Autumn 2005
The Involvement of Regulatory on Clinical Trial Supply
The European Economic Community (EEC) introduced the control of medicines in 1965 (Directive 65/65/EEC) and the UK followed suit shortly after with the implementation of the Medicines Act in September 1971. The primary objectives focussed on safeguarding public health by ensuring medicines on the UK market meet appropriate standards of safety, quality and efficacy. In 1973 the UK joined the EEC and the control of medicinal products matched those of existing European Directives and in some instances exceeded them, for example, Clinical Trials.
Together with other member states, the UK has contributed to the development and updating of the EEC Directives. The Clinical Trial Directive 2001/20/EC implemented on the 1st May 2004 in the UK for which the Medicines and Healthcare products Regulatory Agency (MHRA) played a lead role in developing the detailed guidance for request for authorisation of a clinical trial to the competent authorities. This guidance document, one of many which support the practical implementation of the Directive, introduced a standardised application process for all phases of clinical trials conducted in the EEC. The Clinical Trial Application (CTA) superseded its forerunners the Clinical Trial Exemption, and Doctors & Dentist Exemptions for clinical research in the UK.
The most dramatic impact of the Directive rests in the uniform regulation of Phase I Clinical Trials which historically were performed pending a favourable Ethics' Committee (EC) decision and fell outside of the Competent Authority (CA) approval process of many Member States. This has now been addressed and authorisation is required from each Member State's CA and the EC prior to initiation of the Phase I trial. The most cumbersome preparation for Phase I trial application is the Investigational Medicinal Products Dossier (IMPD) which is a lengthy, costly and detailed compilation of product characteristics.
The Directive has placed further emphasis on the principles of Good Manufacturing Practice (GMP) driven through Annex 13 to EU Directive 2001/20/EC. Furthermore ensuring Investigational Medicinal Products (IMP) are compliant with the requirements of European Commission Directive 2003/94/EC and Good Clinical Practice (GCP) EU Directive 2005/28/EC. The MHRA has recognised that clinical trials supplies (CTS) is a specialist operation facing a unique array of challenges and has provided logical and pragmatic solutions to minimise the impact on business post May 2004. For example, the MHRA made these operations a licensable activity through the issue of the Manufacturers Authorisation (IMP) providing a clear and auditable process and standards for CTS performance within Pharmaceutical Companies, Contract Research Organisations (CROs) and hospital pharmacies. Hence, voluntary inspections were performed prior to May 2004 and all applications received prior to March 2004 were allowed to continue business post May 2004. Subsequent inspections were scheduled, performed and successful applicants received their MA (IMP) licence, essential to the continuation of CTS operations.
As part of the regulatory inspection process the Site Master File (SMF) is made available to the MHRA. It describes the structure of the organisation, the site and the manufacturing activities to be performed, the facility, the personnel and the quality management system employed. The SMF provides the inspectorate with an introduction to the company and its activities/processes pre-inspection. Only activities listed in the MA (IMP) can be performed by the licence holder and any variation to these licensed activities requires authorisation and subsequent amendment to the license.
Interestingly, an MA (IMP) is not required for reconstitution prior to use or packaging activities, where those processes are preformed in hospitals, health centres or clinics, by pharmacists or other persons legally authorised in the Member States to perform such processes and if the IMPs are intended to be used exclusively in those institutions.
The role of Supply Chain in Clinical Trials
Clinical trials supply is a function within the pharmaceutical sector requiring quality and accuracy demands often within tight timelines. Clinical trials supply involves five major stages:
1. Trial planning and forecasting (trial format, pack design, number of dosage units, blinding design, label preparation and component/comparator procurement, stability data, compilation of the IMPD and CTA);
2. Manufacture, drug packaging, labelling;
3. Storage, shipping and distribution;
4. Dispensing;
5. Reconciliation and IMP destruction.
Due to the relatively new regulatory requirements for Phase I studies (in relation to the UK) and to optimise the drug development process it is now common practise to have several objectives within one protocol, such as a single escalating dose design, fast-feed interaction1 and age dependant study. This increases the complexity but allows for maximum data collection and efficiency. To accommodate these requirements the entire supply chain within Roche has been scrutinised and adapted by a cross-functional team of experts to minimise the impact of the Directive. Noticeable changes included front loading of activities and effective planning which primarily focussed on preparation for Phase I studies and regulatory submissions as well as comparator sourcing. The corollary being that there are fewer drug supply elements on the critical path.
