Meetings and Conferences

Joint Pharmaceutical Analysis Group

Implications of new clinical trial directive

The implications of a new European Union directive affecting the production and use of clinical trials supplies was the topic for a Joint Pharmaceutical Analysis Group symposium held at the Royal Pharmaceutical Society, London, on 14 June

Introduction
Overview
CTX applications
Regulatory affairs view
Manufacturer’s view
Issues for hospital pharmacy
Inspection under the directive
Symposium on a harmonised approach to medicines registration

Introduction

European union directive 2001/20/ EC, dated 4 May 2001, is concerned with “the approximation of the laws, regulations and administrative provisions of the member states relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use”. The new directive was published on 1 May in the Official Journal of the European Communities (L121, pp34-44). EU member states have until 1 May 2003 to prepare national provisions for complying with the directive and must adopt those provisions by 1 May 2004.

The six speakers at the JPAG symposium discussed the changes that would have to be made to current clinical trial supply systems and raised a number of questions that would need to be answered before the directive’s implementation date of May 2003.

Overview

Dr ROGER ALEXANDER (Medicines Control Agency) explained the legislative process for transposing the directive, and its incomplete annexes, into United Kingdom law by May 2003. The MCA would prepare a regulatory impact assessment and seek ministerial approval for formal, wide, consultation before draft Statutory Instruments were tabled for “negative resolution”, with any parliamentary objections raised as “prayers”. A further year was allowed to complete implementation.

Reviewing the key issues of the new directive, Dr Alexander said that it was firmly founded on the historic 65/65 and 75/318 directives. Article 1 set out the scope, applying the principles of good manufacturing practice (GMP) to “investigational medicinal products” (IMPs) for human use but excluding “non-interventional” trials (eg, epidemiological studies with already authorised drugs). The definitions in Article 2 applied to trials with new products and also placebo and comparator drugs, and provided wide powers of inspection. Later articles dealt with manufacture and import of IMPs, their authentication and the role of the “qualified persons” (QP), labelling (with some dispensations for academic research trials), inspection, and notification of adverse events. Eight guidance notes, derived from annexes to the directive, were mostly still only in skeletal form (eg, for application format, and for labelling) but the one on GMP was well advanced. Other guidance notes had to be drafted before September 2002, and published in OJ by 1 January 2003, to meet the implementation deadline of 1 May 2004.

The MCA was developing procedures to implement the directive. These involved monitoring GMP for trials supplies, inspection of standards of good clinical practice (GCP), the format of application and approval procedures — and an appropriate fee structure. It would run formal awareness seminars from October, and also a series of meetings with target groups. Some EU member states already had legal GCP systems, but these would now have to be harmonised with the directive.

Dr Alexander coined an acronym, “GCX”, for team inspection that would subsume GMP of supplies, GCP in the clinical studies, and GLP (good laboratory practice) in testing. The novel experience would “place tremendous weight” on the new clinical trials inspectors, who had to be Superman and Wonderwoman.

CTX applications

Dr ELAINE GODFREY (MCA) discussed the effect of the directive on the clinical trail exemption (CTX) scheme, under which a manufacturer could make supplies for clinical trials without having to hold a clinical trial certificate (CTC) or a marketing authorisation. CTX approval depended on the same information as was needed to obtain a CTC, but it was much speedier because a 50- to 60-page summary would be assessed by the MCA within 35 days. The study could then commence, unless extended (for 28 days) or given reasoned refusal.

A CTX applicant gave undertakings to provide reports within 15 days of any serious unexpected adverse drug reactions (ADRs) and then to summarise other ADRs, and any other safety concerns, at time of renewal or end of study report. In addition to the customary chemistry and pharmacy submitted for a new chemical entity, there were special requirements for biotechnology/biological, blood-derived and vegetable-derived products. The CTX scheme operated by negative vetting, with refusal only on safety grounds — including concerns regarding quality of product to be administered.

Dr Godfrey emphasised aspects of GMP for supplies and GCP in the trials, indicating the quality framework, types of authorisations, conditions that may be applied, and guidelines to be expected. She detailed the underlying ethical culture and committee structure in the directive) and — of special concern to the MCA — the format and time-scales of authorisation. She noted scope for uncertainty in the treatment of amendments and that rational reasons must be given for suspension (or prohibition) of a trial and accepted that it was frustrating that guidance notes were not yet available.

Highlighting features of the current system that would be changed, Dr Godfrey said that at present, trial products were manufactured to the principles of GMP, but release by a QP was not essential, and no GMP inspections are required. In addition, there was no statutory basis for research ethics committees and no statutory timelines for ethics committee approvals. After implementation, the directive would apply to all except non-interventional clinical trials. It introduced a legal basis for GCP and GMP and a statutory basis for research ethics committees, and it defined timescales for both the competent authority and ethics committees. Other notable differences included a maximum 60 days for approval (except for gene therapy, etc), inclusion of studies with healthy volunteers, authorisations for manufacturers and importers, and formalised clinical trials inspection. The main effect on the MCA would be an increased workload, shorter timelines and increased cross-agency liaison.

Regulatory affairs view

MOIRA DANIELS (AstraZeneca) analysed the impact of the directive on the drug development process, focusing on issues relating to clinical development in Europe, and not just the UK. She referred particularly to the lack of complete versions of the eight guidance notes, and to differences in preparedness between member states. Across the EU there were wide differences in “time frames” before initiation of phases I to IV studies and in maintenance and variation of trial notifications.

Ms Daniels rehearsed the scope for uncertainty in a catalogue of questions. What exactly was a “non-interventionist trial”? What were mandatory requirements for protection of, and contact with, trial subjects? Why was there an extra 90 days for ethics committee review? Would full documentation be required for every significant change, especially if an applicant was waiting 35 days for an ethics committee decision and 60 days for the competent national authority. Could exchange of information remain confidential to the competent authority and not available through the ethics committee? If a trial was suspended by a member state, why did the sponsor have only one week to respond? The manufacturer of an IMP required his QP to keep documentation for five years, but what would be the interim requirement for a trial straddling the effective date (1 May 2004)? For CT supplies imported from non-EU countries, re-testing might not be required if from a site authorised by the competent national authority, but how would this work in practice — and what about imported comparator material?

For trial reporting requirements, safety remained the primary concern, but Ms Daniels hoped that duplication would be reduced. She looked for a level playing field across Europe in respect of labelling and in the use of the QP. She wanted consultation on adverse drug reaction reporting and clinical safety regulation (in comparison with proposal from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). More generally, she wanted better consultation between member states, the European Medicines Evaluation Agency and all interested parties.

Ms Daniels concluded that, in preparing for the new regulatory framework for clinical trials in Europe, she would like to be able to peep over the wall to see the details of implementation and be able to make on-going plans. Some questions on her paper referred to third country production sites (should a company audit suffice or would foreign inspection be required?) and what extra was required of QPs trained in historic GMP for oversight of CT supplies?

Manufacturer’s view

JOHN BLACKBURN (GlaxoSmithKline), who focused on GMP aspects, began by criticising the draft directive submitted by the EU Commission in September 2000, which would have applied Chapters IV and V of Directive 75/319 to IMPs. The considerable implications would have included full inspection and licensing of facilities for GMP compliance and the requirement for release of each IMP by a QP. For supplies from a third country, each batch would have needed full quality testing at the point of entry into the EU. This was totally inappropriate and would have created serious problems for many multinational companies and serious implications for packed supplies and comparators. The appropriate approach was auditing suppliers and the application of a QP’s judgement on release based on a certificate of analysis and other quality information.

Fortunately, common sense had prevailed and the final version applied GMP to CT supplies via directive 91/356, rather than the (yet to be revised) 75/319. The GCP directive now required release by QP of all supplies, including Phase I trials. Those coming from non-EU countries had to be manufactured to GMP standards at least equivalent to those of the EU. A grandfather clause covered all QPs who currently released IMPs, but the directive would require inspection and licensing of manufacturing facilities. A QP had to be able to guarantee GMP compliance to all medicinal substances used in the trial because Annex 13 would become a legal obligation.

Three unresolved issues were MCA implementation of inspection and licensing in the UK, the effect on multinational trials of variable speed implementation across the EU, and requirements for QP release of IMPs imported from a non-EU country (whether the same company, with similar systems, or another company, with different protocols).

