clinical trial medication: practical and regulatory considerations

INVESTIGATIONAL MEDICINAL PRODUCTS:Regulatory and Practical Considerations for Clinical TrialsNovember 2010 : 

INVESTIGATIONAL MEDICINAL PRODUCTS:Regulatory and Practical Considerations for Clinical TrialsNovember 2010

Investigational Medicinal Products : 

2 Investigational Medicinal Products Introduction EU and UK regulations relating to investigational medicinal products Implications for undertaking clinical trials with IMPs Common challenges across the clinical trial lifecycle Patient population factors and dosage forms Imports from Non-EU countries Labels Expiry dates and stability Technical agreements Other common GMP related challenges CTA VAT GMP: Behind the Scenes Overview of a clinical supply project Introduction

About MODEPHARMA : 

3 About MODEPHARMA Investigational Medicinal Products for clinical trials Comprehensive sourcing and management of trial medication MODEPHARMA is the only UK company to specialise in clinical supplies for non-commercial clinical trials Full support around the IMP solution Introduction Advise, plan and coordinate on all aspects around the IMP MANUFACTURING Placebos to match Tablets and capsules Semi-solids Injectables Powders Inhalers Liquids PACKAGING Bulk supplies Re-labelling Patient kits Ampoules Sachets Blisters Bottles Tubes Vials RELATED SERVICES QP release Imports Randomisation Regulatory support Site monitoring Pharmacy SOPs IMP training

EU and UK Regulations Relating to Investigational Medicinal Products : 

4 EU and UK Regulations Relating to Investigational Medicinal Products EU Directives: Clinical Trials Directive 2001/20/EC The principles of good manufacturing practice should be applied to investigational medicinal products. GMP Directive 2003/94/EC Replaces original GMP Directive 91/356/EEC GCP Directive 2005/28/EC Additional principles and detailed guidelines with regards to IMPs are specified to verify compliance of clinical trials with the Clinical Trials Directive 2001/20/EC. Transposed into Member State Laws: UK: Statutory Instrument 2004/1031: The Medicines for Human Use (Clinical Trials) Regulations 2004 and its amendments. Despite harmonisation, differences remain between Member States in clinical trial requirements Practical guidance: GCP: ICH Guidelines for GCP GMP: Eudralex Vol 4 (EU GMP Guide aka “Orange Guide”) Annex 13: GMP for investigational products Annex 16: QP responsibilities See the MODEPHARMA Knowledge Centre: www.modepharma.com Regulatory Aspects of IMPs

Implications for Undertaking Clinical Trials with IMPs : 

5 Implications for Undertaking Clinical Trials with IMPs All IMPs must be manufactured according to GMP: Requirement for appropriate IMP manufacturing/import authorisation Facility must be licensed for the dosage form & activities required Qualified Person (QP): Ensure compliance with EU GMP (for own sites and contractors), the PSF, and the request for CTA Responsible for the certification and release of batches of clinical trial material before they can be used in a clinical trial. Exception: Regulation 37 in SI 2004/1031 Assembly (repacking, randomising and labelling) in a hospital/health centre under supervision of a doctor/pharmacist for use within that institution No need for QP release but QC recommended There are restrictions! All facilities used for the manufacture or import of IMPs are subject to an inspection by the competent authority If IMP manufactured outside EU, appropriate checks/retests for “Import” and before EU release Regulatory Aspects of IMPs

Common IMP Challenges Across the Clinical Trial Life-Cycle : 

6 Common IMP Challenges Across the Clinical Trial Life-Cycle IMP Considerations Sub-optimal choice of active/placebo dosage forms Lack of awareness on regulatory requirements for IMP manufacturing Hidden costs in quotes making them difficult to interpret and compare One-sided Technical Agreements Poor blinding of IMPs Poor quality IMP and packaging Inadequate labelling of IMPs Inaccurate budgeting of IMP costs Inadequate project planning Little or no experience with contract manufacturers Risks: Non-compliance or high withdrawal rate Poor trial design / wastage of drug Regulatory approval delayed/failed Insufficient funding for the trial to continue Risks: Poor IMP quality and design Paying more than expected Sponsor’s responsibilities not adequately covered Manufacturing delays Risks: Credibility of results Patient safety risk/regulatory non-compliance Patient loss of confidence and drop-outs Early trial stop by Sponsor or MHRA IMP adversely affected during storage and transport Insufficient consideration of patient population factors

Patient Population Factors and IMP Dosage Forms : 

7 Patient Population Factors and IMP Dosage Forms Consider patient population factors and IMP hand-in-hand Blinding mechanisms: New dosage forms (e.g. Over-encapsulation for solid dosage forms) New packaging : Formulation and development of placebo-to-match (e.g. tablets, liquids) Repack into new packaging (e.g. sachets) Other innovative solutions Common issues: Chosen dosage form not the most optimal for the trial’s patient population Not economically feasible to develop a placebo Formulation work is not a precise science Poor quality placebos (e.g. taste, texture, colour, film-coating, hardness, primary packaging) IMP Considerations

‘Imports’ from Non-EU Countries : 

