The one thing that we can always guarantee with non-interventional studies is that the requirements change, and change often.

This edition of our newsletter captures recent updates in legislation in France, Greece and Italy and briefly looks at the impact on NIS.

We've also included further information on the impact of the new EU pharmacovigilance legislation on non-interventional studies.

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

Stuart McCully
CHCUK

On the 8th February 2013, the EMA published new guidance covering the key concepts of the new EU pharmacovigilance legislation, "New EU Pharmacovigilance legislation - key concepts"

According to the EMA:

Pharmacovigilance is the task of monitoring the safety of medicines and ensuring that the risks of a medicine do not outweigh the benefits, in the interests of public health.

The European Union (EU) system of pharmacovigilance oversees the safety of medicines on the European market. The current system has been established for a number of years and its processes have evolved over time.

The European Commission has reviewed the current system and proposed new EU pharmacovigilance legislation1, in order to continue to improve patient safety through better monitoring. This new legislation was adopted by the European Parliament and European Council in December 2010 and will enter into force in July 2012. The European Medicines Agency (EMA), together with the European Member States, is responsible for implementing much of the new legislation.

The new pharmacovigilance legislation will strengthen the current system for monitoring the safety of medicines on the European market making it more robust and transparent. It will also help ensure greater patient safety and improved public health through better detection, assessment, understanding and prevention of adverse reactions or any other problem related to medicines.

In order to raise awareness of the new legislation among healthcare professionals, patients and the public, a series of documents has been developed on the activities carried out by the EMA and the EU national competent authorities following the new legislation that contribute to public health and increasing transparency.

These documents are published below. More documents will be progressively published on the remaining deliverables of the new pharmacovigilance legislation.

More detailed information on the provisions of the new EU pharmacovigilance legislation can be found on the EMA website (www.ema.europa.eu).

For further information, refer to:

• EMA Guidance - New EU Pharmacovigilance Legislation: Key Concepts (Feb 2013)
• European Database of Suspected Adverse Drug Reaction Reports (http://www.adrreports.eu/ )

• EMA Guidance on the 2010 Pharmacovigilance Legislation 
• EMA Regulatory and and Procedural Pharmacovigilance Guidance
• EMA Good Pharmacovigilance Practices (GVPs)  
• EMA Guidance for the Format and Content of the Protocol of Non-Interventional Post-Authorisation Safety Studies (Sept 2012)
• EMA Guidance for the Format and Content of the Final Study Report of Non-Interventional Post-Authorisation Safety Studies (Jan 2013)  
• Implementation Timeframe for the Pharmacovigilance Legislation
• Regulation EU/1235/2010 (amending Regulation EC/726/2004)
• Regulation EC/726/2004 (as amended)
• 2010/84/EU (Pharmacovigilance Directive - amending 2001/83/EC)
• 2001/83/EC (Marketed Products Directive - as amended)
• Eudralex Volume 9a 
• The EU Pharmacovigilance System 
• EU PAS Register 
• EU PAS Register Guide  

 

All of the above references and more can also be found at:

• CHCUK NIS Useful Links 

Non-interventional studies are undertaken in response to a broad range of needs, perhaps best characterized on a continuum bound by the concepts of medical product "value" and "safety."  "Value" embraces processes by which non-interventional studies can generate evidence of real-world clinical, economic, and humanistic benefit and, as such, responds to the more variable and perhaps more discretionary needs of providers, payers, pricing authorities and other stakeholders.  By contrast, evidence of "safety" suggests more of a regulatory mandate, and can include risk minimization planning as well as pharmacovigilance.  It is increasingly recognized that the fundamental strategic rationale underlying a non-interventional study --- where it falls on the safety:value continuum --- will dramatically impact its operational construct, its analytical robustness, and its ultimate usefulness.  However, there remain important obstacles to maximizing the true benefit of non-interventional research, including both marketplace and regulatory evolution.
 
CHCUK is teaming with inVentiv Health Clinical to provide insight and clarity on this critical subject.  Together, we will be presenting a series of recorded and live on-line reports and interactive webinars to present our in-depth experience on non-interventional research, including topics such as:
 

• Establishing the Strategic Foundation for a NIS
• Understanding the Operational Components of a NIS
• Exploring the Analytical and Organizational Constraints associated with NIS
• Understanding the Shifting Regulatory Landscape

 
WEBINAR 1 - How does the new EU PV legislation impact NIS?

