WP 9-10 GRACE GCP

1. WP 9-10 GRACEGCP Good Clinical Practice (GCP) WP9-10 14 September 2007 Stockholm

2. WP 9-10 GRACEGCP GCP  Two basic goals: 1. Ensuring the integrity/quality of data - Documentation (e.g. protocol, audit trail) - Source/study documents to be stored for 15 years 2. Protection of the rights of patients participating in trials - Approval of Ethical Committee (EC) - Qualified investigators - Informed consent procedure

3. WP 9-10 GRACEGCP • Examples of standard GCP procedures: • Approval of Ethical Committee (EC) • Approval of national competent authority (CA) for WP10 (study with medicinal product) • Approval other regulatory authorities • Patient insurance to be obtained within each network • Informed consent procedure

4. WP 9-10 GRACEDrug accountability • Drug logistics: • Manufacturer  pharmacist  NNF Practice  GP • First shipment: • 34 boxes per network • Each box containing 10 medication bottles (randomized) • Checks after receipt: • Supplies must be checked against shipment form • Box: network name and number correct • Arrival at practice: Check trial medication codes of the bottles inside (Always complete boxes are allocated to a practice) • Packaging/bottles should be intact

5. WP 9-10 GRACEDrug accountability • Documentation: • Sign & date for receipt • Fax copy to sponsor and file original form in Site File • Hand out of study medication by GP: • Sequentially, see study medication code:112591,112628,112665, etc • Explain correct use • Explain correct storage • Explain unblinding procedure • Empty bottles/unused medication should be returned at visit 2 • Medication handed out & quantity returned should be documented on the Drug Accountability Log > faxed to NNF every month > data entry into GOS • - Start study medication after all samples are collected • Storage conditions: • Do not store above 30˚C. Protect from light and excessive humidity. • Please keep trial medication in a locked cabinet.

6. WP 9-10 GRACEUnblinding • Unblinding: • When? In case the GP or another treating physician needs to know whether the GRACE patient got an antibiotic or placebo. • How? To break the code they can contact the 24 hour unblinding service by telephone*. The following questions will be asked: • 1. Are you a GP involved in GRACE or another treating physician • 2. Date of birth patient • 3. Trial medication code* • 4. Reason for unblinding • After that the code will be broken without any further restrictions • * See label on medication bottle

7. WP 9-10 GRACESAE • SAE=serious adverse event • SAE classification: • Death • Life-threatening • In-patient hospitalisation • Disability/incapacity • Congenital anomaly/birth defect • Other medical events requiring intervention to prevent one of the outcomes listed above • In case of a SAE, the SAE form (in Site File) should be completed (study number handwritten) on the GRACE platform within 24 hours by GP or NNF* ! • * After fax and telephone call from GP

8. WP 9-10 GRACEGRACE short questionnaire • No return of diary after about 4 weeks • However, it’s very important (>80%) to collect the most relevant data: • Symptoms first 3 days after consult/inclusion • Duration of illness • Study medication: yes or no • Side effects (diarrhoea, nausea, skin rash): yes or no • Reconsultation health service (GP, specialist, emergency department etc) • Send shortQ with letter (approved by EC) to patient • Or complete shortQ by telephone

9. WP 9-10 GRACEMonitoring • According to the WP10 protocol: • GPs will be visited by monitors independent from GRACE* to perform source data verification of a randomly selected part of the patients/data. During these visits also the Site Files could be checked >> SOP in preparation • Also the presence of all signed consent forms will be verified. • Procedure: After inclusion a copy of the signed informed consent will be faxed together with the registration form to the NNF, so monitoring can take place. • * To be organized locally by the networks

10. WP 9-10 GRACEOther GCP needs & SOPs • Slightly modified (if needed at all) GRACE-01 working practices will and can be used for WP9 & 10 also. For example: • GP surgery visit checklist • Signature list and delegation of responsibilities log • Training registration document • Signed & dated CVs from all participating GPs (NEW!) • GP & Network Site File • Screening logs • The Telephone Conversation SOP

12. WP 9-10 GRACEAmendment • Old exclusion criterion: allergic to penicillin • New exclusion criterion: allergic to penicillin or have a contra-indication for amoxicillin because of a major interaction with other medication •  New version of WP10 protocol & patient CRF needed