and Article 16f (1) of the European Union (EU) Directive 2004/24/EC, the Committee on Herbal Medicinal Products (HMPC) at the European Medicines Agency (EMEA) shall establish European Community (EC) herbal monographs and prepare a draft list of herbal substances, preparations and combinations thereof. In January and March 2005, the HMPC discussed and later adopted series of documents aiming to provide details and clarifications on the content of these documents and the procedures related to their preparation. The Community herbal monograph should follow the structure of the Summary of Product Characteristics (SPC) of the EU. The monograph should be read in conjunction with the "SOP on Establishing Community Monograph for Herbal Medicinal Products", which will be published at a later stage. The template of the monograph shall be divided into two parts to enable the individual finished herbal medicines to keep their status in the EU either as medicinal products with well-established medicinal use or as traditional herbal medicinal product for use in specified indication(s) exclusively based upon long-standing use (at least 15 years in the EU). A separate document is published to present the timetable proposed by the HMPC for elaboration of Community herbal monographs. Detailed description of the steps and timeline preview (around 12 months) for establishing the herbal monographs is also provided. Details on the herbal monographs resulting from referral procedures (where i.e. a product has been used in the EU for less than 15 years, but is otherwise eligible for simplified registration as traditional herbal medicinal product), will be published on a later stage. The HMPC proposes in a separate document the structure of the EU draft list of herbal substances, preparations and combinations thereof. The list shall be divided into two parts: scientific content and administrative data. Among the issues requested by the HMPC to be included in the scientific content is a reference to European Pharmacopoeia (Ph. Eur.) monograph (if exists) or a reference to another Pharmacopoeia. Data on traditional medicinal use (indication) and on type of tradition (e.g. Chinese, Indian, where relevant) are also requested. The HMPC prepared as well a separate paper guiding the applicant on the documentation that shall be submitted for inclusion of a herbal substance or preparation into the EU draft list. When the scientific name of the plant should be precised, a reference to a Pharmacopoeia in the following order of priority should be provided: official monograph Ph. Eur., official national Pharmacopoeia, other Pharmacopoeia, Index Kewensis. Other guidance documents are expected to be developed by the HMPC on a later stage. The HMPC will determine what is considered as appropriate information to demonstrate "traditional use" and "plausibility of pharmacological effects and efficacy on the basis of long-standing use and experience", as defined in the existing Law. Status/Enforcement: Released for consultation with the interested parties with deadline for comments August 15, 2005. Link to the original document 1 | Link to the original document 2 Link to the original document 3 | Link to the original document 4 Updated on May 15, 2005 How HMPC Will Appoint Experts and Offer Expert Advice Impacts on pharma industry The HMPC expert advice and opinion could be a valuable tool for companies intending to market plant products in the EU or beyond. Details on how the experts will be appointed at the HMPC and how companies could request expert advice provided by the Committee are important for the industry. The information provided in the documents published by the HMPC would guarantee involvement of the most appropriate EU national experts at the Committee and would encourage the best usage of their knowledge and expertise in the assessment process. Commented on May 13, 2005 Published by EMEA/EC: May 12, 2005 Document: In January 2005 the Committee on Herbal Medicinal Products (HMPC) at the European Medicines Agency (EMEA) discussed and in March 2005 adopted two documents: 1. "Template for Submission of a Request for Expert Advice on Herbal Medicinal Products" 2. "Procedure for the Appointment by the HMPC of a Rapporteur Responsible in the Simplified Procedure for: - the Evaluation of a Proposal for Inclusion in the List of Herbal Substances, Preparations and Combinations Thereof; - The Development of a Community Herbal Monograph". Targeted professionals: producers of herbal / traditional herbal medicinal products / homeopathic medicinal products and food supplements, regulatory affairs and product development managers dealing with pharmaceuticals and food supplements based on plants, herbalists and botanical scientists Summary - The two documents adopted by the