June 2013
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In this Month's Issue
CHCUK NIS Webinar 1: How do the Recent Changes to the EU PV Legislation Impact NIS?
EMA: Revision of GVP Module VIII
EU: Safety Reporting Requirements for NIS
France: Disclosure of Agreements with and Advantages to Healthcare Professionals
France: New Laws Impacting NIS Delayed to 2016
WMA: Declaration of Helsinki 2013?
Hungary: Approval Requirements for NIS
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Introduction to NIS eLearning
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NIS Country-specific eLearning

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Country-Specific NIS Reports
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Summary of NIS Requirements for Europe
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CHCUK: Free NIS Resources

We're almost a year into the implementation of the new pharmacovigilance legislation in Europe so we've focused much of this newsletter on the operational impact of these recent changes on the conduct of non-interventional studies (NIS) and the safety reporting requirements for NIS

I hope you'll find the following information and resources useful.

Best wishes,

Stuart McCully
Tel: +44 (0) 1997 42 33 11
Mobile: +44 (0) 7909 111 510
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CHCUK NIS Webinar 1: How do the Recent Changes to the EU PV Legislation Impact NIS?


How do the Recent Changes to the  EU Pharmacovigilance Legislation Impact NIS?

We've heard alot about the recent changes to the pharmacovigilance legislation in Europe, but what does it actually mean to those of us who conduct non-interventional studies?

The first in our complimentary series of webinars and elearning modules looks at the impact of the recent changes to the EU PV legislation on the conduct of  non-interventional studies. 

Module Format
  • This is a narrated interactive elearning module

Module Content
  • What do the recent changes to the EU PV legislation really mean to those of us who conduct NIS in Europe?
    • Post-authorisation safety studies (PASS)
    • Regulatory approvals and notifications
    • Study registration
    • Templates
    • Mandated versus voluntary PASS
    • Country-specific considerations
  • Safety reports from non-interventional studies
    • What do we need to report, by when, from where and to who?
    • My NIS isn't a safety study so are these requirements applicable?
  • Quality systems
    • Do we need to do anything differently? 

The link below takes you to our complimentary elearning module:
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EMA: Revision of GVP Module VIII
The EMA have Published Revision 1 to GVP Module VIII

On the 25th April 2013, the EMA published revision 1 to EMA GVP Module VIII - the guideline on post-authorisation safety studies. 


Revision 1 contains the following:

  • Clarifications of the text following questions received from stakeholders regarding:
    • Scope of the guidance to EU and non-EU studies (page 5, section VIII.B.1)
    • Classification of a post-authorisation study as a PASS according to its main aim (page 6, section VIII.B.3)
    • Study registration (study registration not limited to studies conducted in the EU and updates of study record to be made preferably within two weeks) (page 7, section VIII.B.4 and page 8, section VIII.B.4)
  • Increased consistency with GVP Module V regarding the four categories of studies included in the risk management plan (page 4, section VIII.A and page 5, section VIII.B.1)
  • Amendments to make reference to published detailed guidance for the format and content of non-interventional PASS protocols and final study reports (page 8, section VIII.B.5.1, page 10, section VIII.B.5.1, page 12, section VIII.B.6.3.2, and page 15, section VIII.B.6.3.2)
  • Amendment of regulatory wording to use that adopted by the Agency or following legal advice regarding that:
    • In the procedure for imposing a PASS, the PRAC may adopt an advice with an assessment report (page 17, sections VIII.C.2.a., VIII.C.2.b. and VIII.C.2.c.)
    • Roles and responsibilities to marketing authorisation holders for non-interventional PASS apply to studies imposed as an obligation as a condition to the marketing authorization (page 19, section VIII.C.4.1.
  • Editorial corrections and improvements (page 4, section VIII.A., page 5, section VIII.B.1., page 10, section 9.6., and page 19, section VIII.C.4.1._
  • Update of the cross-reference to the document "Member States' requirements for transmission of PASS information" (now GVP Module VIII Addendum I).

For further information, refer to:
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EU: Safety Reporting Requirements for NIS
Article Subtitle

CHCUK are increasingly being asked about what is meant by 'primary' data collection in respect to observational studies in EMA GVP Module VI. Our understanding, having read through the EU PV regulations, directive and EMA GVP modules, as well as The Human Medicines Regulations (SI 2012/1916), was that primary data related to data collected from HCP and patients in prospective NIS. Therefore, ALL prospective NIS are subject to the expedited reporting requirements for serious and non-serious suspected adverse reactions.


We asked both the EMA and MHRA to confirm/clarify this. Their answers and guidance are included below:


Thank you for contacting the European Medicines Agency.


Your presumption is correct. As paragraph "VI.C.1.2.1. Non-interventional studies" of the GVP Module VI states:


"Non-interventional studies should be distinguished between those with primary data collection directly from consumers and healthcare professionals, and study designs which are based on secondary use of data such as studies based on medical chart reviews or electronic healthcare records, systematic reviews or meta-analyses." So it means that in specific NIS the data is collected directly from HCP and patients.