A more detailed exploration of the labelling as introducing the greatest flexibility to drug supply is warranted. Traditionally the bottleneck in the clinical supply chain has been in the area of drug supply. Harmonisation introduced by the Directive 2001/20/EC has allowed greater scope for more efficient use of limited drug through exploiting multi-lingual labelling.
As mentioned earlier, Directive 2003/94/ EC stipulates IMP labelling shall be such as to ensure protection of the subject and traceability, to enable identification of the product and trial and to facilitate proper use of the IMP. However, the importance of the labelling of IMPs is often overlooked as it is taken for granted that the label will be comprehensive, readable, legible and regulatory compliant for each Member State. However, consider the consequences of ambiguous directions, for example, take one capsule with meals compared with take one capsule with food three times a day. The former example is not comprehensive as it poses several questions, such as: How often? What happens if I don't eat breakfast or lunch? Do I still take a capsule? The latter is more directive which ultimately results in improved patient compliance.
A well planned study can easily fail to meet its objectives due to poor labelling resulting in poor patient compliance and ultimately inconclusive data. GMP encompasses labelling requirements as outlined in Annex 13. However, several Member States have acknowledged the importance of label text as required in the CTA as part of the IMPD; indeed some States such as the UK, require mock labels in addition to label text.
Due to the increasing complexity of studies and increased pressure to shorten the development process, particularly for diseases with inadequate or no current therapy, studies have become global, in nature, to meet these demands. The obvious advantages are large, diverse patient population pools, rapid patient recruitment and multi-country regulatory submissions. However, co-ordinating study drug distribution and inventory management across a greater diversity of geographies and regulatory authorities are critical to success.
Unsurprisingly, Roche has responded by using several different models dependant upon the study design, therapeutic indication and nature of IMP. Although there is a general trend apparent of transition from single country application IMPs to multi-lingual labelled product for Phase II and III studies. These can be supplied to all countries participating in the studies or on some occasions the countries may be divided into cluster regions of six or seven co-located countries, known as a territory; the multi-lingual label then is designed for application within each of the territories. Due to the finite amount of IMP for each study this allows greater flexibility for inventory management and less resource is required for packaging and labelling operations, particularly with respect to production records and manufacturing runs. Although this works in the majority of cases there must be compliance with each Member State's individual regulatory requirements. Often individual Member States, while allowing multi-lingual IMP labelling will insist that their language features on the outer label of a potential booklet label. In order to take account of the requirements of local regulatory authorities within a global study, project management plays a critical role. Typically, within Roche, master label text is generated for each study and this is cascaded to the individual Country Study Manager who reviews the text in conjunction with the protocol and co-ordinates the local regulatory review and appropriate translation (note – label translation is done by Global Investigational Medicinal Product Supply department (GIPS) using standard 'elements' – these translated labels are then reviewed at country level). All comments are considered and necessary amendments are captured in the country study label which is approved and finalised by the GIPS department, the Country Study Manager and the regulatory partner. The label text or mock label (as is increasingly required) is inserted into the CTA as required by the Member State.
In summary, the historic attitude towards CTS packaging and labelling was for one of large production runs, packing and labelling. This was followed by bulk shipping of localised country supplies to investigator sites to cover all possible combinations of required patient treatments. This led to inefficiencies with drug obsolesce in one country and excess in another. The introduction of the Clinical Trial Directive coupled with increasing globalisation of trials has led to greater efficiency in IMP flexibility and efficient usage by increasing the use of multi-lingual labels thus allowing the same inventory to be used in multiple territories. However, it is critical to recognise differences that still exist between the regulatory bodies of the EC Member States and consequently the key role project management of Country Study Managers play within the overall development for regulatory applications and an efficient early stage development pipeline within successful Pharmaceutical Companies.
Finally, I would like to thank Denise Morgan, Sheelagh McCorry and Professor Graham McClelland (Roche Regulatory Project Manager, Head of Clinical Trials Supply UK, Global Head of Clinical Pharmacology Operations respectively) for their input.
1Fast and feed interaction studies involve dosing the patient after fasting conditions and/or dosing the patient after consumption of food.
Virginia McNally, MRPharmS, PhD
Roche Products Limited