New Pharmacovigilance, and New Inputs to Legislation

December 1, 2003

Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-12-01-2003,

Europe has a new system for pharmacovigilance for human medicines up and running. It's a data-processing network and database management system for dealing with Individual Case Safety Reports (ICSRs) in 18 countries-Iceland, Norway and Lichtenstein, in addition to the 15 European Union member states.

Europe has a new system for pharmacovigilance for human medicines up and running. It's a data-processing network and database management system for dealing with Individual Case Safety Reports (ICSRs) in 18 countries-Iceland, Norway and Lichtenstein, in addition to the 15 European Union member states. It will be operational in 28 countries by the middle of next year, when Poland, the Czech Republic, Hungary, Slovakia, Estonia, Latvia, Lithuania, Slovenia, Cyprus, and Malta become EU members.

The new EudraVigilance

The new system, called EudraVigilance by The European Agency for the Evaluation of Medicinal Products (EMEA), should be "a significant milestone with major implications on the conduct of pharmacovigilance." It is open to industry as well as national regulatory authorities in all participating countries.

Peter O'Donnell

EudraVigilance is a key component in the EMEA's plan to coordinate the supervision of medicines within the EU. The dissemination of adverse drug reaction information through this pharmacovigilance database, the agency says, should help provide advice on the safe and effective use of these products. Already the existence of the network has aided rapid transmission of data between national authorities for alerts relating to faulty manufacture, serious adverse reactions, and other pharmacovigilance data.

EudraVigliance's system accepts secure transmission of ICSRs via email and the Web through an electronic gateway, with appropriate security and encryption systems. The fully automated and secure system includes all aspects of privacy, authentication, integrity and non-repudiation of all transactions in pharmacovigilance. The database management system (DBMS) will acknowledge it receives safe data from users, and can also let users run routing and loading mechanisms, query the database, take a guided tour through an ICSR creation, and oversee the management and security mechanisms.

The EudraVigilance Gateway, which follows ICH recommendations for the Electronic Standards for the Transfer of Regulatory Information (ESTRI-Gateway), offers one common portal for receiving regulatory submissions. Pharmaceutical firms that register on the system have a different common reporting point; each pharma transaction is routed through a "hub and spoke" configuration to the national authorities addressed and to the EMEA. National authorities, in turn, can use it as a secure reporting mechanism to the pharmaceutical industry and to the EMEA.

The heart of the EMEA's new system, EudraVigilance's DBMS, handles safety report information in full compliance with relevant ICH specifications. The DBMS continually updates a cumulative pharmacovigilance database compiled from the importing and consolidation of data from multiple sources, including information on medicines and adverse drug reactions. The extensive query and tracking/tracing capabilities embrace both the scientific and business perspectives.

A Web-based information system known as EVWEB is fully integrated with the EudraVigilance Gateway and Database Management System. EVWEB gives freedom for ICSRs, which users can create, send, receive, and acknowledge getting. Certain users with access rights can even search the ICSR database. The EVWEB facility is specifically designed for smaller firms that do not have a fully ICH compliant pharmacoviglance system or ESTRI gateway in place. It offers similarly secure electronic reporting to the EMEA and all participating national authorities.

The system's benefits include standardization of secure data transmission and elimination of data transcription errors, faster communication for expedited safety reporting, and a reduction in the burden and cost of paper processing for authorities and companies. The design means messages can reach every participant quicker and cheaper than by establishing a connection between each and every endpoint.

National authorities have access to all ICSRs stored in the European pharmacovigilance database. Pharmaceutical companies currently have restricted access to only the ICSRs it has submitted to the EMEA. Each ICSR stored in the database is flagged with the sending organization's ID.

Each report submitted is automatically checked through a Document Type Definition (DTD) validation to ensure compliance with ICH recommendations on component parts of the message and agreed standard terminology.

The system is complemented by two other tools. One is a EudraVigilance Medicinal Product Dictionary (EVMPD), which supports standardized coding, reliable data retrieval, and scientific evaluation of medicinal products reported in ICSRs. The dictionary has been designed to support the collection, reporting, coding, and evaluation of medicinal product data in a standardized and structured way, based on authorized regulatory information. It includes proper style standards for active ingredients, excipients, pharmaceutical forms, routes of administrations, concentration ranges and units, country codes, and the identity of marketing authorization holders. It also provides a standardized approach to support updates and variations to product information through the defined responsible product owner. And to cope with Europe's numerous languages-22 official languages across the 28 participating countries-it is multilingual.

