Univ.-Doz. Dr. Bernhard Fischer, MBA P.O. Box 4, A-1097 Vienna, Austria Phone: +43-(0)664-1432919 Fax: +43-(0)664-1477280 Mail: biotechconsulting@aon.at URL: www.biotechnologyconsulting.eu Regulatory Affairs News Scientific Advice and Protocol Assistance at the EMEA Protocol Assistance Once a company has received the European Commission decision on the designation of Orphan Drug status, the sponsor of an orphan medicinal product is entitled to request Protocol Assistance prior to the submission of an application for Marketing Authorisation. The procedure for provision of Protocol Assistance will follow mainly the procedure for provision of Scientific Advice. The Scientific Advice Working Party (SAWP) will be in charge of Protocol Assistance regarding scientific issues. Protocol Assistance provided to sponsors will be the result of collegial work from the SAWP, its experts, the different Working Parties, the COMP, the CHMP and the EMEA Secretariat. Similar to the Scientific Advice request, the request for Protocol Assistance should contain prospective questions concerning quality (manufacturing, chemical, pharmaceutical and biological testing), non-clinical (toxicological and pharmacological tests) and clinical aspects (studies in human subjects in either patients or healthy volunteers, including clinical pharmacological trials designed to determine the efficacy and safety of the product for pre or post-authorisation activities) relating to the proposed future development of the orphan medicinal product within the scope of the designated indication. Also questions related to the demonstration of one of the designation criteria (significant benefit) for the maintenance of Orphan Status may be raised. Regulatory aspects should be the matter of a separate request. Regulatory and administrative questions will be answered by the EMEA Secretariat directly during a Protocol Assistance Presubmission Meeting if requested. Protocol Assistance Presubmission Meeting The Scientific Advice or Protocol Assistance is restricted to scientific issues. Purely regulatory aspects should, therefore, be dealt with separately at the time of a Scientific Advice or Protocol Assistance Presubmission Meeting if requested. A Presubmission Meeting for Scientific Advice or for Protocol Assistance is requested at time of submission of the letter of intent. The EMEA emphasises the importance of Scientific Advice or Protocol Assistance Presubmission Meetings with companies, especially for first users of these procedures, for SMEs, for broad and more general advice on specific types of medicinal products and therapies.
Presubmission Meetings are an opportunity for companies to: introduce and receive feedback on their proposed development programme from Coordinators and EMEA staff, receive feedback on the list of questions to be included in the request for Scientific Advice with a view to obtaining satisfactory answers (i.e. content and scope of questions; and structure of the request), identify additional issues to be included in the request for Scientific Advice, obtain more detailed information concerning the procedure for obtaining Scientific Advice/Protocol Assistance (see timetable), ask regulatory questions, which are outside the scope of Scientific Advice (e.g. legal basis for submission, GCP/GLP/GMP related questions3, format of Marketing Authorisation Application and Common Technical Document etc.), enable companies to establish contact with the Co-ordinators and EMEA staff closely involved with the application as it proceeds. The Presubmission Meeting will also allow identification of additional expertise to be involved at an earlier stage in the procedure. A letter of intent including a request for a Presubmission Meeting should be sent by email to the EMEA approximately 8 weeks in advance of the anticipated start of the procedure. Once a meeting date is agreed companies will then be requested to send the relevant background information containing the draft Scientific Advice or Protocol Assistance request. These should be sent to at least 10 working days before the anticipated meeting to EMEA. Appointed SAWP Coordinator(s), EMEA Scientific Advice Administrators, Product Team Leaders/Members and Regulatory Affairs Administrators will participate in the meeting. There is no fee involved in this activity. Procedure of Request A Scientific Advice administrator and SAWP Co-ordinators will be appointed at the planning phase. The Scientific Advice administrator will be the contact person for the company during the presubmision/planning and the validation phases. The Scientific Advice administrator will also be in charge of managing the Scientific Advice or Protocol Assistance procedure and will be the contact point for companies for any questions related to planned/ongoing procedures. If a Presubmission Meeting is requested, applicants should submit a draft version of the request (i.e. Letter of intent and, Briefing document including Questions/Company s position as well as a detailed Table of Contents) in electronic MS Word format, ahead of the Presubmission Meeting to EMEA. Any documentation mentioned in the Table of Contents may be requested from the company by the Scientific Advice administrator. A List of Page 2 of 10
