This edition of our NIS Considerations newsletter concentrates mainly on the national changes that have been prompted by the recently implemented European Pharmacovigilance regulations.
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|CHCUK: New Important Milestone|
Stuart McCully accepts a part-time position with PharmaNet/i3 as Director, Observational Research
I'm pleased to announce an important new milestone for both myself and CHCUK. Beginning earlier this month, I accepted a part-time position with PharmaNet/i3 as Director, Observational Research. I see this role as a "win win" --- actually a "win win win win" --- for CHCUK, for myself, for PharmaNet/i3, and for PharmaNet/i3's clients!
My new affiliation will allow CHCUK to continue to serve the industry as a source for critical compliance information on Non-Interventional Studies. At the same time, I will be charting a course for the evolution of CHCUK, fully leveraging PharmaNet/i3's leadership in Observational Research. In the meantime, please continue to look to CHCUK for eLearning, reports, and newsletters supporting high-quality non-interventional study processes.
Part of my new role with PharmaNet/i3 will be developing a Non-interventional Study start-up group. As the majority of PharmaNet/i3's observational studies and registries are global in nature, I will be leveraging my expertise in the varying and evolving regulatory and ethics approval processes to ensure that our projects are initiated in the most efficient (yet compliant) manner possible. PharmaNet/i3's staff is second to none, allowing me to build a start-up capability on an already solid foundation.
So in most ways, nothing will change in terms of your interactions with CHCUK: our training and consulting services will remain available directly to our clients. However, those organizations seeking a broader array of services in support of a specific research initiative can likely be best served through my new affiliation with PharmaNet/i3. Ultimately, I envision there to be even closer linkages between CHCUK and PharmaNet/i3, particularly in view of their parent organization, inVentiv Health, a broadly diversified company providing Clinical, Consulting, and Commercial services to the pharmaceutical, biotech, and device industry. Indeed, in the very near future, I hope to see CHCUK expanding to embrace an even wider array of features and tools in support of non-interventional research (including serving as a home base for PharmaNet/i3's celebrated Survey on Observational Research, the newest edition of which being currently available at https://www.surveymonkey.com/s/ObsSurvey7, as well as an access point for their unique Physician Network at www.pharmanetpn.com).
I would welcome the opportunity to respond to any questions this announcement may inspire, and encourage you to visit often as I keep you updated on CHCUK's exciting evolution over the weeks to come.
|CHCUK: New Free NIS Resources |
CHCUK have added NIS montoring guidelines and study classification resources
New Complimentary CHCUK Resources
CHCUK have added two new free NIS-specific resources to their website:
Monitoring Guidelines for NIS
- NIS Considerations - Monitoring Guidelines
- NIS Considerations - Study Classification
We all know that monitoring is key to ensure patient safety and data quality. However, non-interventional studies (NIS) are not randomised controlled clinical trials. Monitoring of NIS needs to be tailored to accomodate a range of NIS considerations including the study design, regulatory requirements, study duration, number of sites and patients and study outcomes.Read on ...
There are new European legal requirements for Post-Authorisation Safety Studies
(PASS) effective from 21 July 2012:
These requirements are more stringent than was previously seen for PASS. All
obligatory PASS (and voluntary?!) must comply with the new PASS requirements.
Therefore, it is important that you correctly classify your study during the planning phase because there are significantly different requirements for non-interventional PASS than for other non-interventional studies.
The new CHCUK free resources can be accessed from:
|Europe: New EU PASS Protocol Guidance|
EMA have published detailed Guidance for the format and content of the protocol of non-interventional post-authorisation safety studies
On the 26 September 2012 the EMA published their Guidance for the format and content of the protocol of non-interventional post-authorisation safety studies
From 10 January 2013, marketing authorisation holders are obliged to comply with the format and content of the study protocol for post-authorisation safety studies (PASS), as specified in Art 36 to 38 and Art 40 of the Commission Implementing Regulation (EU) No 520/2012. Use of the format is encouraged for PASS protocols submitted before that date.