Our first short on-line report will delve into the far-reaching implications of the new EU regulations on pharmacovigilance, particularly in terms of the design, conduct and reporting of non-interventional studies.  The new regulations impact not only post-approval safety surveillance, but a surprisingly wide variety of research and related initiatives.  Our first session will present innovative, yet compliant approaches for transforming these regulatory requirements into strategic opportunities.

Registration details will be sent out in the next few weeks.

Acknowledgements: Jeff Trotter, Executive Vice President, Late Stage, InVentiv Health Clinical

The official journal of November, 9th 2012 published Decree n° 2012-1244 of November, 8th 2012, thus completing the transposition of the European Directive 2010/84/EU regarding pharmacovigiance.

 

 

Summary of the Main Dispositions of the Decree

 

This decree "pharmacovigilance" transposes the pharmacovigilance Directive in France as a complement to the "law drug".

 

1-    Dispositions regarding the Marketing Authorisation (MA)

• Data on pharmacovigilance organization should be added to the MA application.
• MA Renewal must be anticipated 9 months (not 6 months).
• The drug MA may impose the excecution of one or more of the following conditions:
  • Measures, particular conditions or restrictions intended to guarantee a safe use;
  • Undertaking of safety or efficacy studies post-MA;
  • Particular obligations related to the recording and reporting of adverse events;
  • Implementing an adapted pharmacovigilance system.
• These obligations may be imposed at any time through the drug life cycle;
• The ANSM (Agence Nationale de Sécurité du Médicament et des produits de santé) can automatically change a MA to bring it into compliance with a European decision ;
• The ANSM may prohibit or suspend the drug prescription or delivery including for drugs with centralized procedure. The text provides the reasons of the decision, the conflicting procedure with the company and the maintaining of the drug delivery in exceptional cases.

   

2- Dispositions regarding the drug leaflet

• Inciting to report the adverse events in all leaflets.
• Drugs under reinforced monitoring: specific mention and black symbol

[*** These provisions come into force on the date of announcement by the EMEA of the implementation of the new EudraVigilance functionality.  In the interim period, the ANSM must inform the EMA and MAH, within 15 days of receipt of any SAEs (as per previous provisions) and the MAH must declare SARs that occurred in France to the ANSM within 15 days.  However, if the MAH reports the serious suspected adverse reactions via EudraVigilance they aren't obligated to declare them to ANSM]

A new Greek law was published on the 21 February 2013 (Ministerial Decision Nr. Î"Î¥Î"3(α)/οικ. 18910)  that impacts the conduct of all clinical trials in Greece, making processes simpler and defining concrete timelines for approvals and contract execution. It also mandates the use of one contract template nationwide.  It does away with LEC submission fees but rather institutes the use of a 15% overhead for the Hospital and a 5% overhead for the Regional Health Authority.

PROCESS MANDATED BY THE NEW LAW

• The financial management institutions do not change
• For the University Hospitals/Clinics the financial management institution is the University
• For the public Hospitals/Clinics the financial management institution is the Regional Health authorities/district (RHA)
• All clinics/hospitals whether University or public have to follow same process

1. Local ethics committee (LEC) submission and contract and budget submission in parallel
2. Four party bilingual national contract template will be used (signed by PI, Hospital Director, Financial management institution, Sponsor/designee)
3. Any changes to the national contract template have to be submitted and approved by the Central EC
4. Within 30 days from submission, the LEC has to other provide an approval in writing or the approval is silent. Any objections have to be communicated prior to the 30 days
5. By Day 35 (since the submission), the Hospital Director signs the  contract and has another 5 days to transfer the signed contract to the Financial management institution.
6. By Day 40, therefore the Financial management institution has the contract in hand and has another 10 days to sign
7. By Day 50, the contract is fully executed

FINANCIAL IMPACT

• Overhead is 5% for the Financial management institution and 15% for the Hospital (paid directly to the Hospital)
• 250€  and 500€ non-refundable review fees for the LEC and Financial management institution, respectively
• No other LEC submission fees