Committee on Herbal Medicinal Products (HMPC) at the European Medicines Agency (EMEA) are aimed to give details on how to request expert advice provided by the Committee and how HMPC shall appoint rapporteurs in the development of European Community (EC) herbal monographs and draft list of herbal substances, preparations and combinations thereof. The Template for Submission of a Request for Expert Advice specifies a range of documents that a company or organization should submit to prepare the HMPC for the advice. The following is mentioned as documental support: investigator's brochure, briefing document, monograph, scientific references, and pharmacopoeia monograph. The specific questions on quality, safety or efficacy matters that need to be addressed by the HMPC should also be precised in the request form. In a separate document, the HMPC describes the procedure for appointment of a Rapporteur responsible for preparation of European Union (EU) herbal draft list and monographs. Information is provided on the mechanisms of appointments, the criteria used for that and the procedural aspects related to this process. In principle all HMPC members, co-opted members and alternates could express interest to be appointed as rapporteurs. The request should be formally submitted by the Member State regulatory authority / Medicines Agency. The final appointment is made on the basis of objective criteria, which will allow the use of the best available expertise in the EU on the relevant scientific area. Past experience in the assessment of relevant herbal substance class and the Member States delegations workload are duly taken into account. Sometimes the appointment may take into consideration other factors such as, the distribution of Rapporteurships between delegations. At the end, the final appointment depends on the discretion of the HMPC's Chairman. Status/Enforcement: Released for consultation with the interested parties with deadline for comments August 15, 2005. Link to the original document 1 | Link to the original document 2 Updated on May 13, 2005 EU view on Herbals Containing Capsicum / Capsaicin, Asarone, Pulegone and Menthofuran Impacts on pharma industry The HMPC Public Statements on Capsicum/Capsaicin, Asarone, Pulegone and Menthofuran will influence the decision making process and related procedures in the marketing authorization process of herbal medicines not only in the EU but worldwide. In view of safety concerns the industry may be requested to make supplementary investments in re-doing some scientific tests and in performing supplementary new studies and trials. There is also a risk of limiting or reconsidering by the regulators of some indication(s) / field(s) of applications of herbal products containing Capsicum / Capsaicin, Asarone, Pulegone and Menthofuran until a full benefit/risk assessment has been carried out. Commented on May 17, 2005 Published by EMEA/EC: May 12, 2005 Document: The following documents were adopted by the Committee on Herbal Medicinal Products (HMPC) on April 25, 2005: 1. "Public Statement on Capsicum / Capsaicin Containing Herbal Medicinal Products" 2. "Public Statement on the Use of Herbal Medicinal Products Containing Asarone" 3. "Public Statement on the Use of Herbal Medicinal Products Containing Pulegone and Menthofuran". Targeted professionals: producers of herbal / traditional herbal medicinal products / homeopathic medicinal products and food supplements, regulatory affairs managers and experts in pharmacovigilance dealing with pharmaceuticals and food supplements based on plants Summary - The three Public Statements released by the Committee on Herbal Medicinal Products (HMPC) at the European Medicines Agency (EMEA) focus on the pharmacovigilance issues of the herbal substances, preparations and combinations thereof. Based on the available data, no pharmacovigilance action was recommended at this time by the HMPC in relation to herbal medicinal products containing Capsicum / Capsaicin. The existing pharmacovigilance data for authorized herbal medicinal products containing Capsicum and/or Capsaicin differ considerably from EU Member State to Member State due to the variations in the regulatory requirements for herbal medicinal products and the placement on the market of many herbal products available without a product authorization or under the status of food supplements. This is likely a function of under-reporting in some countries as well. The HMPC conclusion was that the existing data are inadequate to establish any real risk associated with herbal medicinal products containing Capsicum/Capsaicin for oral use. According to the HMPC the rhizomes of Asarone calamus are worldwide and extensively used as constituent(s) in traditional herbal medicinal products. Reported indications