This document provides guidance for drafting the study protocols for non-interventional PASS in order to support consistency of the presentation and information provided. The template is based on Art 38 of Implementing Regulation No 520/2012 with the additional instructions of Module VIII of the Good pharmacovigilance practices. For interventional PASS, instructions provided in Volume 10 of the Rules Governing Medicinal products in the European Union should be followed.
The study protocol should be concise, while providing the information needed to understand how the study will answer the research question and assess the validity of the study design.
All headings and sub-headings of the format presented in this guidance should always be included and the same numbering should be used. Additional sub-headings can be added as necessary. Where a heading or sub-heading does not apply to the study (eg. Protection of human subjects), "Not applicable" should be stated with a short justification. All dates should be indicated in the format "DD Month YYYY" (e.g. 24 June 2012). Annex 1 should be used to list stand-alone documents not included in the protocol, e.g. contact details of responsible parties and all investigators, or sections 9.6. Data management, 9.8. Quality control and 10. Protection of human subjects, which can be maintained apart from the study protocol where they represent standard procedures applied to all studies. In this case, a summary should be provided in the corresponding section of the protocol and reference should be made to Annex 1. Annexes can be added to provide documents referred to in the protocol.
The marketing authorisation holder(s) involved should keep a copy of the protocol signed by the qualified person in pharmacovigilance (QPPV) or his/her delegate (with the date of the signature)available for any future request or inspection.
For further information on PASS refer to:
All of these links, and more, can be found on our website:
|Europe: EU PAS Register|
ENCePP E-Register as a temporary EU PAS Register
The 2010 pharmacovigilance legislation requires transparency to the public of ongoing research and surveillance relating to medicines used in clinical practice, including information on post-authorisation studies.
Registration of protocols and final study reports in a public register of studies is a means to achieve these objectives, while supporting transparency, quality and methodological standards and exchange of information between the EMA, Member States and marketing authorisation holders.
The 2010 pharmacovigilance legislation also requires the EMA to publish in a publicly available register the protocols and public abstracts of results of post-authorisation safety studies (PASS) imposed as an obligation by a competent authority in accordance with Articles 10 or 10a of Regulation (EC) No 726/2004 or with Articles 21a or 22a of Directive 2001/83/EC. It also specifies that the final report of such studies must provide the date of registration in this register.
Information about PASS which are initiated, managed or financed voluntarily by a MAH and which are required in the Risk Management Plan (RMP) to further investigate safety concerns or to evaluate the effectiveness of risk minimisation activities, or any other PASS should also be entered into this register in order to support the same level of transparency, scientific and quality standards.
Further information about the requirements for the registration of PASS is available in the guideline on Good Pharmacovigilance Practices (GVP) module VIII, chapter VIII.B.4.
The publicly available register referred to is the 'EU PAS Register', which is to be maintained by the EMA and built as an upgrade of the ENCePP E-Register of studies (http://www.encepp.eu/encepp/studiesDatabase.jsp).
Before the EU PAS Register is fully operational, the ENCePP E-Register of Studies serves as the 'EU PAS Register' for all pharmacoepidemiological and pharmacovigilance studies regardless of whether they are initiated, managed or financed by a MAH; or are conducted by a research centre that is a partner of the ENCePP network; or any other research centre within the EU. MAHs should, therefore, for now register non-interventional PASS as required in the GVP Module VIII in the ENCePP E-Register of Studies. The future EU PAS Register will include all studies already registered in the ENCePP E-Register of Studies.
It is important to note that the registration of a study in the EU PAS Register is independent from the application for the 'ENCePP Study Seal' which provisions are explained in the ENCePP Study Seal Application - Step by Step Guide
. However, all studies which apply for the ENCePP Study Seal by definition have to be registered in the ENCePP E-Register which currently is the EU PAS Register.
For clinical trials conducted in the EU, registration in the EudraCT database is a legal obligation. Additional registration of clinical trials in the EU PAS Register is only mandatory for clinical trials applying for the 'ENCePP Study Seal'.
