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Old 11-09-2007, 07:52 PM #1
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Default Europoe/UK...Clinical Trials Directive Hammered at EMEA Meeting in London

Clinical Trials Directive Hammered at EMEA Meeting in London

Oct 9, 2007
By:Peter O'Donnell
Applied Clinical Trials
http://www.actmagazine.com/appliedcl.../463968?ref=25

EMEA

October 3, London—A major meeting hosted in London by the European Medicines Agency provided plenty of examples from industry and academia of what doesn't work in this 2001 legislation (Directive 2001/20/EC). Even Thomas Lönngren, the Agency's executive director, acknowledged that there are problems in the implementation of the directive, and that there was "a need to find a way forward." But the contributions that European Union officials made to the debate fell a long way short of offering any dramatic improvements in the foreseeable future.

The catalogue of problems was extensive. For Alan Morrison, vice president international regulatory and safety at Amgen, the legislation needed changing, at the European and national level. There was "an urgent need to address fundamental issues" on loose definitions (particularly of what constituted "substantial" and "nonsubstantial" amendments to a trial), divergent information requirements for trial authorization applications, divergent national rules on manufacturing and labelling of investigational products, and inconsistencies in review processes both at the regulatory and ethics committee level. He pointed out that some member states impose "unreasonable" requirements going beyond the directive—such as refusal by some of them to accept the qualified person's declaration as an assurance of GMP compliance for third-country manufacturers.

Mats Ericson of Wyeth Research insisted that improvements to clinical trial authorizations had to be achieved. This would require renewed commitment from all national authorities to implementing the directive so that it resulted in harmonization. National exceptions from EU guidelines would have to be removed, agreed EU guidelines would have to be respected, and no further national guidelines should be issued. It would also need a clearer focus on public health issues—notably safety reporting.

The current duplicative assessments are not the best use of EU resources, said Ericson. Above all, what is needed is a new, additional and optional alternative procedure. This should provide one assessment and a single approval per study—particularly valuable for multinational studies. He recognized that this would require some tough decisions about which body would become responsible for the scientific review (and how it was resourced and funded), and how its "approvals" would be transposed across all member states involved in a trial. Eventually, it might even require a tough decision to switch to a single EC review, he suggested. But it was necessary to consider radical change, because there was "a fundamental flaw in the Directive which cannot be addressed within the current framework," he insisted.

For Gaby Danan of Sanofi-Aventis, safety reporting was bedevilled by divergent behaviour from country to country. He listed variations between national rules on reporting SUSARs [Suspected Unexpected Serious Adverse Reaction] (in relation to whether they originated locally, within the EU or beyond), on investigational products, on trials, on indications, and on unblinding rules. He said national practice varied on annual safety reports, with some countries demanding serious adverse reaction reports periodically, others cumulatively, some local and some global, some by trial and some inclusive, some blinded and some unblinded.

Similarly, practice in electronic transmission of case safety reports to EudraVigilance resulted sometimes in high duplication rates, and sometimes no report at all, while data quality varied widely (sometimes with no narrative or containing inconsistencies), and occasionally failed even to identify the investigational product. The variations were wide too in national requirements for transmitting information to ethics committees and investigators-whether to supply all or just local SUSARs (and whether on paper or in electronic format), whether to supply line listings or just a fraction with specific data, whether to supply expedited or periodic safety information, and whether to include SUSARs from approved trials only or from any other trials involving the investigational product.

The criticisms from academia were even more virulent. Rory Collins, BHF Professor of Medicine & Epidemiology at the Clinical Trial Service Unit at the University of Oxford, argued that the proliferation of laws and guidelines may make clinical research less reliable, and so harm patients, rather than help them. He claimed that the entire EU approach was misconceived, with an obsessive attention to procedural detail obscuring the real purpose of clinical trials.

His central thesis was that moderate effects of treatments can have large effects on public health, and reliable assessment of moderate effects on mortality and major morbidity requires large randomized trials. "Consequently, bureaucratic obstacles to large randomized trials may well inadvertently reduce public safety," he said. The directive-and its associated good clinical practice requirements-was making large trials increasingly difficult, maintained Collins: They had doubled the costs of running noncommercial cancer trials in the UK, and had added 6 to 12 month delays to starting; and they introduced uncertainties over interpretation, and increased demands for documentation. "Clinical trial units are unable or unwilling to start trials in non-UK centers due to different interpretations in different European countries," he said.

His concerns were echoed by Silvio Garattini of the Istituto Mario Negri. Increased red tape and bureaucratic requirements have doubled or quadrupled the cost of trials, and made approval of multicenter international trials more complicated. The result has been a drop in the number of independent trials, he said.

Monique Podoor, Director of the Data Centre at the European Organisation for Research into Treatments for Cancer, also complained that inefficient harmonization at member state level and disharmony at regulatory and ethics committee levels across the EU was making multinational trials more complex and increasing the administrative workload and the costs. Like many participants from academia, Podoor also highlighted the particular difficulties the directive presented for noncommercial research—because it covered only drug treatments, and imposed requirements that were excessive or irrelevant on reporting and on sponsorship.

