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EU's new rules will be influenced by more than just those primarily responsible for pharmaceuticals.
It is important to "strike the necessary balance" on European pharmacovigilance, say officials of the European Union. The mildly admonitory tone appears in a consultation (yet another consultation) that they have launched over how to connect the dots in the EU's new pharmacovigilance rules; adopted at the start of this year, but a lot of details need filling in before the rules can come into force.
The detailed rules must be "fit for purpose," say officials in the introduction to the consultation document ("Implementing Measures in Order to Harmonize the Performance of the Pharmacovigilance Activities Provided for in Directive 2001/83/ec and Regulation (EC) no 726/2004: The Concept Paper Submitted for Public Consultation"). The balance they must strike is between protecting public health and allowing the European market for medicines to function—in other words, not too much bureaucracy that will clog up the system.
A glance at the details that have to be agreed upon indicates clearly where the risks of clogging up the system might lie. The list of topics extends from "the content and maintenance of the pharmacovigilance system master file kept by the marketing authorization holder" to "the format of protocols, abstracts, and final study reports for the post-authorization safety studies," and from "the minimum requirements for the quality system for the performance of pharmacovigilance activities by the national competent authorities, the European Medicines Agency (EMA), and the marketing authorization holder" to "the format and content of electronic periodic safety update reports and risk management plans."
That's not all. The list also extends to "the use of internationally agreed terminology, formats, and standards for the performance of pharmacovigilance activities," "the minimum requirements for the monitoring of data in the Eudravigilance database to determine whether there are new risks or whether risks have changed," and "the format and content of the electronic transmission of suspected adverse reactions by member states and the marketing authorization holder."
The consultation document has been drafted on the basis of technical work by a team of experts from member states and the EMA. That means, say Commission officials, introducing another twist of complexity to the exercise, that it does not necessarily represent the position of the European Commission. "Instead, it is a tool to explore the views of interested parties on a preliminary proposal."
There is not space in this column (or indeed in this entire issue of Applied Clinical Trials, I fear) to set out the proposals, but as a taster here are some elements from an annex entitled "Protocols, Abstracts, and Final Study Reports for the Post-Authorization Safety Studies." Across seven pages and several thousand words, this provides definitions, preconditions (including "a written study protocol...notified to EMA").
Marketing authorization holders will have 12 months from the end of data collection to send EMA the final study report, including a public abstract indicating the rationale and background, research question and objectives, study design, population, variables, data sources, study size, data analysis, and milestones.
By way of example, this is what the annex requires on data sources: "Strategies and data sources for determining exposures, outcomes, and all other variables relevant to the study objectives, such as potential confounding variables and effect modifiers. Whenever validated data source, instruments and measures are used, the validation method should be described. If data collection methods or instruments are tested in a pilot study, plans for the pilot study should be presented. Any expert committees and evaluation procedures to be used to validate diagnosis should be described. Whenever the study will use an existing data source, such as electronic health records, any information on the validity of the recording and coding of the data should be reported. In case of a systematic review or metaanalysis, the search strategy and processes and any methods for confirming data from investigators should be described."
Data analysis will have to set out all the major steps that lead from raw data to a final result including: methods used to correct inconsistencies or errors; impute values; modify raw data; categorize, analyze, and present results and procedures to control sources of bias and their influence on results; and any statistical procedures to be applied to the data to obtain point estimates and confidence intervals of measures of occurrence or association and any sensitivity analysis.
Under "limitations of the research methods," marketing authorization holders are required to indicate any potential limitations of the study design, data sources, and analytic methods, including issues relating to confounding, bias, generalizability, and random error. The likely success of efforts taken to reduce errors should also be discussed, says the draft text.
Details are required of how companies plan to manage and report adverse events or reactions. This covers procedures for collecting, managing, and reporting of individual cases of adverse events or adverse reactions. It should always be stated where it is not feasible to make a causality assessment at the individual case level, for study designs such as case-control or retrospective cohort studies, particularly those involving electronic health care records, systematic reviews, and meta-analyses.
Laconically, after several more pages of the same density, the annex concludes with the bald question: "Do you agree with the proposed format? Please comment."
The consultation ends on November 7. "All contributions will be carefully analyzed. The implementing Regulation will build on the consultation," say EU officials. So if you are worried about how the pharmacovigilance rules could clog up your systems, take a look at the document and put your views in. [Editor's Note: To view an on demand webinar, "Understanding the New EU PV Regulations," go to http://bit.ly/oS77Nk].
While this column may occasionally draw attention to a consultation of particular interest to drug developers, it isn't its usual role to alert readers to upcoming calls for proposals for research funding. Plenty of other sources do that, and on timelines that are much tighter than the more leisurely rhythm of a monthly magazine. But it is certainly germane to give wider prominence to some of the research funding opportunities that crop up in Europe—and on this occasion, might also serve as an alert to some of those opportunities too.
The European Union's research program is inviting bids for funding for a range of clinical (and sometimes pre-clinical) projects. One is a call relating to preclinical and/or clinical development of substances with a clear potential as orphan drugs. The EU is offering support to pharmacological, pharmacodynamics, pharmacokinetics, and toxicological studies in models, and/or to clinical studies, including Phase III trials, of EU-designated orphan medicines.
The clinical studies should be focused on biopharmaceutical studies (including bioavailability, bioequivalence, and in vitro-in vivo correlation), human pharmacokinetic and pharmacodynamic studies, human efficacy, and safety studies, say the specifications, and trials will have to be appropriately powered to produce statistically significant evidence.
The EU "strongly recommends" the involvement of industry, and particularly of smaller firms, but diagnostics and therapies for cancer and nervous system diseases are excluded from the scope of this call. Plans to engage with patient organizations and the EMA will be expected as part of the proposal, and the projects should contribute towards the International Rare Diseases Research Consortium's goal of seeing 200 new therapies developed for rare diseases by 2020.
Smaller projects can ask for up to $6 million in support, and in return they are expected to deliver appropriate information to start clinical development of orphan drugs, if the project includes preclinical development, and/or to improve care of patients with rare diseases if the project includes clinical development. Collected data should be of sufficient quality to be further exploited in marketing authorization requests.
Another invitation—with $3 million on offer per project—concerns observational trials in rare diseases. The aim is to improve clinical practice in the management of rare diseases patients, and research should include the comparison of outcomes of various prevention or treatment/intervention regimens for those rare diseases for which no orphan drug is available and that are being treated off-label. Studies should include the evaluation of effectiveness and adverse events, and look particularly at the definition of appropriate outcome measures. For this call, studies on cancer, infectious diseases, and nervous system diseases are excluded. And again, projects should include plans to engage with patient organizations and to ensure uptake of developed guidelines widely and rapidly. The projects should lead to accepted evidence-based clinical guidelines for better care of patients afflicted by rare diseases for which no dedicated treatment is currently available.
Support of up to $2 million is being made available for sharing best practice and knowledge in the clinical management of the widest range of rare diseases. The principal aim is to sponsor development of a networking platform for collecting standardized and validated data, and for exchanging information about best management. But a secondary objective is to identify additional research needed for improving clinical practice. The project must be designed so that the platform will remain sustainable after the EU financing—nearly $600 million for all related projects.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.