PROBLEMS RELATED TO NEW LAW

1. Most parties with vested interest such as the RHAs, universities, LECs and hospitals were not informed about the new law when it was released
2. Most parties do not know at this moment how to implement the law
3. Even though the law is now in effect, the processes for the implementation are not in place
4. Exactly how the law applies to Non-interventional studies is not certain
1. Even though these studies are mentioned in the law, it is not clear whether the national contract template will be used for these studies
2. If they are to be used, since the CEC is typically not involved in the process of NIS  conduct, which authority will review the national template if the Sponsor proposes changes?
5. Timelines for implementation of the law cannot be accurately predicted

For further information refer to:

• Ministerial Decision Nr. Î"Î¥Î"3(α)/οικ. 18910 

Acknowledgements: Christina Papageorgopoulou, Coordinating Network CRA, Late Stage, InVentiv Health Clinical

The Italian data protection agency (The Guarantor for the Protection of Personal Data ) has published a general authorisation to the processing of genetic data which is applicable to scientific researcher and therefore relevant for non-interventional studies where such data is collected and/or processed either directly from medical notes or indirectly from biosamples.

According to Authorization no. 8/2012 - General authorization to the processing of genetic data - December 13, 2012(Published in the Official Gazette no. 3 of 4 January 2013):

Scope  

 

This authorization shall be granted:

1. to health care professionals, in particular medical geneticists, limited data and the operations required exclusively for the purpose of protection of the health of the person or a third belonging to the same genetic line as the;
2. public and private health organizations, particularly in clinical medical genetics, to the data and with the operations exclusively for the purpose of protecting the health of the person or a third belonging to the same genetic line as the;
3. medical genetics laboratories, limited to the operations required with respect to data, also necessary, to be processed for the exclusive purpose of preventing and genetic diagnosis towards the person, or intended to be used for the sole purpose of carrying out investigations defensive or to assert or defend a right, even by one third in the courts or, for the sole purpose of family reunification, to ascertain the existence of consanguinity of nationals of non-EU nationals, stateless persons and refugees;
4. natural or legal persons, bodies or research institutes, associations and other public and private organizations whose purpose is to research, limited data and the operations required for exclusive purposes of scientific research, statistics, aimed at protecting the health of, third parties or the public in the medical, biomedical and epidemiological context of the duties pertaining to the medical genetics, as well as for purposes of scientific research to develop techniques of genetic analysis;
5. to psychologists, consultants, technicians and their assistants, as part of multidisciplinary interventions of genetic counseling to the data and with the operations exclusively for the purpose of consultation in respect of the individual or family members;
6. to pharmacists, to the data and with the operations exclusively for the purpose of complying with his obligations under a supply of drugs to the holder;
7. the defenders, including by means of substitutes, technical consultants and private investigators licensed, limited to the operations and data necessary for the exclusive purpose of carrying out the investigations by defense counsel as per Act No. 7 December 2000. 397, shall also be granted to enforce or defend a right, even by third-in court, provided that the law is of rank at least equal to that of the person and the data are processed exclusively for said purposes and for no longer than necessary therefor;
8. bodies of public and private mediation of its operations and data necessary for the exclusive purpose of carrying out the activities relating to the exercise of mediation aimed at settling disputes in civil and commercial pursuant to legislative decreeMarch 4, 2010, n. 28 and subsequent amendments and additions, in accordance with law and respect for private entities with the requirements of the general n. 5 to the processing of sensitive data by different categories of rightholders and public bodies, the measure of the Ombudsman on 21 April 2011 that identifies the types of data and can do in relation to the purpose of overriding public interest referred to in ' art. 71, paragraph 1, lett. b) of the Code;
9. international organizations deemed eligible by the Ministry of Foreign Affairs and the diplomatic missions or consular posts to issue certifications (regulated by the state. dPR 49 January 5, 1967, n. 200) for the sole purpose of family reunification and limited to cases where the person concerned can not provide official documentary evidence of the ties of consanguinity, because of its status, or even the absence of a recognized authority or the alleged unreliability of the documents issued by the local authority.