include: stomach cramps, dysentery, asthma, anti-helmintic, insecticide, tonic, stimulant. In view of the toxicity of beta-asarones, the HMPC concluded that beta-asarones concentration in herbal medicinal products should be reduced to minimum and diploid varieties should always be preferred. In analogy with the food regulation a limit of exposure from herbal medicinal products of approximately 115 μg/day, i.e. about 2 μg/kg b.w./day was accepted temporarily until a full benefit/risk assessment has been carried out. No immediate regulatory actions were proposed with regard to Pulegone and Menthofuran. According to the HMPC the use of penny royal oil should be discouraged. The HMPC alerted on pharmacovigilance towards peppermint oil and mint oil containing products and recommended increased awareness of health professionals concerning high intake of products containing peppermint oil and/or mint oil as a potential cause of liver reactions. The view of the HMPC was that the monograph for mint oil of the European Pharmacopoeia should introduce a limit for Menthofuran. Similar measures should be taken into consideration to other herbal products containing significant amounts of Pulegone and Menthofuran. Status/Enforcement: The deadline given for comments is June 30, 2005. The re-discussion of the document is anticipated in July 2005. Link to the original document 1 Link to the original document 2 Link to the original document 3 Updated on May 24, 2005 EU View on Allergic Potency of Chamomilla and Soya or Peanut Protein Impacts on pharma industry The HMPC Public Statements on Chamomilla, and Soya and Peanut Protein intends to make more caution the regulators and consumers/patients on the allergic potency of these plants. The inclusion in the package leaflet of warning text about contraindications and side effects of soya or peanut proteins risks to damage consumer's confidence and to discourage users' preferences towards these types of products. For safety concerns, the industry may be requested to perform supplementary studies and trials to justify lack of allergic capacity of products containing soya or peanut proteins. Commented on May 17, 2005 Published by EMEA/EC: May 12, 2005 Document: The following documents were adopted by the Committee on Herbal Medicinal Products (HMPC) on April 25, 2005: 1. "Public Statement on Chamomilla Containing Herbal Medicinal Products" 2. "Public Statement on the Allergenic Potency of Herbal Medicinal Products Containing Soya or Peanut Protein". Targeted professionals: producers of herbal / traditional herbal medicinal products / homeopathic medicinal products and food supplements, regulatory affairs managers and experts in pharmacovigilance dealing with pharmaceuticals and food supplements based on plants Summary - The two Public Statements released by the Committee on Herbal Medicinal Products (HMPC) at the European Medicines Agency (EMEA) address the allergic potential of the herbal substances, preparations and combinations thereof. Following a consultation with the EMEA pharmacovigilance Working Party, the HMPC decided to propose an amendment of the labeling of herbal medicinal products containing Chamomilla recutita. Section 4.8 Undesirable effects of the Summary of Product Characteristics (SPC) shall be amended to read: "Hypersensitivity reactions to (German) chamomile (e.g. contact dermatitis) are very rare. Some cases of anaphylactic shock or asthma have been reported. Cross reactions may occur even in people with allergy to compositae (e.g. artemisia/mugwort)". The references that support this statement are mostly originating from German scientific sources. In a Public Statement on the allergenic potency of herbal medicinal products containing soya or peanut proteins the HMPC provide clarification and guidance to the regulators as to what extend the adverse reactions to soya and peanut products should be defined as allergic. According to the HMPC, allergy should be suspected in case of type I reactions reported after intravenous infusion of major quantities of soya oil, soya and peanut products and skin rashes observed after use of soya oil /arachis oil baths. The HMPC view is that since no safe threshold for the exposition to topical oil preparations can be defined and data point to the possibility of allergy induction due to the use of oil containing ointments in infants, all medications for topical use containing soya or peanut products should be treated as allergenic. Appropriate labeling and warnings irrespective of the protein content should be considered, especially for soya and peanut containing medications used in children. Statements on cross-reactions and contra-indications for patients with known allergies to other plants should also be included. Different type of statements to