Comments (LoC) will be forwarded from the EMEA to the company in writing after the meeting. The complete final request will be validated by the Scientific Advice administrator. Once the request has been validated, the complete final request should be forwarded to the EMEA in 1 unbound copy (in ring binder) and 5 full electronic copies on CD-Roms. At least the Cover letter, the briefing document including the question(s)/company s position(s) and the table of contents should be submitted in these final sets in MS Word format, the Annexes and References can be either MS Word or PDF documents. Timing of request The EMEA Secretariat should be formally notified of the intent to submit a Scientific Advice or Protocol Assistance request. If a Scientific Advice or Protocol Assistance Presubmission Meeting is requested with the letter of intent, the deadline is approximately 2 months before the start of the procedure. If no Presubmission Meeting is requested the deadline for submitting the letter of intent is approximately 1 month. In case of a parallel advice with the FDA the request must be sent in well in advance i.e. more than two months before the start of the procedure. Structure of request The request should be presented as follows: 1. Letter of intent The letter of intent submitted at time of notification will be attached to the request for Scientific Advice or Protocol Assistance. This letter form should be kept in MS Word format. 2. Table of contents of the request 3. Briefing document including the Questions and Company's positions The Briefing document is the most important section of the request. The review of the Scientific Advice or Protocol Assistance request by the SAWP will primarily be based on the questions and company s positions presented by the Applicant in the briefing document. The following should also be provided in an introductory section: background information about the product, the intended indication(s) planned to be supported by the development programme, the worldwide regulatory status of the product [e.g. Marketing authorisation(s), planned submision(s) timelines], the stage of development (pharmaceutical, non-clinical, clinical) and in particular the stage(s) of clinical studie(s) proposed (completed, ongoing, planned). Where applicable, a short overview table listing (non)clinical data requirements. Page 3 of 10
The questions are ordered and numbered sequentially to address scientific issues (order: quality/biotech/non-clinical/clinical issues/significant benefit). Multidisciplinary questions should be labelled accordingly. Each question is followed by a separate company s position including a justification(s) of the company s strategy for each topic. The company s position should include all relevant information about the topic. Cross-references to the relevant parts of the annexes can be included if needed. 4. Annexes include e.g.: Background information (Product Profile if available, Investigators Brochure) Information relating to the questions (e.g. relevant study protocols as detailed as possible or draft study protocol or study outlines) Bibliographical data (references: a list of all references and full versions of the most relevant ones.) Content of previous Scientific Advice received (national EU Authorities, other relevant International authorities, e.g. FDA) Relevant guidelines (other than CHMP Guidance documents) Contract agreement when the request is submitted by a consultant/cro on behalf of the company Discussion Meeting At D+30 of the procedure the SAWP will discuss the Co-ordinators' first reports. It will be decided at this stage, whether to invite the company for a Discussion Meeting. For Scientific Advice and Protocol Assistance, the company may mention its preference for having a Discussion Meeting in the letter of intent. However, the decision to invite the company will be made by the SAWP on a case-by-case basis following the identification of the issues, which need to be discussed by the company. In case of SAWP s disagreement with the company s development plans, the company will be invited to a discussion meeting. For Protocol Assistance, the sponsor will be invited to a Discussion Meeting in the majority of cases. When the need for a Discussion Meeting is agreed by the SAWP, the Co-ordinators and other SAWP members may nominate experts to participate in the meeting including patients representatives. In addition, the meeting will be open to all SAWP members. A detailed list of issues to be addressed by the company during the Discussion Meeting will be adopted (D+30) and sent to the company following the SAWP meeting, together with the invitation and the meeting agenda. The list of issues is divided in two categories: Issues to be addressed during the Discussion meeting Issues to be addressed in writing by the company prior to the Discussion meeting Page 4 of 10
The company may also propose additional points for discussion at the meeting. These must strictly relate to the topics initially raised in the request submitted. Additional points should be forwarded in writing to the EMEA secretariat to the attention of the Scientific Administrator. Furthermore, if upon receipt of the list of issues, the company intends to present at the Discussion Meeting major amendments to the development initially proposed, a document summarising the main changes of the quality/non-clinical/clinical development programme should be provided to the EMEA at least one week in advance of the meeting. The Discussion meeting will take place at the EMEA at D+60 during the SAWP meetings. The company will be informed of the exact timing 15 days before the Discussion meeting. Fee reduction Orphan medicinal products designated in accordance with Article 5 of Regulation (EC) No 141/2000, are eligible for fee reductions for all fees payable under Community rules pursuant to Regulation (EEC) No 2309/93. This includes, among others, fees for Protocol Assistance. Sponsors of orphan medicinal products wishing to have a fee reduction should send a notification letter to the EMEA. The notification letter for fee reduction for Protocol Assistance should be submitted as early as possible, at least 2 weeks in advance of the request. The submission of a letter of intent to obtain a fee reduction for an Orphan Medicinal Product should be sent to the EMEA. The letter should include the following information: Name of the medicinal product as designated Name of the sponsor, with its contact details (telephone; fax; e-mail) Orphan indication EU Designation Number EMEA-SME Number (if applicable) A copy of the Decision on designation (in English) should be attached to all fee reduction requests. Depending on the nature of the application concerning the Orphan Medicinal Product, the following additional information should be provided: For Protocol Assistance: Scope of request for protocol assistance Planned submission date of request for protocol assistance All Requests should be sent by letter to the EMEA The EMEA will check the letter of intent, particularly that the applicant and the sponsor of the designation are identical and will only send an acknowledgement of receipt, via fax or e-mail. Page 5 of 10
