August 2010

In this issue:

New guidance on setting specifications for related impurities in antibiotics

A Guideline on setting specifications for related impurities in antibiotics (Draft) has been released. Antibiotics can be manufactured via three mechanisms: chemical synthesis, fermentation or fermentation followed by one or more synthetic steps (semi-synthesis). At present, there is no guideline for setting specifications for product-related impurities in fermentation products or semi-synthetic substances. Case-by-case setting of specifications for related impurities has lead to inconsistencies, as different impurity thresholds have been set for the same class of antibiotic. This draft guideline is intended to address this problem.

The scope of this guideline is to provide guidance for marketing authorisation applications (MAA) and for variations, rather than for investigational medicinal products for clinical trials. It provides thresholds for reporting, identification and qualification of related impurities, but does not cover residues from the fermentation process as these are covered by the Ph. Eur. general monograph "Products of fermentation". While this monograph does not apply directly to semi-synthetic substances, the guideline states that it should be used to justify the specification for the fermented starting material used in semi-synthetic substances.

Related impurities are defined as by-products, intermediates and degradation products of fermentation (and chemical synthesis steps for semi-synthetic substances). Non-related impurities should use the thresholds given by ICH Q3A.

Limits of related impurities in the drug substance should be set for:

Advice is given for the exceptional cases where identification of an individual impurity is not possible and also on how to handle very closely related peaks where it is not technically feasible to separate them fully.

For semi-synthetic substances, the thresholds given in ICH Q3A apply. If the product of semi-synthesis consists of a family of very closely related compounds, the thresholds for a family of related compounds of fermentation products should be followed (see below), but this must be justified. For single compounds produced by fermentation, the reporting threshold is set at 0.10%, while the identification and qualification thresholds are set at 0.15%. If the product of fermentation is a family of related compounds, the reporting threshold and identification thresholds are unchanged, but the qualification threshold is raised to 0.50%/0.15%. The qualification threshold of 0.50% pertains to structurally closely related compounds, while the qualification threshold of 0.15% covers other related compounds. HPLC and mass spectrometry or HPLC and diode-array detection must be used to determine which related compounds are structurally closely related and which are not.

Specific guidance is further given on the extent of characterisation, identification and qualification of impurities (including the need for non-clinical and clinical tests) for new active substances, known active substances which are not covered by a Ph. Eur. monograph and known active substances covered by a Ph. Eur. monograph (with and without a transparency statement and/or means of identification). Guidance is also given on which analytical procedures to use.

Specifications are also given for medicinal products as well as active substances. Specifications should be set for degradation products only, and not for impurities from manufacturing of the active substance. For medicinal products where the active substance is semi-synthetic, the thresholds are: 0.10% for reporting and 0.20% for identification and qualification. If the active substance is a single compound fermented product, the reporting threshold is 0.15%, while the identification and qualification thresholds remain at 0.20%. If the active substance is a family of compounds produced by fermentation, the qualification threshold is raised to 0.50%/0.20% for structurally closely related compounds and other related compounds, respectively.

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Procedural advice on combined ATMPs

Procedural advice on the consultation of Notified Bodies in accordance with Article 9 of Regulation (EC) No. 1394/2007 has been released by the Committee for Advanced Therapies (CAT). This procedural advice outlines how the European Medicines Agency (EMA) and the CAT will interact with Notified Bodies (NB) during the assessment of combined advanced therapy medicinal products (combined ATMPs; i.e. ATMPs which incorporate one or more medical devices), and provides details of possible scenarios and timelines for these interactions.

Applicants are strongly advised to consult with a NB prior to MAA submission, and this will be discussed at pre-submission meetings. The CAT can advise on which NB would be suitable for the device in question. Even if the results of assessment by a NB are included in the MAA dossier, the CAT may still decide that further consultation is necessary.

The applicant must identify an NB in the centralised MAA Application form, and must ensure that this NB is suitable for the device in question. If the results of an assessment by this NB are available, they must be included in Module 3, Section 3.2.R of the CTD, under the “medical device” section. The NB should ideally use the format and principles of the NBOG Guidance on Design - Dossier Examination and Report Content. Once the MAA is submitted, the CAT can request any further information related to the device component, and the applicant will be liable for the timely submission of this information. If the device is being manufactured by a separate legal entity, the applicant is responsible for ensuring that any necessary agreements for timely and continuous access to this data are in place.

If the results of the assessment of the device by the NB are not included in the MAA dossier, the CAT can decide to consult a NB of their choice on Day 1. The CAT will discuss the choice of NB with the applicant. The applicant will be informed of all correspondence between the CAT and the NB regarding their application, and will pay for all associated costs.