alert the user about the possible contraindications and side effects of parenteral, oral or topical application of arachis oil, peanut oil, soya oil, soya lecithin are listed in a table attached to the document. These formulations shall be included in the package leaflet of herbal medicinal products containing soya or peanut protein. Status/Enforcement: The deadline given for comments is June 30, 2005, as the re-discussion on the documents is scheduled for July 2005. Link to the original document 1 | Link to the original document 2 Updated on May 24, 2005 Post-menopausal Osteoporosis Guidance to Be Revised Impacts on pharma industry The CHMP Recommendation is calling for a re-evaluation of key determinants that are important for designing concept and criteria of clinical studies performed in postmenopausal women. The intention of the CHMP to include in the population analyses postmenopausal women not fulfilling the WHO operational definition of osteoporosis but presenting with a high risk of experiencing future fractures is of benefit to the industry. The intention of CHMP to introduce in the document a Chapter describing the minimal requirements for granting a marketing indication for treatment of osteoporosis in males is also rather important for the companies. Commented on May 18, 2005 Published by EMEA/EC: May 18, 2005 Document: The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) published the "Recommendation on the Need for Revision of CHMP Note for Guidance on Post-menopausal Osteoporosis in Women". Targeted professionals: clinical trials planners/managers, research and product development, scientific, medical affairs and regulatory affairs managers Summary - The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) announced that the EU "Note for Guidance on Postmenopausal Osteoporosis in Women" issued on January 25, 2001, would need revision. The Committee's recommendation is based on the new data, coming from well designed epidemiological trials, as well as from randomized, prospective, placebo-controlled studies and meta analyses. According to the CHMP several key issues would need re-evaluation. It would be more worthwhile instead of, or in addition to, the indication "prevention of osteoporosis", to include an indication targeting postmenopausal women not fulfilling the World Health Organization's operational definition of osteoporosis but presenting with a high risk of experiencing future fractures. Semi-quantitative diagnostic procedures could be mentioned among the assessment criteria for efficacy. The duration of randomized treatment in pivotal studies showing antifracture activity could be shorter than the current recommendation of "at least 3 years". The requirement of separate demonstration of "vertebral, hip, and other fractures", or the acceptance of "vertebral" versus "all non-vertebral" fractures, should be re-discussed. It seems possible a new Chapter to be included in the new guidance. The Chapter shall describe the minimal requirements for granting a Marketing Authorization for treatment of osteoporosis in males. Status/Enforcement: The CHMP Recommendation will serve as a basis for a draft revised guideline which very probably will be issued by the CHMP in October 2005. Afterwards the draft will be released for external consultation and finalized within 6 months. Link to the original document Updated on May 18, 2005 EMEA Finalizes New Procedure for EU Pharmaceutical Guidelines Impacts on pharma industry The long-overdue streamlining of the terminology and disclosure of the EMEA guidelines procedure are expected to benefit the pharma industry bidirectionally. Upon implementation, the higher clarity in the legal and scientific binding of the guidelines should provide a rationale in the planning and development of new products. The increased transparency should better position the industry in submitting opinion, suggesting modifications or objecting requirements. Commented on July 1, 2005 Published by EMEA/EC: June 20 and June 30, 2005 Document: The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) published on June 20 and June 30, 2005 respectively, two documents entitled: 1. "Procedure for European Union Guidelines and Related Documents within the Pharmaceutical Legislative Framework" 2. "Press release: European Medicines Agency finalises new procedure for EU pharmaceutical guidelines" Targeted professionals: product developers, business development and regulatory affairs managers, scientific and medical affairs managers; regulatory affairs managers and experts working in life science sectors (biotechnology, medical devices and pharmaceuticals) Cont. Summary - The released documents on the procedures for development, consultation, finalization and implementation of EMEA guidelines is an important