But this also means that there is the other type of NIS, which is based on already existing data. For this type of non-interventional study designs, adverse reactions reporting is not required. Reports of adverse events/reactions should only be summarised in the study report, where applicable.


As the legislation states: "In case of doubt, the reporting requirement should be clarified with the concerned competent authorities in Member States."


For more information please refer to the whole VI.C.1.2.1. paragraph and also at paragraph "VI.C. Reports originating from organised data collection systems and other systems" and  "VI.B.1.2. Solicited reports of the same GVP module VII", on the following website   

Take home points/considerations (from the MHRA GVP Inspectorate):


  • As defined in ICH-E2D guideline, solicited reports of suspected adverse reactions are those derived from organised data collection systems, which include clinical trials, non-interventional studies, registries, post-approval named patient use programmes, other patient support and disease management programmes, surveys of patients or health care providers, compassionate use or name patient use, or information gathering on efficacy or patient compliance. Adverse reactions reports obtained from any of these data collection systems should not be considered spontaneous. The implications being:
    • Serious and non-serious adverse reaction (not unrelated adverse events) reports form non-interventional solicited sources (excludes interventional clinical trials) shall be recorded and accessible in the EU
    • Non-serious non-interventional solicited adverse reaction reports that occur with the EU have to be expedited (where required) in accordance with current requirements
  • Ensure that there is a mechanism for your pharmacovigilance department to be made aware of these studies (this applies for all studies not just those conducted in the EU). The PSMF should contain a complete description of sources of data
  • Clearly stipulate in study protocols what safety data is to be collected and how
  • Sponsors should specific in protocols any adverse events to be actively sought and reported by investigators e.g., the sponsor could specify, based on an appropriate risk rationale that the only non-serious adverse events to be collected as part of the protocol are those events of special interest (e.g., events bring monitored as part of an RMP). A justification for exemption should always be provided
  • Design case report forms to collect the required safety data
  • Ensure personnel involved in studies (including contractors and investigators) are made aware of safety reporting processes and requirements
  • Include these requirements in relevant agreements e.g., investigator agreements
  • Implement mechanisms to monitor compliance. There should be a mechanism to identify cases from this source and from the database
  • Ensure that final study reports are produced in a timely manner and are made available to the pharmacovigilance department
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France: Disclosure of Agreements with and Advantages to Healthcare Professionals
Publication of Decree No. 2013- 414 dated 21 May 2013 regulating the disclosure of agreements with and advantages to healthcare professionals
Flag of France

During the second part of 2011, the French government decided to review the current French Health Product system following the Mediator scandal. Law No.2011-2012 on sanitary safety of medicinal and Health products was adopted on 29 December 2011. This law aims among others at restoring the confidence in the decisions taken by the Authority and the transparency in the relationships between the industry and healthcare professionals. 

Law No. 2011-2012 inserts a new Article L.1453-1 in the French Public Health Code (CSP) on the disclosure of agreement signed and any financial advantage offered to healthcare professionals, patient group or hospitals.

Decree No. 2013- 414 dated 21 May 2013 lays down the implementation provisions of Article L.1453-1 of the CSP. These new provisions will come into effect on 1st June 2013. At this date, the companies will have to disclose all the agreements signed and advantages granted in 2012.
According to the provisions of new article L.1453-1 CSP, pharmaceutical companies must now disclose the existence of agreements that they concluded with:
  • Healthcare professionals,
  • Associations of healthcare professionals,
  • Students in medicine and odontology,
  • Associations of patients,
  • Health establishments,
  • Foundations,
  • Press organs for health professionals for all media (press, radio, TV or online communication);
  • Medical prescription and deliverance software editors;
  • Learned societies.
Each company must disclose the information for each agreement concluded.
Above a limit of 10 euros all taxes includes, the obligation of disclosure also applies to the advantages in nature or in money granted directly or indirectly by pharmaceutical companies to the above listed recipients. Consequently, all advantages granted to persons listed above that are above 10 euros will have to be disclosed.
The said information will be disclosed in French on a unique public website held by an authority to be created by an order of the Ministry of Health.
The companies will have to transmit the above-mentioned information to this authority within 15 days from the execution of the agreement and at least on 1st August of each year for the advantages granted during the 1st semester of the year and at least on 1st February of each year for the advantages granted during the 2nd semester.
The authority must then disclose the information on the website for the 1st semester of the year on 1st October and for the 2nd semester on 1st April.
Before the establishment of the relevant authority, a transitional period is put in place. For the time being, the information will be disclosed on the website of the relevant professional society of the healthcare professional (if a physician, on the website of the Medical Doctor Society) or on the website of the company if no relevant professional society exists. A professional syndicate may also take the responsibility to disclose this information for its members.
Regarding the agreements concluded and the advantages granted in 2012, the companies have to transmit all relevant information before 1st June 2013. The information shall be made available on the website of the professional societies, of the professional syndicates or of the companies at least on 1st October 2013.
Since the publication of Law No. 2011-2012, companies were prepared to gather this information but the level of detail and the amount above which disclosure is requested were uncertain. Now, companies will have work during the next days to compile the information requested in order to comply with this requirement.
Paule Drouault-Gardrat and Juliette Peterka
PDG Avocats