For further information, refer to:
|Hungary: Reporting of Post-Authorisation ADRs|
Obligations of the marketing authorization holder concerning the reporting of post-authorization adverse drug reactions in Hungary (as of 21 October 2012)
(as of 21 October 2012)Legal background
In order to facilitate the exchange of information on pharmacovigilance in the Community, and in accordance with current pharmacovigilance legislation as laid down in Reg. (EC) 726/2004 as amended by Reg. (EU) 1235/2010 and Dir. 2001/83/EC as amended by Dir. 2010/84/EU, marketing authorization holders shall submit all suspected serious adverse reactions reported spontaneously by healthcare professionals and patients or originating from a non-interventional study to the National Competent Authorities and/or the European Medicines Agency via EudraVigilance, the data processing network and management system of the European Economic Area (EEA).
Electronic reporting of spontaneous individual case safety reports (ICSRs) and reports from non-interventional studiesSerious suspected adverse reactions that occur within the territory of Hungary
MAHs are requested to transmit all serious spontaneous ICSRs received from healthcare professionals or patients and reports from post-marketing non-interventional studies that occurred in the territory of Hungary to National Institute of Pharmacy (NIP) via EudraVigilance with the message receiver identifier OGYIP in accordance with the requirements of expedited reporting observing the 15-day timeline. Beginning from 21 October 2012, all these reports shall be submitted simultaneously to the message receiver identifier EVHUMAN as well which means a direct transmission to EudraVigilance Post-Authorization Module (EVPM). The Institute will not forward the reports originating from MAHs to EVPM from now on. This new reporting requirement is valid for both initial and follow-up reports.Serious suspected adverse reactions that occur in the territory of a European Union Member State other than Hungary
The Institute does not require these reports to be submitted to OGYIP, not even if Hungary is the reference member state or rapporteur/co-rapporteur for the product concerned. For serious adverse reactions occurring in the territory of a European Union Member State other than Hungary, the reporting requirements of the relevant competent authority shall be followed (i.e. forwarding the report directly to EVPM, to the NCA or to both - for further guidance, please refer to the EV website
). NIP can extract these reports from EudraVigilance for further analysis, if necessary. Serious suspected adverse reactions from outside the European Union
The Institute does not require these cases to be submitted to OGYIP either. Serious cases originating from outside the EU shall be submitted directly to EVPM (ID EVHUMAN). Furthermore, certain Member States shall also be informed (please refer to the EV website
for further guidance). NIP can extract these reports from EudraVigilance for further analysis, if necessary.
The Institute does not require non-serious cases to be submitted to OGYIP. There is no such an obligation to submit the report to EVHUMAN either, until full functionality of the EV will be established and announced. The requirements of non-serious adverse reaction reporting may vary during the transitional period among Member States of the EU, please refer to the EV website
for further information.
Testing and pilot phase
All literature cases transmitted to OGYIP should be accompanied by the submission of an electronic reprint of the original article to NIP via e-mail (email@example.com
NIP does not request any of its partners to perform testing or complete a pilot phase.
In case of spontaneous reports and reports from non-interventional studies, an e-mail notification (firstname.lastname@example.org
) is required simultaneously, when a MAH is submitting to NIP via EudraVigilance for the first time. The report should be submitted via EudraVigilance in "Production environment" to OGYIP. The receipt of the report will be acknowledged either via EudraVigilance or in an e-mail. Should an error occur in transmission, the sender will be notified in e-mail to inform him/her that the report has not arrived.
In case the MAH would still like to perform a test with the Institute, please send a notification in e-mail as we are not checking the test environment every day and confirming the receipt of the case may be delayed.
