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.

Stuart McCully
CHCUK

We'll be releasing the latest update of our of Part 2 of the NIS Considerations (Europe) report in October.

If you have previously purchased  the report you will automatically receive a complimentary copy.

The MHRA were asked the followinh question at a recent MHRA GPvP Symposium:

  

How often do we need to collect non-serious reactions from non-interventional studies?

 

Please clarify the expectation for non-serious reports from non-interventional studies.

 

 

MHRA Response: 

In accordance with legislation, "Marketing authorisation holders shall record all suspected adverse reactions in the Union or in third countries which are brought to their attention, whether reported spontaneously by patients or healthcare professionals, or occurring in the context of a post-authorisation study................ Marketing authorisation holders shall submit electronically to the Eudravigilance database information on all non-serious suspected adverse reactions that occur in the Union, within 90 days following the day on which the marketing authorisation holder concerned gained knowledge of the event".

 

In the transitional period, some National Competent Authorities are already requesting direct reporting of non-serious cases which may include non-serious from post-authorisation studies. Non-serious reports from non-interventional studies should also be considered as part of ongoing safety evaluation.

 

Therefore, the MAH should ensure an appropriate periodicity of case collection such that they can comply with the legal requirements.

 

For further information, refer to:

• MHRA GPvP Symposium Questions: 17/06/2013

The ePRO Systems Validation Good Research Practices Task Force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) has published a report on the 'Validation of Electronic Systems to Collect Patient-Reported Outcome (PRO) Data - Recommendations for Clinical Trial Teams'

 

Abstract

Outcomes research literature has many examples of high-quality, reliable patient-reported outcome (PRO) data entered directly by electronic means, ePRO, compared to data entered from original results on paper. Clinical trial managers are increasingly using ePRO data collection for PRO-based end points. Regulatory review dictates the rules to follow with ePRO data collection for medical label claims. A critical component for regulatory compliance is evidence of the validation of these electronic data collection systems. Validation of electronic systems is a process versus a focused activity that finishes at a single point in time. Eight steps need to be described and undertaken to qualify the validation of the data collection software in its target environment: requirements definition, design, coding, testing, tracing, user acceptance

 

 

The report is a guide on the requirements and documentation needed from a data collection systems provider to demonstrate systems validation. It is a practical source of information for study teams to ensure that ePRO providers are using system validation and implementation processes that will ensure the systems and services: operate reliably when in practical use; produce accurate and complete data and data files; support management control and comply with any existing regulations. Furthermore, this short report will increase user understanding of the requirements for a technology review leading to more informed and balanced recommendations or decisions on electronic data collection methods.

 

For more information, refer to:

• Validation of Electronic Systems to Collect Patient-Reported Outcome (PRO) Data - Recommendations for Clinical Trial Teams: Report of the ISPOR ePRO Systems Validation Good Research Practices Task Force (2013)

 

The PRO Good Research Practices for the Assessment of Children and Adolescents Task Force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) has published a report on 'Pediatric Patient-Reported Outcome Instruments for Research to Support Medical Product Labeling'

 

ABSTRACT

 

Background: Patient-reported outcome (PRO) instruments for children and adolescents are often included in clinical trials with the intention of collecting data to support claims in a medical product label.

 

Objective: The purpose of the current task force report is to recommend good practices for pediatric PRO research that is conducted to inform regulatory decision making and support claims made in medical product labeling. The recommendations are based on the consensus of an interdisciplinary group of researchers who were assembled for a task force associated with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). In those areas in which supporting evidence is limited or in which general principles may not apply to every situation, this task force report identifies factors to consider when making decisions about the design and use of pediatric PRO instruments, while highlighting issues that require further research.

 

Good Research Practices: Five good research practices are discussed: 1) Consider developmental differences and determine age-based criteria for PRO administration: Four age groups are discussed on the basis of previous research (<5 years old, 5-7 years, 8-11 years, and 12-18 years). These age groups are recommended as a starting point when making decisions, but they will not fit all PRO instruments or the developmental stage of every child. Specific age ranges should be determined individually for each population and PRO instrument. 2) Establish content validity of pediatric PRO instruments: This section discusses the advantages of using children as content experts, as well as strategies for concept elicitation and cognitive interviews with children. 3) Determine whether an informant-reported outcome instrument is necessary: The distinction between two types of informant-reported measures (proxy vs. observational) is discussed, and recommendations are provided. 4) Ensure that the instrument is designed and formatted appropriately for the target age group. Factors to consider include health-related vocabulary, reading level, response scales, recall

period, length of instrument, pictorial representations, formatting details, administration approaches, and electronic data collection (ePRO). 5) Consider cross-cultural issues.

 

Conclusions: Additional research is needed to provide methodological guidance for future studies, especially for studies involving young children and parents' observational reports. As PRO data are increasingly used to support pediatric labeling claims, there will be more information regarding the standards by which these instruments will be judged. The use of PRO instruments in clinical trials and regulatory submissions will help ensure that children's experience of disease and treatment are accurately represented and considered in regulatory decisions.

 

 

For more information, refer to:

• Pediatric Patient-Reported Outcome Instruments for Research to Support Medical Product Labeling: Report of the ISPOR PRO Good Research Practices for the Assessment of Children and Adolescents Task Force (2013)

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:

• WMA Press Release (15 April 2013)
• The document for public consultation may be downloaded here 

The Code of Marketing Practice of the Irish Pharmaceutical Healthcare Association (IPHA) was updated in July 2013.

The changes include revision of Section 12.3 and addition of ANNEX IV, see below:

 Further information can be found at:

The European Network of Centres for Pharmacoepidemiology & Pharmacovigilance (ENCePP) is a pan-European initiative that brings together pharmacoepidemiology and pharmacovigilance expertise and resources in a functioning network. Participation in ENCePP is voluntary and the network aims to build capacity and take pharmacoepidemiology to the next level guided by the principles of transparency, scientific independence and robust methodologies.

 

The ENCePP Work Plan 2011 -2012 defined the objectives and milestones for the period in the context of the operation and future development of the net work. One of the essential deliverables of the

work plan was the development of approaches to facilitate the conduct of multi-national studies in the context of differences at national level in the implementation of Directive 95/46/EC on the protection of individuals with regard to the processing of personal data and on the free movement of such data.

 

To progress the deliverable, led by the ENCePP Working Group 'Data sources and multi-source studies' (WG 3), it was agreed to establish current status regarding meeting national legislative requirements for data privacy among individual EU Member States as a baseline for future work.

 

Further information can be found at:

• ENCePP Survey of EU Member States National Legal Requirements on Data Protection (July 2013)

The Guide continues to be the single most downloaded document on the ENCePP website with over 30,000 hits in 2012. The Guide is updated annually to maintain its dynamic nature and ENCePP has just published a second revision. New sections on 'Effect modification' and 'Handling of missing data' are included. A set of 'Specific topics' with two chapters on 'comparative effectiveness research' and 'vaccine safety and effectiveness' has also been inaugurated.

The revised guide continues to offer a single overview document and web resource for methodological guidance for both experienced and new researchers in pharmacoepidemiology and pharmacovigilance. For each topic covered, direct electronic access is given to internationally agreed recommendations and key points from important guidelines, published articles and textbooks after an introductory review. Where relevant, gaps in guidance have been addressed with what ENCePP considers good practice.  For ease of access to individual topics of interest, a web version has been published with links to each chapter and section. A consolidated version is also available for download.

Further information can be found at:

• ENCePP Guide on Methodological Standards in Pharmacoepidemiology (Revision 2, June 2013) 

Läkemedelsindustriföreningen is the trade association for the research-based pharmaceutical industry in Sweden.

The Ethical Rules for the Pharmaceutical Industry" which came into force on 1 October 2007 and were latest revised in May 2013, with the revisions in force from 1 July 2013.

The revisions are minor and have no direct impact on the contact of non-interventional studies.

Further information can be found at:

• Ethical rules for the pharmaceutical industry in Sweden