Tabulated Summary of the Procedure Planning Phase ~ Well in advance (<< ~ D -60) ~ D -60 ~ D -60 to Date of Presubmission Meeting Date of Pre-submission meeting ~ D -10 ~ D -5 Evaluation phase D 0 Action FDA Parallel Advice Applicable if Parallel Advice with the FDA will be requested and agreed by SAWP Letter of intent sent in by Company Appointment of coordinators The company submits a letter of intent for SA or PA requests to the EMEA Secretariat. The letter of intent is forwarded by the EMEA Secretariat to the SAWP for appointment of 2 coordinators and, where appropriate, a third coordinator for questions relating to significant benefit (only applicable for PA). Organisation of Pre-submission meeting Submission of the SA or PA request. EMEA appoints in-house personnel, with following actions: * EMEA review of evidence: scientific memory (previous and ongoing MAA), including checking existing EPARs and previous advice, literature review. Additional Experts/patient representative identification. Pre-submission meeting Pre-submission meeting with coordinator(s) (and/or coordinator s experts) and EMEA secretariat. List of Comments (LoC) is forwarded to the company. This document will be prepared by EMEA in order to improve validation of SA/PA requests, and flag issues identified at the presubmission meeting to the SAWP. Identify requests for which expertise is particularly needed. Working Party consultation (ad-hoc). Validation of draft The company revises the request and includes potential additional issues. Submission of revised draft request to the EMEA Secretariat Positive validation of draft at the EMEA Secretariat Submission Submission of final SA or PA request from company to the EMEA Secretariat and to the nominated coordinators. The validated SA or PA request is forwarded by the EMEA Secretariat to the SAWP and to the relevant Working Parties. SAWP 1 The coordinators introduce the company s request highlighting the main issues. Formal Working Party consultation. Page 6 of 10
~ D +20 ~ D +30 Additional expert appointment. The coordinators send their first reports to the EMEA Secretariat. The reports are forwarded for comments to the SAWP, the relevant Working Parties, the additional experts and to the COMP (for PA). EMEA qualityassurance: scientific memory (previous MAA), literature review, checking existing EPARs and previous advice. SAWP 2 Discussion of the first reports focusing on controversial issues. The SAWP confirms at this stage whether the advice can be adopted at Day 40 or whether it is necessary to invite the applicant for a discussion meeting (Day 70 procedure e.g. in case of disagreement with the proposed development). In the latter case, a list of issues to be addressed by the company at the discussion meeting is adopted by the SAWP and sent to the company. The applicant may also propose in writing to the EMEA additional points for discussion that are not part of the adopted list of issues and submit in writing ahead of the Discussion meeting. Amendments/changes to the development programme should be notified to the EMEA/SAWP ahead of the discussion meeting. The SAWP may request the applicant to address issues in writing only. In this case a list of issues to be addressed in writing is adopted by the SAWP and sent to the company. In this case the 70-day procedure will apply. 40-day procedure SAWP decides that there is no need for a discussion meeting and that the procedure can be finalised in 40 days. The coordinators send their joint report to the EMEA ~ D +33 Secretariat. The joint coordinators' report and the draft advice letter to the company are adopted by the SAWP through a written procedure. CHMP/SAWP/EMEA peer review (content/consistency/coherence). CHMP 2 ~ D +40 The final advice letter is adopted by the CHMP (and by the COMP in case of question on significant benefit for PA) and sent to the company. 70-day procedure SAWP decides that there is a need for a discussion meeting and that the procedure be finalised in 70 days. The coordinators send their joint report, highlighting ~ D +50 the controversial issues from SAWP 2 discussion, to the EMEA Secretariat. The report is forwarded to the SAWP, the relevant Working Parties, the additional experts, and to the Page 7 of 10
~ D +60 ~ D +63 ~ D +70 COMP (for PA). SAWP 3 Discussion meeting with company and SAWP. The coordinators present a preliminary conclusion at the end of the discussion meeting. The coordinators present the outcome of the discussion meeting to the SAWP. The coordinators send their revised joint report to the EMEA Secretariat. The joint coordinators' report and the draft advice letter to the company are adopted by the SAWP through a written procedure. CHMP/SAWP/EMEA peer review (content consistency/coherence). CHMP 3 The final advice letter is adopted by the CHMP (and by the COMP in case of question on significant benefit for PA) and sent to the company Page 8 of 10
Graphic Overview of the Process Page 9 of 10
Dates and timelines for 2008 Page 10 of 10