Purpose of the treatment

 

Can  process genetic data and biological samples used within the following goals that can not be achieved on a case by case basis, by processing data or anonymous samples or personal data is not genetic:

1. protection of public health, with particular reference to diseases of genetic nature and the protection of genetic identity of the interested party, with his consent, except as provided by Articles. 26 and 82 of the Code with respect to the case where the person concerned can not give their consent for failure to act, physical impossibility or inability to understand or want;
2. protection of public health, with particular reference to genetic diseases and protection of genetic identity of third belonging to the same genetic line as the with the latter's consent, if the consent is not provided or can not be performed because of physical incapacity to act or inability to understand or want, as well as unavailability of effective, treatment may be used solely to genetic data available where it is essential to allow the third party to make a choice reproductive aware or is justified by the need for the third, interventions of a preventive or therapeutic. In the event that the individual is deceased, treatment may include genetic data extrapolated from the analysis of biological samples of the deceased person, if it is necessary to enable the third party to make a conscious reproductive choice or is justified by the need for the third, interventions of a preventive or therapeutic;
3. scientific and statistical research aimed at protecting the health of, third parties or the public in the medical, biomedical and epidemiological research, including in clinical trials of drugs, or scientific research to develop the techniques of genetic analysis (assuming the availability of only anonymous data on samples of the population does not allow research to achieve its goals), to be carried out with the consent except in the case of statistical surveys or scientific research provided by law or as otherwise referred to in par. 8.1 of this authorization.

 

For the purposes referred to in points a) and b) of this paragraph, the authorization shall be granted for the sole purpose of allowing recipients to comply or enforce compliance with specific obligations or to perform specific tasks under Community legislation, laws and regulations, in particular in terms of hygiene and public health, prevention of diseases, diagnosis and treatment, including activities transfusion and transplantation of organs, tissues and hematopoietic stem cells, rehabilitation of states of disability and physical disability and mental health, to mental health care, pharmaceutical assistance, in accordance with law. Treatment may also involve the compilation of records, certificates and other medical documents.

 

The processing of genetic data and the use of biological samples for testing presymptomatic and susceptibility is exclusively limited to the pursuit of the objective of protection of health, also to make informed reproductive choices and for research aimed at safeguarding the health .

 

Consent
In accordance with the requirements of Art. 23 and 26 of the Code, the genetic data can be processed and biological samples used only for the purposes set out in this authorization and in respect of which the person has indicated in advance and in writing informed consent. In accordance with Art. 23 of the Code, the consent shall be valid only if the person is free of any bias or coercion and may be revoked at any time freely. In the case in which the person concerned withdraws the consent to the processing of data for research purposes, is also destroyed the biological sample that is always been taken for such purposes, except that, in origin or as a result of treatment, the sample can not be more refers to an identified or identifiable person.

For treatments carried out through genetic testing, including screening, even for research purposes or for family reunification must be obtained informed consent of the subjects which is collected biological material required to carry out the analysis. In these cases, the person is required to declare if he wants to know whether the results of the examination or research, including any unexpected news concerning him, should they represent for the person concerned a specific and direct benefit in terms of treatment or prevention or awareness of reproductive choices.

  

For information on unborn consent is validly given by the expectant mother. In the event that the processing carried out by prenatal testing can also reveal genetic data related to the future occurrence of a condition of his father, has also previously obtained the consent of the latter.

  

When the processing is necessary to protect the life and physical integrity, and the latter can not lend your consens0 because of physical disability or inability to act of understanding or willing, the consent is given by his legal guardian, a spouse, a family member, a partner or, in their absence, by the head of the institution where the person concerned. The provisions of Article. 82 of the Code.

  

The opinion of the child, to the extent that it allows its age and maturity of the child, is, if possible, be taken into account, it being prominent in all cases the interests of the child. In other cases of incapacity, the treatment is permitted if the purposes sought involve a direct benefit to the person concerned and his opinion is, if possible, be taken into account, it being prominent in all cases the interests of the incapacitated person.

  

The data and biological samples from people who can not give consent for failure can be treated for purposes of scientific research that does not involve a direct benefit for the same interested whenever all of the following conditions:

1. the research is aimed at improving the health of other persons in the same age group or suffering from the same disease or are in the same condition and the research program is the subject of reasoned opinion of the competent ethics committee at planning;
2. a search for similar objectives can not be achieved by means of the processing of data relating to people who can give their consent;
3. the consent to treatment is acquired by his legal guardian, a spouse, a family member, a partner or, in their absence, by the head of the institution where the person concerned;
4. research does not involve significant risks to the dignity, rights and fundamental freedoms of the persons concerned.
5. In such cases, remains stationary as provided above regarding the need to take into account, where possible, the views of the minor or incapacitated person.