The CAT can also decide to consult with an NB on Day 80 of the MAA assessment procedure (if an NB has not yet been chosen, they will discuss the choice with the applicant). The list of questions (LoQ) for the NB will be drawn up, as well as a timetable for responding to this LoQ, which will be proposed by the CAT and agreed to by the applicant and the NB. If the response from the NB is not provided to the CAT by Day 120, the clock is stopped and will not restart until the responses are provided. If the responses provoke additional questions from the CAT, they may launch another consultation with the NB. As before, a LoQ and timetable will be drawn up and the LoQ will be given to the NB. If the response to this consultation has not been provided by Day 170, another clock stop can occur. The clock will not restart until the responses from the NB are provided.

After marketing authorisation is granted, the applicant must inform the CAT of any new data relating to the safety of the medical device(s) that may have an effect on the safety, efficacy or quality of the combined ATMP.

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New and updated position statements on CJD

CJD risk in plasma- and urine-derived products

The Position statement on CJD in plasma-derived and urine-derived medicinal products is undergoing revision to include the latest evidence concerning the risks of Creutzfeldt-Jakob disease (CJD) transmission associated with these products, and a draft is available for comment.

Since the last update to this position statement in 2004, four cases of apparent iatrogenic variant CJD (vCJD) infection have occurred following blood transfusions in the UK, providing strong evidence that vCJD can be transmitted through infected blood. In 2009, vCJD was detected in a haemophilia A patient who had received Factor VIII prepared from plasma sourced in the UK prior to 1998, confirming that plasma can also be infective. The existing position statement had assumed that vCJD would be transmissible by blood and plasma, and so the advice on the preparation of plasma-derived medicinal products has not been updated. However, recent animal studies have shown that low levels of infectious Transmissible Spongiform Encephalopathies (TSE) agents can be detected in the urine of scrapie-infected rodents, but at present, there is no epidemiological evidence of CJD transmission by urine-derived medicinal products. Nonetheless, it is advised that the manufacturing processes for urine-derived medicinal products contain at least one step that might be capable of reducing TSE infectivity and that the same exclusion criteria are applied (with respect to CJD and vCJD) for urine donors as for blood and plasma donors.

CJD risk for Advanced Therapies

A draft of a new Position statement on Creutzfeldt-Jakob disease and advanced therapy medicinal products has also been released. As ATMPs include components of human origin, there is a risk of vCJD transmission.

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Updated guidance for the quality of modified release oral dosage and transdermal dosage forms

A new Concept paper on the revision of the note for guidance on quality of modified release oral dosage forms and transdermal dosage forms: Section I (quality) has been released. The current guideline released in 2000 (CPMP/QWP/604/96) covers both modified release (MR) oral dosage forms and transdermal dosage forms, but will be revised to cover both of these areas in more depth.

In the context of MR oral dosage forms, the guideline will be updated to give more advice on the various topics, including:

The concept paper also outlines new topics to be discussed in the context of transdermal dosage forms. These include:

The deadline for comments on this concept paper is the 31st October 2010, with a revised draft of the complete guideline anticipated in Q1 2011.

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COMP gives advice on seeking orphan status

The Committee for Orphan Medicinal Products (COMP) has released a paper entitled Recommendation on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation. Drawing on experience of several hundred orphan applications they have received in recent years, the COMP outlines the level of evidence normally required to support arguments for the:

Guidance about how to support these arguments can also be found in a Commission Guideline (ENTR/6283/00) and in a communication from the Commission (2003/C 178/02 of 29 July 2003), and these should be read alongside this discussion paper.

In order to support the argument for medical plausibility, the paper highlights the importance of discussing the relevance of pre-clinical studies, especially as orphan applications are often made before clinical data has been collected. The use of an established in vivo model is recommended, as is direct comparison with existing products (if applicable), and a plan of future pre-clinical studies should also be presented. If any pre-clinical or clinical data exist for the product to treat other indications, this should also be presented briefly, though clearly differentiated from data relevant to the orphan indication. A summary of any important safety data gathered from pre-clinical and clinical studies (in the orphan indication and other indications) should also be included.

Arguments for significant benefit can be broken down into three broad categories:

  1. arguments based on the assumption of improved efficacy,
  2. arguments based on the assumption of improved safety, and
  3. arguments based on the assumption of a major contribution to patient care.

When making arguments for significant benefit in indications where an existing product is available, the product under development must be directly compared to the existing product. The strength of the argument for significant benefit will be considered based on the evidence available at the time of designation. The paper reminds applicants that existing authorised medicinal products for comparison are those that are considered to be satisfactory for the diagnosis, prevention or treatment of that indication, as authorisation is only granted if the benefit/risk assessment is positive. Methods for the prevention/treatment of a disease that are not subject to a marketing authorisation also count as satisfactory existing methods if there is scientific evidence to support the use and efficacy of these methods.

Arguments based on improved efficacy must provide pre-clinical or clinical data to support any theoretical benefit, with results of studies involving a direct comparison to existing treatments. If sufficient data are not available, data from exploratory studies or comparison with data available in the literature can be used. If the only available data come from a preliminary clinical study, then the COMP will bear in mind the limitations that apply to such data. If the pharmacological concept is sound and the pre-clinical data is compelling, then orphan status can be granted even if the preliminary clinical results are not conclusive.