What to do in case of system failure
Further information / Contact details
If you are unable to generate an ICH M2 safety messages from a spontaneous report or a report originating from a non-interventional study, or transmit it to OGYIP, switch to alternative means of reporting (e.g. reporting via fax: +36.1.886.9472 or e-mail: email@example.com
), and notify NIP that there is a failure at the sender's site. The receipt of these reports will be acknowledged. If the problem resolved and electronic reporting is resumed, NIP should be informed and the electronic version of the report should be submitted to OGYIP.
National Institute of Pharmacy is an EVWEB client, using exactly the same business rules as the European Medicines Agency.
Contact persons for spontaneous reports and reports from non-interventional studies (reports submitted to OGYIP):
Katalin Rácz, PharmD
Pharmacovigilance Department, National Institute of Pharmacy
+36.1.886.9300 / 238
Györgyi Fodor, Pharm D
Pharmacovigilance Department, National Institute of Pharmacy
+36.1.886.9300 / 222
Melinda Pálfi, PharmD (EV Responsible)
Pharmacovigilance Department, National Institute of Pharmacy
+36.1.886.9300 / 159
For further information refer to:
|Germany: New Requirements for Non-Interventional Safety Studies|
New Requirements for the Conduct of Non-Interventional Safety Studies as of 26 October 2012
The German Law on the distribution of medicines (Medicines Act - AMG) has recently been amended by the Second Act Amending Drug Act and other regulations in order to capture, amongst other things, the new Pharmacovigilance requirements for Post-Authorisation Safety Studies.
These changes are effective as of the 26th October 2012
The Following Articles of the AMG have been amended:
§ 63f General Requirements for non-interventional safety studies (NEW)
§ 63g Special conditions arranged for non-interventional safety studies (NEW)
§ 67(6) General Obligations (AMENDED)*
*This is the key section of the AMG that sets forth the regulatory requirements for non-interventional studies.
There is currently no official English translation of the amended text available so we have included a very rough, non-certified translation for your information. No reliance should be placed on the accuracy of the translation provided here.
§ 67(6) General Obligations
Version in force until 26 October 2012:
(6) The pharmaceutical company has research, intended to collect evidence in the application of approved or registered medicines, the physicians' federal associations,the Central Federal Association of Health as well as the NCA immediately. In this place, time, destination and monitoring plan shall be indicated as well as the observational study will inform the National Association of Statutory Health Insurance Physicians and the Central Federal Association of the health insurance for the participating doctors by name. Payment which is paid to physicians for their participation in investigations pursuant to sentence 1 are calculated according to their nature and level so that there is no incentive for a preferred prescription or recommendation of specific drug is produced. Unless involved providing medical benefits at the expense of public health insurance, are on display in sentence 1 and the type and amount of payments made to them compensation where relevant, and to submit one copy with the concluded contracts, except for the ads except with respect to the responsible authorities. For drugs that are intended for use in animals, the ads in sentence 1 shall be only to the NCA report.
Version in force from 26 October 2012:
(6) Who will carry out studies, which are designed to gather information in the application of approved or registered medicines, this has the NCA, the physicians' National Association, the Central Federal Association of Health and the Association of Private Health Insurance eV reported immediately . In this place, time, destination and monitoring plan are to provide the observational study, and of the National Association of Statutory Health Insurance Physicians and the Central Federal Association of the health insurance companies, the doctors by name , indicating the number lifelong doctor named. Payment which is paid to physicians for their participation in investigations pursuant to sentence 1 are calculated according to their nature and level so that there is no incentive for a preferred prescription or recommendation of specific drug is produced. Unless involved providing medical benefits at the expense of public health insurance, are on display in sentence 1 and the type and amount of payments made to them compensation where relevant, and to submit one copy with the concluded contracts, except for the ads except with respect to the responsible authorities. For drugs that are intended for use in animals, the ads in sentence 1 shall be only to the NCA report.Paragraphs 1 to 5 shall not for safety testing 63f according to §.