For further information, refer to:


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France: New Laws Impacting NIS Delayed to 2016

The Implementing Decrees of Law No. 2012-300 of 5 March 2012  likely to be released after publication of European regulation on clinical trials in human medicine ... not expected before 2016.
Flag of France

It's been over a year since the law "Jardé"  No. 2012-300 of 5 March 2012 on the person applying research was published in the Official Journal and integrated in the printed version of the Code of Public Health.The implementing decrees are still not published, thus delaying the entry into force of the new framework law on clinical trials and non-interventional studies (refer to NIS Considerations - April 2012


According to a recent article by Fidal Advocats, at present, it appears that the orders are in limbo while their publication was originally scheduled for September 2012 and the first quarter of 2013.    


So why the silence?

The French authorities find themselves in an uncomfortable situation of having reformed the legal regime applicable to biomedical research in France, while a redesign of the subject was also under discussion at EU level.

The European Commission published in July 2012 a proposal for a European regulation on clinical trials of medicinal products for human use, which should cancel and replace the Directive 2001/20/EC.

Field of application of the Loi Jardé is much wider than proposed European Regulation: the Regulation will apply only interventional studies on the drug while "Jardé" Act regulates the interventional drug research, interventional research on products other than drugs, and non-interventional research - all products.

Also the requirements for the protection of persons who consent to research are different and some inaccuracies regarding the implementation of National and European authorization procedures remain to be clarified.
=> The coordination of these two texts appears thus complicated.
Unlike Directive 2001/20/EC, the regulations will apply directly in all Member States and will promote harmonization of the legal framework of clinical trials in the EU.  In case of discrepancy with Jardé law, the provisions of European Regulation will apply in France.
Therefore a part of the Jardé law will never apply, at least some clause related to interventional drug studies.

The decrees of the law Jardé probably will only be released after publication of European regulation on clinical trials in human medicine ... not expected before 2016.


Link to the Article (in French):


Acknowledgements: Benedicte Bonnet, Senior CN CRA, Late Stage Department, inVentiv Health Clinical IHC - 4 Arrows


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WMA: Declaration of Helsinki 2013?
Public Consultation on WMA Helsinki Declaration
A two-month public consultation on the World Medical Association's Declaration of Helsinki on medical research involving human subjects began on Monday 15 April 2013 with the posting of a revised version of the Declaration on the WMA website.

The public and the WMA's 102 national medical association members were invited to comment on the proposed changes which have been drawn up following an 18-month process of deliberation. A WMA workgroup has held comprehensive discussions and three expert conferences to help it draft the changes.

In an explanatory note on the WMA website, the workgroup states that the proposed changes provide for more protection for vulnerable groups and all participants by including the issue of compensation, more precise and specific requirements for post-study arrangements and a more systematic approach to the use of placebos. In addition the workgroup states that the revised text maintains the unique character and length of the Declaration. It also provides better readability by reorganising and restructuring the document with sub headings.

For details of the major changes, people should refer to the WMA website.

All experts and stakeholders were invited to submit comments to the WMA secretariat no later than 15 June 2013.

The workgroup will then produce a final revised draft to be considered by the WMA's ethics committee and Council at their meetings in Fortaleza, Brazil in October 2013 when a decision will be taken whether to forward the document to the WMA Assembly at the same meeting for adoption.

Further information can be found on the following links:
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Hungary: Approval Requirements for NIS
The National Institute of Pharmacy Clarifies Approvals Requirements for NIS
The Hungarian National Institute of Pharmacy has recently provided CHCUK with confirmation of the approval requirements for non-interventional studies - see below:

The National Institute of Pharmacy (Hungarian abbr.: OGYI) works as one of the several directorates of the National Institute for Quality- and Organizational Development in Healthcare and Medicines (Hungarian abbr.: GYEMSZI). Since 21st September, 2012, it is the GYEMSZI-OGYI that authorizes non-interventional studies, including PASS (but not ones obliged by the Authority.) Review of the submission procedure of a non-interventional study is not yet available on the home page of OGYI in English language.

Application for authorisation of a non-interventional study must be submitted to GYEMSZI-OGYI. After validation (i.e. checking if all documents are submitted; being made sure that the study supplies the conditions of a non-interventional study) GYEMSZI-OGYI forwards the documents to the Scientific and Research Ethics Committee of Medical Research Council (Hungarian abbr.: ETT-TUKEB). ETT-TUKEB performs a scientific control on the protocols, on the ICFs and PILs; especially focusing on the patent's legal and healthy safety.

Both GYEMSZI-OGYI and ETT-TUKEB is allowed to demand a missing information or document.

If the ETT-TUKEB provides a favourable opinion about the study and the GYEMSZI-OGYI also finds the study correct from scientific aspects, a decision is done by the Authority. The procedure must be done in 60 days. The clock stops during question-response procedure.

The application must be posted to GYEMSZI-OGYI (see address on homepage), personally to Tamasne dr. Nemeth Agnes, Head of Clinical Studies Department.

All documents must be submitted in Hungarian language except of the original protocol of an international study.


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