For Stefan Bielack, a leading pediatric oncologist from Stuttgart, the directive has meant "too much paper," with safety reporting "unbelievably and unnecessarily complex for multinational trials." For expedited reports in particular, there is "too much garbage to too many recipients."

GCP inspectors too have problems with the current situation, according to Pierre Henri Bertoye of the French regulatory agency, Afssaps. Despite the directive, there is an unmet need for a harmonized reference for GCPs as an EU standard, he said—for investigators, for ethics committees, and for inspectors themselves.

Speaking for the European Network of Research Ethics Committees, Michael Fuchs from Bonn University said the directive has not changed the status quo as far as membership of ethics committees is concerned, and has allowed the continuation of differing national structures. But many of them are suffering from an increased bureaucratic burden and the complicated legal situation created by the directive—as well as, in many countries, funding difficulties.

Recommendations made during the meeting included provision of pan-European training for assessors, so as to promote consistency of approach, and a single clinical trial authorization for the whole of Europe based on mutual recognition of harmonized requirements, and with a single submission point. There was much talk of a single ethics committee opinion per member state, with clarification of the responsibilities of central and local ethics committees, a common application form for ethics committees, and parallel review of applications by the competent authority and ethics committees. There was wide support for a strengthened role of the Clinical Trials Facilitation Group operated by the Heads of Medicines Agencies in Europe. This, it was repeatedly urged, could play a key role in coordination—and arbitration—of the review process, and in providing an appeal mechanism for sponsors.

Other issues raised included academics' desires to see the scope of the directive widened to cover all clinical research, contract research organisations' concerns over the liability of the legal representative, patient representatives' concerns over transparency of trial information and informed consent of subjects, and ethics committees' aspirations for funding and training.

Hartmut Krafft of the Paul-Ehrlich Institute in Germany, representing the Clinical Trials Facilitation Group (CTFG), suggested that many of the problems identified could be solved without any change to legislation. In his view it would be enough simply to ensure greater coordination-either among member state authorities, or with more presubmission contact between sponsors and national authorities, using a voluntary harmonized clinical trial application. "At present, CTFG sees no need for a new legal framework," he said.

Similarly, Brian Davis of the UK's Medicines and Healthcare products Regulatory Agency, and another key figure in the CTFG, acknowledged gaps in the current system, but dismissed the need for major legislative changes. He conceded that there were imprecisions in definitions and divergences in national practice, and that EudraCT information is "not up to date" and Eudravigilance data "can't be analyzed." But he believed it was possible to remedy these problems within the present legal framework, with the need only for a new mandate for electronic SUSAR reports, and modified requirements relating to ethics committees.

Georgette Lalis, the European Commission director with specific responsibility for pharmaceuticals, acknowledged that there are problems with the directive, but said it had brought improvements to the quality of clinical research and the protection of patients. There would be no dramatic solutions to the issues raised, she stated. The Commission would reflect carefully on the views expressed, and would consult widely on possible remedies to the deficiencies identified. But she made it clear that most of the focus would be on achieving better coordination among national authorities within the existing legal framework.
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I long to accomplish a great and noble tasks, but it is my chief duty to accomplish humble tasks as though they were great and noble. The world is moved along, not only by the mighty shoves of its heroes, but also by the aggregate of the tiny pushes of each honest worker. ~~Helen Keller
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Old 11-09-2007, 08:05 PM #2
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Default Getting Efficacy into European Trials

Getting Efficacy into European Trials
Expect a raft of new or revised EU guidelines for efficacy testing of pharmaceuticals in '08
.

Nov 1, 2007
By:Peter O'Donnell
Applied Clinical Trials
http://www.actmagazine.com/appliedcl.../468089?ref=25

Europe remains as challenging as ever for clinical trials, but also for everyone trying to make sense of Europe as a political entity. The jumbo meeting on clinical trials at the European Medicines Agency in early October—on which a report appears at www.actmagazine.com—provided further evidence of just how complex life can become in the European Union. This unique organization binds 27 member states together tightly, voluntarily, legally—but not completely. And the conduct of clinical trials is one of the activities that keeps slipping between the gaps in the curious configuration of EU rules, which resemble wickerwork more than cast-iron.

This is not the place for a lengthy disquisition on the constitution of the EU. Suffice it to say that the 27 member states not only disagree with one another on clinical trials regulation, but that even where they do agree in principle, they frequently disregard at national level the rules they have created at the European level.

At the end of the meeting at the Agency, Georgette Lalis, the senior official from the European Commission, openly acknowledged that the majority of member states just do not comply with the guidelines they have signed up to on clinical trials. Worse, under the system in force, there is no way that either the European Commission—supposedly the watchdog of compliance —or the Agency can do anything to oblige member states to comply.


EU Documents Set for Release in Early 2008
Thomas Lönngren, the executive director of the European Medicines Agency, told Applied Clinical Trials that it was outside his powers. The Agency handles only some of the technical work on clinical trials, such as site inspections and databases, he insisted. "It is not involved in clinical trials legislation. That is in the hands of the member states and it is their responsibility," he underlined. And, he made clear, it will require "a political decision" to change the system.