(7) Any person who intends, commercial or professional standard drugs, which are approved in another Member State of the European Union to market by another pharmaceutical company, for the first time from that Member State within the scope of the Act for the purpose of marketing in the scope of the law to spend, this show has the authorization holder before the start of the activity.Were for drugs for which a marketing authorization under Regulation (EC) No 726/2004 is, Theorem 1 with the proviso that the display is to be submitted to the holder of the authorization and the European Medicines Agency.The agency is a fee for the verification of compliance with the conditions laid down in the EU law and the law on drug marketing authorizations to pay and the amount of the fee is determined by the laws of European Union law.
§ 63f General Requirements for non-interventional safety studies
(1) Non-interventional safety studies that are carried out by the authorization holder on its own initiative, are reported to the NCA. The NCA may request authorization from the owner of the protocol and progress reports. Within one year after completion of data collection, the holder of the authorization of the NCA has to submit the final report.
(2) For non-interventional safety audits to be performed by the holder of the authorization on the basis of a support according to § 28 paragraph 3, 3a or 3b is the The method of § 63g.
(3) The implementation of safety evaluation, paragraphs 1 and 2 is not allowed when first through them, the application of a drug that could be awarded 2nd to compensation for the participation of health professionals in such audits by their nature and extent not on the time required and the costs incurred or restrict third an incentive for a preferred prescription or recommendation of specific drug is produced.
(4) The holder of the authorization has safety testing in accordance with paragraphs 1 and 2 and the physicians' National Association, the umbrella organization show Federation of Health and the Association of Private Health Insurance eV immediately.In this place, time, destination and protocol testing and the name and number of lifetime medical doctors involved are indicated. Unless participating physicians provide services at the expense of public health insurance, are on display in sentence 1 and the nature and amount of remuneration paid to them is to specify and submit one copy with the concluded contracts.
§ 63g Special conditions arranged for non-interventional safety studies
(1) The consent holders in non-interventional safety studies that have been arranged according to § 28 paragraph 3, 3a or 3b, the draft test protocol prior to firstthe NCA, if it is a test that is performed only within the country, second the Committee for Risk Assessment in pharmacovigilance, if it is a test that is carried out in several Member States of the European Union, shall be provided.
(2) A non-interventional safety examination under paragraph 1 may only be commenced if the draft protocol on tests specified in paragraph 1 point 1 of the NCA has been approved or in trials approved in accordance with paragraph 1, point 2 by the Committee for Risk Assessment in pharmacovigilance and has the draft minutes of the NCA is present. The NCA has decided after submission of the draft protocol within 60 days whether to approve the audit. A license shall be denied if the use of this product should be promoted, the objectives of the test design can not be achieved or there is a clinical examination according to § 4 Paragraph 23, sentence 1.
(3) 1 After initiating a test of paragraph are substantial changes to the protocol before its implementation, first if it is a test is to be conducted only within the country, by the NCA, second if it is a test is being conducted in several Member States of the European Union, of the Committee for Risk Assessment in pharmacovigilance approve. If the test in cases of sentence 1 number 2 also performed in Germany, informed the holder is the NCA on the approved changes.
(4) Upon completion of an examination under paragraph 1 is the final audit report first in the cases referred to in paragraph 1, point 1 of the NCA, second in the cases referred to in paragraph 1, point 2 of the Committee for Risk Assessment in pharmacovigilance within twelve months after the end of data collection to present, if not has been waived by the competent authority under sentence 1 number 1 or 2 spot on the template. The final report shall be transmitted electronically along with a brief presentation of the results.
|Spain: Updated Post-Authorisation Study (EPA) Q&A Document|
The Q&A supplement to the SAS/3470/2009 Order of December 16 - Guidelines on post-authorization observational studies for medicinal products for human use was updated in July 2012.
There is very little difference from the original document. The wording of the answer to question 28 has been amended. Where question 28 asks whether the sponsor of a post-authorisation study has to report serious adverse reactions from drugs for which they are not the marketing authorisation holder, as well as their own drugs.
Answer, in these cases the SARs should be forwarded to the marketing authorisation holder of the 'other' drug.
Refer to the following for further information: