An Agency Fore-warned Is an Agency Fore-armed

As every attentive reader of this column knows only too well, the final word on the European Unions three-year-long review of pharmaceutical regulation is awaited almost dailyand this will change many of the ground rules and operating conditions for the London-based agency, giving it responsibility for assessment of an even wider range of medicines.

At the same time, the 10-year countdown to the EUs biggest-ever enlargement has just weeks to go: on 1 May 2004, the current 15 EU member states will be joined by 10 additional members, with eight of them from the former Soviet bloc. The EMEA is going to have to cope with a flood of new business, new people, and, undoubtedly, new problems.

By coincidence, this historic date also marks another deadline, long-awaited by the clinical trials community in Europe. This is the date when the EUs member states are due to start enforcing the provisions of its clinical trials directive adopted three years ago¹in their national legislation. These new rules are going to route much more work through the EMEA, since it will be responsible for scientific assessment of new medicines, and all EU states will be readying or submitting marketing authorization applications to the agency.

Not surprisingly, therefore, the agency is trying to make sure it is ready for so much change.

To prepare for the final decision on the EUs review of pharmaceutical legislation, the agency is aiming to reinforce its scientific evaluation processes with greater professionalism. A spokesman for the EMEA said the immediate changes are not pre-empting EU legislation, but merely implementing policy decisions already taken to streamline the agencys work.

The EMEA action plan focuses particularly on quality management, in light of a 2003 audit of the scientific committee responsible for human medicines, the Committee on Proprietary Medicinal Products (CPMP). The integrated quality management system available at the EMEA will be strengthened to achieve what the agency sees as an adequate level of scientific and regulatory consistency in the outcome of the scientific evaluation processes.

One of the key elements to boost the quality and the scientific and regulatory consistency of the work undertaken by the EMEA and the CPMP will be increased consultation with pharmaceutical companies during the early development of new medicines. Increased interaction with companies, including thorough oral explanations and discussion of development plans, can lead to greater efficiency in providing EMEA scientific advice and assistance in developing drug-testing protocols, the agency says.

More high-level specialized expertise will be brought into the scientific evaluation processes, so that the agency is able to do justice to authorization applications for products on the frontiers of new science. At the same time, the monitoring of medicines already on the market will become more proactive through the agencys pharmacovigilance services, again with the involvement of specialized expertise.The preparations are also well under way to ease the impact of EU enlargement in May.

The EMEA has been working systematically on this since July of last year, providing information and guidance to applicants and marketing authorization holders during the run-up to accession of the new member states. There have been numerous meetings with the regulatory staff of the acceding states and with the pharmaceutical industry, focusing on the phasing-in of the EMEAs centralized authorization procedure, pharmacovigilance, documentation requirements, product information, and linguistic review. There is a huge task to be accomplished just in ensuring that labels, leaflets, and other documentation are adequately translated into the 19 official languages that the EU will work with starting in May.

As to the impending deadline for the full implementation of the clinical trial directive, events are currently in the hands of the member states, who are supposed to be putting into place all the necessary regulations and guidelines to operate according to the new rules. By the end of Januaryjust a dozen weeks away from the deadlineonly Denmark, Sweden, and Italy had actually transposed the directive into their national law, so the chances are not looking too good for an EU-wide outbreak of clarity, harmony, and understanding on 1 May. The European Commission, the EUs civil service legally responsible for ensuring that member states obey EU rules, laconically informed Applied Clinical Trials in January: The Commission is carefully following the implementation process of Directive 2001/20/EC in the member states.

The EMEA has, however, already earmarked some of the time allocation of its efficacy working party in 20042005 to assessing the implementation of the directive (see also below).

Efficacy expectations
Meanwhile, the EMEAs specialized working party on efficacy, which handles most of the clinical trials-related business of the agency, has drawn up a formidable work program for 20042005. It aims to meet four times a year, for two days each, and it is going to have plenty to talk about if its plans are to be realized.

Most of the work will take the form of creating and consulting on a huge series of guidance notes on clinical investigation of different product groups. By mid-2004 it is planning to release concept papers relating to neuropathic pain management and social anxiety disorder for consultation, and to finalize notes for guidance relating to products for generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder.

In the cardiovascular field, it is planning by mid-2004 to finalize further guidance relating to acute cardiac failure and lipid disorders, and, by the same time, to put out updated draft guidance or concept papers on stable angina pectoris, hyptertension, secondary prevention of cardiovascular events, and fixed combinations of antihypertensives and lipid-lowering agents.

The first half of 2004 is also the expected release date for draft guidance on steroid contraceptives, ankylosing spondylitis, juvenile arthritis, and psoriatic arthritis. At the same time, a new concept paper is scheduled on hepatitis B, as well as a final version of guidance on bacterial infections.

Consultation is going to be opened up during 2004 on some of the biostatistical and methodological issues arising out of the agencys scientific discussion of marketing authorization applications. Top of the list is the choice of the inferiority margin, but draft advice is also forthcoming on flexible design and analysis of confirmatory clinical trials and on data management boards.

Pharmacokinetics, too, will be under the spotlight during this year. Draft guidance is scheduled on clinical investigation of the pharmacokinetics of peptides and proteins, and on the pharmacokinetics of medicines in children and in patients with hepatic impairment. Plus, a finalized version of guidance on pharmacokinetics in patients with impaired renal function is also due to appear shortly.