8 ‘Imports’ from Non-EU Countries IMP manufactured outside EU: QP to verify that the IMP was manufactured to GMP standards equivalent to EU GMP QP may have to performs site audits Additional analytical testing of IMPs may be required on import to Europe QP declaration on GMP equivalence to EU GMP using the template available on the MHRA website Signed by a QP named on the manufacturer’s authorisation of the importer Should be trial and product specific Applies to placebos as well Common issues: Lack of substance behind QP declaration How does the QP know the actual site of manufacture? How does the QP assure EU GMP? Transportation conditions not known The QP certified an imported IMP as free of Transmissible Spongiform Encephalopathy (TSE) but no evidence was available to support this decision. IMP Considerations

Technical Agreements Set Out the Roles and Responsibilities of Each Party : 

9 Technical Agreements Set Out the Roles and Responsibilities of Each Party Common issues: Non-existent Essentially commercial in nature Agreement not in place before manufacturing commences Lack of detail concerning GMP responsibilities: Sourcing of materials QP duties Recall responsibilities Approval and supply of relevant documents Taking of samples/testing/retention No requirement for signed QP certification Refer to Appendices that do not exist IMP Considerations

Labels : 

10 Labels GMP Directive 2003/94/EC: Preamble 9: In order to protect the human beings involved in clinical trials and to ensure that investigational medicinal products can be traced, specific provisions on the labelling of those products are necessary. Article 15 Labelling: In the case of an investigational medicinal product, 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 investigational medicinal product. Detailed guidance in Annex 13, paragraphs 26 to 33: Paragraph 26 and Table 1 sets out 11 items of information which should be included on labels unless absence can be justified, e.g. use of a centralised electronic randomisation system Paragraph 33 covers labelling to change use-by-dates Common issues: Missing labels with CTA applications Labels missing key information Different batch numbers/expiry dates for active and placebo IMP Considerations AMAZING_TRIAL FOR CLINICAL TRIAL USE ONLY EudraCT No: 2007-00534-99 28 x Lisinopril 5mg Tablets or Placebo-to-Match Patient Trial No: J789 Visit: _____ Dispensing Date: ________ Dose Instructions: Take ONE tablet orally once a day. Batch No: 09B897 Expiry Date: 12/DEC/2010 Storage Instructions: Store below 25ºC. KEEP OUT OF THE REACH OF CHILDREN Professor XXXXX, SPONSOR NAME, Address, City, Post Code, UK, Tel: 07979797979

Expiry Dates and Stability : 

11 Expiry Dates and Stability IMP expiry date and stability information is the Sponsor’s responsibility! GCP Guideline 5.14.5 (a): Sponsor should take steps to ensure that the investigational product(s) are stable over the period of use Annex 13 (§20): The expiry date stated for the comparator product in its original packaging might not be applicable to the product where it has been repackaged in a different container that may not offer equivalent protection, or be compatible with the product. A suitable use-by date, taking into account the nature of the product, the characteristics of the container and the storage conditions to which the article may be subjected, should be determined by or on behalf of the sponsor. Such a date should be justified and must not be later than the expiry date of the original package. There should be compatibility of expiry dating and clinical trial duration. Common issues: Not considering shelf-life of IMPs Having to commission additional [unplanned] manufacturing Cost of analytical method development, validation and stability studies IMP Considerations

Other Common GMP Issues : 

12 Other Common GMP Issues Creation and maintenance of the Product Specification File: Not available or incomplete Lack of structure to the file No system for updating the file following changes in instructions, packaging etc. Recall SOP Insufficient detail with reference to recalls instigated by manufacturers of comparator products No consideration that the IMP may identify defects with comparator products during handling/use Failure to notify the MHRA in the event of a potential recall situation being identified. Transport and storage conditions Lack of controlled storage Temperature deviations IMP Considerations

CTAs : 

13 CTAs Common issues: “Invalid” applications Failure to supply an XML file Missing sponsor authorisation letter Non-machine readable PDFs Password protected disks Quality of applications Section on IMPs (active and placebo) left blank Confusion on final EU site releasing the IMP Missing supporting documents: Sample labels IMPD / IB / SmPCs Manufacturing authorisations TSE certificates IMP Considerations

VAT : 

14 VAT VAT Clinical supplies for non-commercial trials are not automatically VAT exempt VAT exemptions only for trials funded by charitable sources See www.modepharma.com/vat for further guidance IMP Considerations

Overview of a Clinical Supply Project : 

15 Overview of a Clinical Supply Project Client Enquiry and Requirement Definition Confidential Disclosure Agreement Proposal Acceptance and Payment of Deposit Technical Agreement Project Manager and Project Plan Documents for CTA including Product Specification Files Label Design and Approval Approval of Batch Manufacturing Record Procurement of Raw Materials Randomisation Code Clinical Manufacturing, Packaging and QC Testing QP Release Storage Shipment on Demand Invoicing Project Close Clinical Supply Manufacturing and Packaging Activities

Annex 13 Manufacture of IMPs : 

16 Annex 13 Manufacture of IMPs Sections on: Principle Glossary Quality Management Personnel Premises and Equipment Documentation Production Packaging materials Manufacturing operations Principles applicable to comparator products Blinding operations Randomisation code Packaging Labelling Quality Control Release of Batches Shipping Complaints Recalls and Returns Destruction Further Reading

Slide 17: 

17 h t t p : / / w w w . m o d e p h a r m a . c o m MODEPHARMA Registered Office: Suite 16, Beaufort Court, London E14 9XL, UK Company No: 6332969 in England and Wales VAT Registration: GB 909535016 Phone: +44 (0) 2070 432 442 Email: info@modepharma.com Contact www.modepharma.com