There were also issues with current GMP guidance in Annex 13 of 91/356/EEC. In some cases, the guidance was virtually impossible to follow (eg, requiring expiry labelling before the investigator’s name and trial date were known) or it applied “poor science”, such as manipulated comparator expiry dates. Other aspects to resolve included the product specification file, labelling requirements, retention sampling, transfers of supplies between trial sites (including security, continuing suitability and relabelling) and retention of unused CT supplies until the final report, which was “impracticable and illogical”. Mr Blackburn hoped that the same common sense approach would be taken over revision of Annex 13 as had been taken over the final version of the Directive.

Issues for hospital pharmacy

STEPHEN POTTER (Queen Elizabeth Hospital, Birmingham), presented a personal view of the issues facing hospital pharmacy in providing support to both commercial and research clinical trials, described the types and ranges of studies being undertaken, and the “conflicts and confusions” created by the stakeholders.

He distinguished three strands: ethical approval (without regard to workload); then hospital research approval (could the trust cope without a major resource budget?); and ultimately, could the trust afford the patient treatment cost of a successful outcome (ie, without sponsor help for “compassionate” cases)? Current areas of research ranged from studies with licensed products to those with novel substances, including cytotoxics, biomodifiers and gene therapy.

Mr Potter was critical of clinical research assistants, who were “ignorant of constraints and guidance” and suffered “trialist fixation”. Then there were problems with sponsors, such as poor structure (or translation) of trial protocol, stop/start delays, poor supply of trial material, and inaccessibility when needed. Current trials and tribulations included: the disproportionate lack of CT resource for National Health Service hospital pharmacy; the variable complexity of tasks and products (eg, gene therapy); a lack of dedicated staff available to deal with trials; too much rule-breaking, such as changing to an alternative product not in the original protocol, and lack of consistent conduct of trials; and environmental constraints, including small dispensaries and a need for special facilities for the preparation of intravenous and cytotoxic regimes.

Mr Potter recalled experiences resulting from a voluntary GCP site inspection of non-commercial clinical trial activity. The inspection findings emphasised the importance of always writing a standard operating procedure, and induced a raised awareness within the trust. The chief executive had found it “useful and instructive”. Mr Potter’s initial anxieties had been removed by this inspection — only to be replaced by a new set.

Mr Potter therefore welcomed the principle of the harmonised GCP directive and shared his thoughts on its impact on hospital pharmacy practice and possible outcomes. He singled out separation of commercial trials, sharing of dedicated staff, wider availability of QPs, and specialist environmental facilities (which few sponsors were willing to fund). The directive might lead to regional, centralised, units, but such units, although safe and efficient, would unfortunately reduce local ownership and enthusiasm.

Inspection under the directive

DAVID COCKBURN (a senior medicines inspector) addressed developments in GMP inspection initiated by the directive through the application of the principles and guidelines of GMP and obligation to inspect. Necessary consequential amendments to the GMP directive 91/356 included a definition of “blinding”, emergency unblinding, specific training on IMP production and controls, retention times for records, and validation.

Mr Cockburn explained that GMP guidelines had three tiers: principles and guidelines (defined in directive 91/356), for which compliance was mandatory; interpretative guidelines (EC GMP guide); and the 17 supplementary annexes to the GMP guide. A proposed revision of Annex 13, now at an advanced stage, removed superfluous texts that duplicated the requirements of the main GMP guide. It provided advice for QPs on “release” and guidance on specific labelling for CT supplies. And it drew attention to products used in trials other than the test product, comparator or placebo, which had to be “suitable for purpose”.

Examining the duties of QPs, in certifying manufacturing compliance for IMPs, Mr Cockburn admitted that it was far from clear how to ensure GMP compliance of third country sourced comparators.

On inspection of trials supplies, he said that a voluntary scheme had operated since 1994. Future strategy was likely to include GMP compliance visits, plus assessor-initiated and other targeted inspections. Preapproval type inspections might result from any agreement with the US Food and Drug Administration and might involve aspects of manufacture of IMPs.

Symposium on a harmonised approach to medicines registration

The harmonisation of quality requirements for the registration of medicines was the subject of a joint symposium of the JPAG and the British Institute for Regulatory Affairs in London on 22 June 2000. The meeting examined new drug and compendial specifications, stability testing and post-authorisation variations. A report of the meeting has recently been made available to The Journal. It will not appear in the printed Journal but can be downloaded from PJ Online in PDF format (45K).

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— Contributed by Professor Geoffrey Phillips, secretary, Joint Pharmaceutical Analysis Group