1. Clinical Pharmacy’s Role in Research Trials Sheree Miller Pharm.D. Investigational Drug Service University of Washington Medical Center

2. Investigational Drugs New Drugs Investigational use of approved drugs new indications, new combinations, new components

3. Phases of Product Development Preclinical – lab and animal testing ***File IND at FDA*** Phase I- determine safety and dosage Phase II-evaluate efficacy, look for AEs Phase III- Verify Efficacy, Monitor AEs »Evaluate long term use

4. Drug Approval Process File NDA at FDA FDA Review process Phase IV studies- postmarketing

5. Local oversight of trials Institutional Review Board –Human Subjects Review Committees Appointed by institution Membership: at least 5 members Protects Human Subjects (Risk: Benefit) Informed Consent Annual Review

6. Off Study Use of Investigational Agents Emergency use of a drug at an institution- Informed consent and institutional approval necessary Treatment INDs- to make certain drugs available to desperately ill patients who do not qualify for a clinical trial or when clinical trial is not available

7. Responsibility for Investigational Product(s) Inventory and storage Preparation and use per protocol Dispensing and reconciliation Patient counseling Drug disposal Archiving source documents & records Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance; page 16 4.6 Investigational Product(s)

8. Clinical Pharmacy’s role Assure route of administration Monitor drug dosage, dosage regimen, treatment period, anticipated blood concentration Assure for proper dose at appropriate interval Ensure for drug compatibility Monitor for drug interactions

9. Clinical Pharmacy’s role Drug Information Investigational versus comparator drug Verify clinical pharmacological effects Monitor for appropriate –Absorption –Distribution –Metabolism –Excretion Clinically assess and evaluate –Safety –Efficacy

10. Clinical Trials Process Pre-Initiation - before clinical trial Initiation - start of clinical trial Maintenance - during clinical trial Termination - after completion

11. Pre-Initiation Sponsor protocol & amendments IRB documents including 1572 Patient consent form Investigational brochure Budget proposal Sponsor correspondence Industry-Sponsored Clinical Trials Administrative Start-Up Handbook, School of Medicine http://www.hscer.washington.edu/clinicaltrialshandbook/

12. Pharmacy Initiation Phase Standard operating procedures (SOPS) Protocol design review Investigational drug brochure review Study Notebook forms –Minimize systematic and random errors –Increase QA and QC CRF forms Document correspondence and visit log

13. Pharmacy Study Notebook Protocol description & drug summary Drug order entry & label procedures Drug preparation procedures Drug dispensing procedures Patient enrollment / randomization logs Patient dispensing log Patient adverse drug reaction & un-blinding procedures

14. Investigational Drug Drug shipment records Inventory & storage of drug(s) –Secured –Disposition upon arrival –Storage conditions (temperature) –Expiration dates –Disposal of used and unused Perpetual drug inventory log –Reordering mechanisms

15. Dispensing Drug Drug order entry set-up –No patient drug charges –Proper patient drug label –Proper drug packaging Patient dispensing –Randomization –Blinding strata Final cross verification

16. Protocol Mechanics and Guidelines Operational agreements and definitions –Who, What when, where, how –Patient consent forms –Drug start / stop criteria –Drug preparation & administration –Patient counseling –Patient withdrawal, drop outs, follow-up, replacements Optional considerations –Pharmacy in-service teaching and demo –Mock trial run

17. Adverse Drug Reactions Adverse effects –Expected –Unexpected Drug toxicity –Dosing –Administration –Length of treatment Patient withdrawal - discontinue study drug Patient follow-up - rescue therapy Blinding & breaking randomization codes

18. Maintenance Phase Changes to therapy and procedures –Protocol amendments IRB approval Patient consent Randomization and stratification –Investigational drug notification Stability issues - GMP New adverse drug reactions Drug dosing or addition/elimination –Regulatory announcements FDA and Med-watch Clinical reports

19. Maintenance Phase Daily cross checks and timely reviews –Patient Enrollment criteria and consent Drug assignment and randomization Drug preparation and dispensing Patient label and drug orders –Drug Perpetual inventory re-supply Expiration - unused and prepared Daily storage conditions and security –Reconciling discrepancies Drug records and patient dispensing Study Notebook for CRF

20. Patient Counseling Confirm patient consent Drug - use, handling, storing, returning Concomitant medication –Drug-drug interactions –Food-drug interactions Inter-current medical conditions –Medical condition-drug interaction Drug compliance Adverse drug symptoms & reporting

21. Termination Phase Reconcile –Patient dispensing to drug inventory Drug reconciliation Return to sponsor Dispose within pharmacy Used and unused drug Drug disposal –Pharmacy guidelines –Return to sponsor

22. Pharmacy Completion Pharmacy materials archived –Study Notebook Dispensing Logs Drug inventory receipts and inventory records –All clinical trial related materials IRB documentation Protocol & amendments Correspondence CRF Document archiving –Accessibility for retrieval –Length of storage