The other complementary tool is MedDRA, which has been integrated into the EudraVigilance DBMS and EVWEB to support the coding, classification, retrieval, presentation, and communication of medical information presented in ICSRs. MedDRA-the Medicinal Dictionary for Regulatory Activities-was developed as a clinically validated international medical terminology for regulatory authorities. MedDRA is used in the pharmaceutical industry during all phases of the regulatory process; it's the standard for clinical studies, reports of spontaneous adverse reactions, events, regulatory submissions and regulated product information. Use of MedDRA codes in participating countries became mandatory in 2003 for all adverse drug reaction reporting. Smaller firms based in the participating countries can obtain reduced-price access to MedDRA at just $1,000 a year, since the EMEA recognizes that the $3,500 lowest level of normal subscription can be prohibitively expensive. Very small firms, who submit fewer than 100 ICSRs per year, can even obtain free MedDRA access.

New inputs to legislation

The major update of the EU rules on pharmaceuticals (see "No End to European Evolution" in this issue) was still being vigorously fought over as this issue of ACT went to press. The conflicting points of view argued by research-based and generic segments of the pharmaceutical industry in Europe have led to haggling over the details of intellectual property protection in the current draft text. But the tone and scope of the debate-and especially how it has drifted toward the political-can also be gauged from another principal protagonist in the discussions, the patients' lobbies.

One of the most visible organizations in this broad coalition of pro-patient (and often anti-industry) groups is the self-styled Medicines in Europe Forum, a Paris-based pressure group of scientists and political activists. As a counterpoint to the industry views on how EU rules should be changed, the Medicines in Europe Forum has been calling loudly for "a policy on medicines that puts patients first." The time for listening to the pharmaceutical industry is over, it says, suggesting that the EU is largely under the influence of international drug firms.

And it urges that patients' needs include "knowing which are the active ingredients of a drug, being informed on the added therapeutic value of a new drug, benefiting from a compassionate use programme when it is vital, reporting an adverse effect, and contributing to the transparency of regulatory agencies' activities by having a place on management boards."

As it says, with irrefutable logic, "ultimately medicines are used and paid for by patients/citizens/national insurance contributors." Accordingly, the EU rules review should place the emphasis on the needs of patients and of European citizens in general. So, they should have the information that is "key to making the best possible use of medicines." With open disdain for what it sees as secretiveness among drug firms and regulators, it asserts: "The days when doctors and pharmacists spoke Latin and prescribed secret remedies whose properties were known only to them are long over." Today, patients have the right to know what decisions are taken about their health and to be told about the expected effects of their treatments, and this includes being informed of the precise active ingredients of medicines, the Forum claims. So, it insists that packaging and in advertisements should feature International Nonproprietary Names. And patients should know "whether the medicines they are using really are the most suitable for their particular condition." One of the Forum's most strongly expressed complaints is that "many new medicines are sold without having been compared to the most appropriate drugs for the same disease already available on the market."

The remedy, it argues, is for independent information to be compiled and disseminated. "Health authorities must be able to supply comparative information on the added therapeutic value of new medicines-or on the lack of it," it says. And "this information can be obtained only if the appropriate clinical trials are carried out." What is not wanted is "information put out by the pharmaceutical companies and designed for promotional purposes."

A similarly democratic strand runs through the Forum's arguments on representation of civil society on the boards of medicines agencies. "Each day European and national medicines agencies take decisions that concern patients' health: the evaluation of new medicines and their marketing authorization; monitoring adverse effects and withdrawing drugs from the market for safety reasons; the production of information for health professionals and patients," says the Forum. And "given that the pharmaceutical industry represents huge financial stakes, it is essential for the decisions taken by the agencies to be transparent, and for this duty of transparency to be enshrined in law." In concrete terms, what the Forum wants is patient advocates in healthcare and social protection systems so they can continually "remind these institutions of their duty to protect the public interest."

The wide range of the Forum's arguments also take in the need for more scope for compassion "for patients in a therapeutic impasse," which it defines as "patients with terminal diseases, and for whom there are no effective existing treatments." They should have access to promising medicines that have not yet been authorized, it says. The principle will become practice only if national authorities are "forced to set up compassionate use programmes," by creating application procedures to allow health professionals or patient groups to seek compassionate use, and if such procedures are fully funded.

The other plea the Forum makes is for patients to be encouraged to get involved in direct reporting of adverse effects. Doctors, pharmacists and other health professionals are not all strongly motivated to report adverse effects, and do not necessarily place the same degree of importance on some adverse effects as the patients themselves, it argues. Patients should be allowed to report directly to the public pharmacovigilance system any adverse effects-for instance by filling in a form available from community surgeries and pharmacies.

The sometimes-cloistered world of clinical trials may imagine that the discussions in Brussels on future legislation are focused on the academic and scientific matters that lie at the heart of their professional activity. But, as the Forum's lucubrations demonstrate, it just isn't like that when it comes to European politics.

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