Arguments based on improved safety must bear in mind that the full safety profile of a product can only be known after it has been on the market for several years. It is acceptable to present long-term safety data for the medicinal product when used to treat other indications. Theoretical safety concerns for which there are no documented occurrences of for an authorised medicinal product cannot be compared with a theoretical lack of risk in the product under development, and therefore may not be used to support the argument of significant benefit. Enhancing the quality of the product in compliance with the relevant guidelines also does not count as a basis for the assumption of significant benefit.

Arguments based on the assumption of a major contribution to patient care are generally made on the basis of more convenient modes of administration or improved availability of the product in the EU. The relevance of any alteration in mode of administration will be considered, and arguments for improved availability must be shown to offer potential significant benefit for patients in all Member States.

When it comes to filing a marketing authorisation application (MAA) for an orphan drug, arguments for significant benefit must be borne out by a critical review of the pre-clinical and clinical data. Most of these data should be generated form a direct comparison of the new and the authorised product during the clinical development phase, and sponsors are strongly advised to seek scientific advice to discuss how to generate these data.

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Developing Legislation and Guidance Update

Guidance documents adopted in the past month and Committee News:

EMEA/CHMP/SWP/150115/2006 - Reflection paper on non-clinical evaluation of drug-induced liver injury (DILI)
EMEA/CHMP/EWP/431734/2008 - Guideline on the clinical investigation of medicinal products for the treatment of attention deficit hyperactivity disorder (ADHD)
EMA/CHMP/EWP/12575/2010 - Overview of comments received on 'Guideline on the clinical investigation of medicinal products for the treatment of attention deficit hyperactivity disorder (ADHD)'
EMA/618604/2008 Rev. 2 - Questions & Answers: Positions on specific questions addressed to the EWP therapeutic subgroup on Pharmacokinetics
EMA/CHMP/ICH/604661/2009 - ICH topic E7 Studies in Support of Special Populations: Geriatrics Questions and Answers
EMA/CHMP/SWP/81714/2010 - Questions and answers on the withdrawal of the 'Note for guidance on single dose toxicity'
EMA/CHMP/BPWP/94033/2007 rev. 2 - Guideline on the clinical investigation of human normal immunoglobulin for intravenous administration (IVIg)
EMA/CHMP/BPWP/604687/2009 - Overview of comments received on the guideline on the clinical investigation of human normal immunoglobulin for intravenous administration (IVIg)
CHMP/EWP/430004/10 & CHMP/EWP/430144/10 - Clinical efficacy and safety: Radiopharmaceuticals and Diagnostic Agents
EMA/611366/2009 - Overview of comments received on 'Guideline on Clinical Investigation of Medicinal Products in the treatment of epileptic disorders' (CHMP/EWP/566/98 Rev.2)
EMA/CHMP/476111/2010 - Committee for Medicinal Products for Human Use (CHMP) - July 2010 plenary meeting monthly report
EMA/CAT/407854/2010 - Committee for Advanced Therapies (CAT) - July 2010 meeting monthly report
EMA/CHMP/310263/2010 - Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP)
EMA/COMP/364048/2010 Corr. - Committee for Orphan Medicinal Products (COMP) - July 2010 plenary meeting monthly report
EMA/PDCO/451774/2010 - Meeting highlights from the Paediatric Committee
EMA/170165/2010 - European Medicines Agency communication on (emerging) safety related issues for medicines for human use
EMA/502619/2010 - Medicinal products for human use: Monthly figures - July 2010
Q&A: Good Manufacturing Practice (GMP) updated.
CMDh/094/2003/Rev9 - CMDh Best Practice Guides for the Submission and Processing of Variations in the Mutual Recognition Procedure
CMDh Recommendation for classification of unforeseen variations according to Article 5 of Commission Regulation (EC) No 1234/2008
EMA/62345/2010-Rev.1 - Centralised procedures and MRL procedures Recommended submission dates for new and extension applications.
EMA/CHMP/VWP/141697/2009 - Committee for Medicinal Product for Human Use (CHMP) Guideline on quality, non-clinical and clinical aspects of live recombinant viral vectored vaccines
EMA/INS/GCP/454280/2010 - Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials
EMA/CAT/450145/2009 - Mandate, objectives and rules of procedure for the CAT Cell-based Products Temporary Working Party (CPWP)
EMA/CAT/422310/2009 - Work plan for the Cell-based products working party 2010

Guidance documents released for consultation in the past month:

EMA/CHMP/SWP/44609/2010 - Questions and answers on 'Guideline on the environmental risk assessment of medicinal products for human use' (Draft)
EMA/CHMP/SWP/336670/2010 - Question and answers on the 'Note for guidance on photosafety testing' (Draft)

For more information on any of the topics mentioned in this newsletter, please email .