Undiminished energy


Nonetheless, the key clinical trials experts at the Agency have, meanwhile, been looking ahead with undiminished energy. The Agency's efficacy working party has just agreed on its workplan for the next two years under its chairperson Dr. Barbara van Zwieten-Boot of the Netherlands. In terms of direct contact with individual sponsors, it expects to provide support in terms of scientific advice on 15 occasions each year, protocol assistance five times a year, product assessment six times a year, and postauthorization pharmacovigilance issues related to a product or a class of products just twice a year.

But the bulk of the work will, as usual, consist of the generation or revision of guidelines for efficacy testing. The ones to watch out for particularly are those still in the consultation process because there, everyone in the clinical trials community has a chance to influence the outcome. The first quarter of 2008 looks like it will see a volley of consultation documents released. A revised draft on clinical development of medicinal products for treatment of HIV infection is expected to be released for consultation in early 2008, following the adoption of a concept paper last February. So too are drafts of new guidelines on the clinical development of medicinal products for tuberculosis and Hepatitis C, now that there has been time to digest comments on the concept papers adopted in April 2007 (see Table on page 38 for a list of other consultation documents expected to see the light of day next year).

No cynicism

A cynic might be tempted to discourage the clinical trials community from getting involved in a discussion of these guidelines if the member states are not going to take them seriously. But cynicism has no place in Europe—or in this column. In general, the guidelines from the efficacy working party have tended to harmonize thinking—among regulators as well as sponsors—on new medicines development. The conspicuous member state noncompliance at present relates to the detailed guidance on methodology for the conduct of clinical trials in line with good clinical practice.

Cynics might also interpret the delays in another EU policy as evidence that it is going adrift. The Innovative Medicines Initiative (IMI) is taking on the appearance of a mythical beast—frequently referred to, but never seen. This is the partnership-in-the-making between industry and the public sector to boost pharmaceutical research and speed valuable medicines through to market. It is invoked at every pharmaceutical-related meeting in Europe as a panacea for all ills—but it still hasn't happened.

The IMI is one of six so called "Joint Technology Initiatives" introduced in the EU's new research support program, aimed at bringing together universities, hospitals, public authorities, patient organizations, clinical centers, and pharmaceutical companies to boost biomedical research and the development of new therapies. The idea is that it will create partnerships through open calls for tender, with the main focus on precompetitive pharmaceutical research—tools to make early and reliable predictions on safety and efficacy of candidate products. Priorities will be treatments for diseases like cancer or Alzheimer's, and the total budget will be o2 billion ($2.8 billion) for 2007 to 2013—half from the EU budget and half from research-based pharmaceutical companies, in the form of staff, laboratory equipment, and clinical research. The EU funding will go exclusively to smaller firms, nonprofit organizations, academia, authorities, clinical centers or patient organizations, but not to big companies.

Blessings and bottlenecks


Recently, EU ministers gave another blessing to the concept. But the European Parliament, which has to give its opinion on the exercise, is taking an uncommonly long time to get around to even a preliminary discussion of the proposal. The French MEP appointed by the Parliament to prepare its opinion, Françoise Grossetête, has still not managed to produce an initial working paper—and requests to her office for information about the drafting are stonewalled.

Things are moving faster (though no less bizarrely) in another Parliament committee that is merely offering a secondary view. Dagmar Roth-Behrendt's draft welcomes the concept of support to the development of high tech medicines, but it also insists that research into herbal and nonprescription medicines should be included too.

Meanwhile, so nervous are some pharma industry organizations becoming about the entire project that they too are clamming up, refusing to divulge not only how far they have gone toward joining the project, but also ducking questions about where they find difficulties with the proposal. "We don't like to say anything about it to outsiders," darkly muttered the spokesperson for one high tech research organization, "because every time we raise any criticism we get into trouble with the EU authorities."

Now, about that constitution...


Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.
__________________
You're alive. Do something. The directive in life, the moral imperative was so uncomplicated. It could be expressed in single words, not complete sentences. It sounded like this: Look. Listen. Choose. Act. ~~Barbara Hall

I long to accomplish a great and noble tasks, but it is my chief duty to accomplish humble tasks as though they were great and noble. The world is moved along, not only by the mighty shoves of its heroes, but also by the aggregate of the tiny pushes of each honest worker. ~~Helen Keller
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Old 11-09-2007, 09:51 PM #3
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Default Carolyn...

This whole business of investigative new drugs and the obvious need for more , larger, and testing of greater complexity in Human trials , when it was obvious that the animal tests were not translating well into the human and became increasingly more perplexing, we would often say in exasperation " what the hell are we suppossed to do, test our new drugs in human babies". Of course it was never meant to infer that further extensive human clinical trials should not be done, and NOBODY ever wanted to cut things short and lose ten times what the expected profit margins were in litigations, but clinical trials in a population of unhealthy patients (the only ones who were willing to sign off on the no contest papers), often gave results that sent many a good medicine down the drain. What's a drug research company to do? THe terrible truth is that there is always a generation that has to "pay" by taking chances for a good medication to come on stream. I don't think that will ever change. Just look at Mercks COX2 inhibitor that almost destroyed one of the country's largest drug manufacturers?
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