Finalization is also envisioned before the end of 2004 for guidance on clinical documentation for metered dose inhalers, on products for the treatment of psoriasis, on products for allergic rhino-conjunctivitis, on clinical requirements for modified release products submitted as a line extension, and on comparability of products containing biotechnology-derived proteins as their active substance.

New draft guidance is scheduled on products for sepsis, anti-emetics for use in oncology, clinical trials in small populations, post-marketing data on products for use in pregnancy, and risk assessment of human reproductive products. And an efficacy working party paper on quality of life is due for publication before the end of 2004.

The working party is also due to contribute to International Conference on Harmonisation activities during 2004, including making its input to reflections on assessing QT prolongation potential, and pharmacovigilance planning.

Without a fixed date, and therefore more likely in 2005 than 2004, are plans for draft guidance on local products containing known ingredients, fixed combination products, and clinical trials with haematopoietic growth factors for the prophylaxis of infection following myelosuppressive or myeloablative therapy.

It comes as no surprise that the list of guidance notes and activities for 2005 is less complete and explicit: if the working party manages to do everything already scheduled for 2004 it will deserve a breakand so will the clinical trial community!

Throughout the entire two-year period, the working party is also expected to play its part in EU regulatory activities, such as following up the implementation of the common technical document that is being introduced for marketing authorization applications, and offering views on possible changes to EU rules on the summary of product characteristics (as well as following up on the clinical trial directive, as mentioned above). And it is tasked with liaisoning with the FDA and other national and international agencies, and meeting with learned societies and organizations of health professionals, patients, and drug companies.

In addition, the working party expects to be requested to give scientific advice on 10 products per year, as well as six times a year on protocol assistance, product assessment, and postauthor-ization issues.

Scientific advice
The provision of scientific advice by the EMEA is a rapidly growing activity. New figures just released show how busy the CPMP is becoming in its fieldas part of its bid to become more proactive and professional in its dealings with applicants and potential applicantsof marketing authorizations for innovative products.

In January 2004 alone, the CPMP issued nine separate advice letters and accepted requests to give advice in another five cases. The type of advice covers straightforward scientific advice and guidance on developing protocols, and companies can come back for follow-up after receiving initial input. The topics on which advice can be sought are classified by the agency as pharma-ceutical, preclinical, clinical, and significant benefitbut in every case in January, it was the clinical area that companies were seeking assistance on.

The products the CPMP was asked to advise on were biologicals for prophylaxis of HPV infection, Fabry disease, and treatment of multinodular goiter, as well as chemical-based treatments for Parkinsons disease, uraemic pruritis, type 2 diabetes, functional dyspepsia, chemotherapy-induced nausea and vomiting, and prostate cancer.

Even further ahead
Looking to an even more distant future, the European Union has just announced plans aimed at helping Europe develop in the growing field of tissue-engineered products, a market predicted to be worth 4 billion worldwide by 2007, and subsequently 400 billion and beyond. It may not mean more work for the EMEA, because the current haphazard classification of such products keeps them separate from medicines. But their development is sure to mean a big boost to the clinical trials sector, even if its a different regulatory authority that will be in charge.

A new study carried out for the EU anticipates developments outstripping the current range of tissue-engineered products such as artificial skin, cartilage, and bone, and predicts the emergence of complex products in cardiovascular and central nervous system indications. It raises the prospect of tissue-engineered heart valves, vessel grafts, and heart muscle tissue, or treatments for Alzheimers and Parkinsons, and for damaged nerve fibers and spinal cord injury. The breakthrough will come when tissue-engineered products appear that can save life or that are much more effective or cheaper than existing conventional treatments, says the reports author, Anne-Katrin Bock, of the EUs Institute for Prospective Technological Studies. Further ahead, the report suggests the construction in vitro of human organs to overcome the scarcity of donor organs, and to improve treatment of diseased urinary bladders, kidneys, hearts, livers, and pancreases.

The EU is promising to bring in a new and clearer regulatory framework to stimulate the sector. European Research Commissioner Philippe Busquin says divergent European regulations are an obstacle to the growth of tissue-engineering markets in Europe. He aims to help tissue engineering companies overcome the challenges they face because of uncertainties in market development, and nonreimbursement of their products by health insurance systems. He recognizes that the small biotech companies involved do not have the resources for large, long-term clinical trials to provide information on the cost-effectiveness of the treatment compared to conventional alternatives. And, says the study, the lack of cost-effectiveness data is the main reason insurance companies refuse to reimburse treatment with tissue-engineered products.

References1. Directive 2001/20/EC relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

SIDEBAR: Whos Who in the Enlarged Europe
The 10 new member states that will join the European Union on 1 May 2004 are: Poland, the Czech Republic, Hungary, Slovakia, Estonia, Latvia, Lithuania, Slovenia, Cyprus, and Malta. These will make a 25-member EU, as they are added to the existing 15: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Italy, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, and the United Kingdom. The work of the EMEA also covers Iceland, Norway, and Liechtenstein. Those three countries are linked to the EU on pharmaceutical matters through their membership of the European Economic Area, a grouping designed to bring the members of the EU and the European Free Trade Association together. It will have 28 members after the EU enlargement. Switzerland, although a member of EFTA, did not subscribe to the EEA and remains therefore autonomous in pharmaceutical legislation.

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