step in line of the EMEA Transparency policy, and the findings of the CPMP audit conducted in 2003. It has been widely acknowledge that the current guideline procedures are inconsistent - most importantly to other non-EMEA guidelines within EU pharmaceutical regulations. As the most telling example is cited the present - and rather confusing, especially outside EU, practice to interchangeable use "guideline" and "guidance", as now only the former is favored for future use. Next to the elucidation of the pathways from initiation to the completion of new guidelines is the clarification of the non-binding power of the adopted guidelines and their positioning to the binding EU documents (Directives, Decisions, etc.). Upon entering into effect, the EMEA shall recognize 13 types of guidelines as follow: Regulatory Guidelines; Scientific Guidelines related to Quality, Safety and Efficacy; Good Manufacturing Practice (GMP) Guidelines; Maximum Residue Limits Guidelines; Pharmacovigilance Guidelines; Good Clinical Practice (GCP) and conduct of clinical trial Guidelines; Orphan Medicinal Products Designation Guidelines; Herbal medicinal products Guidelines; Good Distribution Practice (GDP) Guidelines; Good Laboratory Practice (GLP) Guidelines; European Directorate for the Quality of Medicines (EDQM)5 and the European Pharmacopoeia; Other technical and procedural EMEA guidelines; and Other related Community documents prepared/published by EMEA (Public statements, Reflection Papers, Questions and Answer documents, and Compilation of Community Procedures on Inspections and Exchange of Information). Status/Enforcement: Coming into operation on September 1, 2005. Link to the original document 1 | Link to the original document 2 Updated on August 18, 2005 EMEA Concludes Action on COX-2 Inhibitors Impacts on pharma industry The finalized opinion on the cardiovascular safety of COX-2 inhibitors is expected to produce a dual impact on the industry. The Marketing Authorization Holders shall be required to more vigorously collect, analyze and announce appropriate findings and observations during the postmarketing period. Developers of new products from the same class should plan more comprehensive pharmacological and clinical assessment of the investigational COX-2 inhibitors. All together will results in a considerable increase of the development expenditures, regulatory hurdles and marketing restrictions. The repercussion on the larger NSAID segment is predicted to be much more severe. Commented on July 7, 2005 Published by EMEA/EC: June 27, 2005 Document: The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) published on June 27, 2005 two Press Releases entitled: 3. "European Medicines Agency concludes action on COX-2 inhibitors" 4. "Questions and Answers on COX-2 Inhibitors" Targeted professionals: experts in pharmacovigilance, regulatory affairs managers, clinical trials planners/managers, medical representatives, research and product development, scientific and medical affairs managers Summary - The conclusive opinion of EMEA review marks the end of the first round of Europe-wide re-evaluation of the whole NSAID (non-steroidal anti-inflammatory drugs) class, whose safety profile will from now also be examined. Initially, the review was prompted in November 2004 by the reports cardio-vascular toxicity, resulted in the suspension of Bextra and was widened in April to include skin adverse events. The opinion upholds the suspension of valdecoxib for at least one more year, after that the Marketing Authorization Holder (Pfizer) can summit additional data in an attempt to regain the Marketing Authorization for Bextra. All marketed drugs based on 5 active compounds (celecoxib, etoricoxib, lumiracoxib, parecoxib and valdecoxib) have been reviewed as the medicinal products based on the first four compounds could be marketed with new warnings and contraindications related to serious cardiovascular and skin reactions. A sixth compound - lumiracoxib has been authorized only in one Member State (UK), however not yet on the market and hence exempted from the EMEA review. COX-2 inhibitors belong to the NSAID pharmacological class - a large and heterogeneous group containing products having nothing in common aside from being non-steroidal. While not expected initially to exert the NSAID-associated gastro-intestinal toxicity and actively developed by the industry, the present regulatory ruling may limit not only their current therapeutic use, but any future product development as well. Status/Enforcement: The finalized opinion of EMEA is to be sent to the European Commission in order to be enforced as a decision. Link to the original document 1 | Link to the original document 2 Updated on August 18, 2005 EU Pharma IMPACTS January-June 2005 EUP_I_001 - 3 -