1. 1 Denise K. Thwing, MAS, RN, CCRA March 31, 2010 Version: Final 31-Mar-2010

2. 2  Amendments  Deviations, Violations, and Exemptions  Monitoring for Protocol Adherence Version: Final 31-Mar-2010

3. 3  Amendments  An amendment is a permanent change to a protocol  A deviation can trigger an amendment  Example: The protocol states that a 0.5 ml aliquot plasma is needed for bioanalytical method for a certain test, and the sample was run on 0.3 ml aliquot for one sample only.  It is determined that a larger sample is needed e.g. 1.0 ml for bioanalytical method.  Protocol amendment & acceptance form is needed  Changes may impact ICF, IB

4. Version: Final 31-Mar-20104  IND Amendments  21 CFR 312.30-33 - once an IND is in effect, a sponsor shall amend it as needed to ensure that the Clinical Investigations are conducted according to protocols included in the application.  21 CFR 312.30  New protocol – study not covered in the IND  Changes in a protocol – that effect safety, scope or quality  Increase in dosage, duration of exposure, increase subjects  Design change e.g. addition or drop control group  Addition or deletion of a new test or procedure  New Investigator (notify required within 30 days of being added)  Must submit to FDA, IRB approval needed before implementation  Content and Format

5. Version: Final 31-Mar-20105  CFR 312.31 IND Information Amendments  New toxicology or other technical information  Discontinuance of a clinical study  Other, not within scope, safety report, annual report

6. Version: Final 31-Mar-20106  Deviations  A minor or administrative departure from the protocol procedures approved by the IRB that was made by the PI/ subject/ staff without prior protocol approval. Minor deviations do not affect soundness of the research plan, or the rights, safety or welfare of human subjects.  Emergency Exception - Unanticipated problem involving risks that could affect safety must be reported immediately to the IRB, no later than 5 days.  New risks  Maintain deviation log, review by PI, CRA, IRB  Part of data submission

7. Version: Final 31-Mar-20107  Deviations  Unplanned unintentional events that pose no significant threat to safety or scientific integrity  Sponsor input  Out of window visits  Missed lab test, unable to obtain, re- scheduled  Missed or late vital signs

8. Version: Final 31-Mar-20108  Waivers, Violations, Exemptions  Eligibility exceptions or waivers - are not deviations  Subject does not meet inclusion/exclusion criteria  Approval must be given in advance, not after the fact  Could impact study statistics, sample size  Document in “real time”, study director, PI, MA  CAPA

9. Version: Final 31-Mar-20109  Major deviations  Subject given incorrect dose  Subject did not sign ICF  Missed visits  Subject taking exclusionary medication

10. Version: Final 31-Mar-201010  Clinical practice does not equal Clinical Research  Special training is needed  Research must be conducted according to protocol  Laws, regulations, guidelines govern conduct Harvey M. Arbit, Pharm D 11/16/07

11. Version: Final 31-Mar-201011  Clinical Investigation:  Any experiment which involves a test article and one or more human subjects 21 CFR 50.3  Routine Practice  No protocol  Treats all patients  Some documentation  Not intended for publication  Billable  Research  Protocol  Treat some patients  Document, document, document  Publish  Not billable Harvey M. Arbit, Pharm D 11/16/07

12. Version: Final 31-Mar-201012  Practice of medicine  The practice of medicine combines both science as the evidence base and art in the application of this medical knowledge in combination with intuition and clinical judgment to determine the treatment plan for each patient. (ref. WIKIPEDIA, 2007)

13. Version: Final 31-Mar-201013  Monitoring for protocol adherence  It does not matter who wrote or funded the protocol - no changes can take place without IRB approval and in some cases FDA notification.  Monitoring must assure adequate protection of the rights of human subjects  Safety of all subjects in the study  Quality and integrity of the data submitted to FDA  Data must be verifiable from source  Comply with GCP and regulatory requirements  GCP training

14. Version: Final 31-Mar-201014  Focus of Monitoring  ICF/s  Source Documents  CRFs  Product accountability  Protocol adherence/deviations  AE/safety reporting

15. Version: Final 31-Mar-201015  What does the FDA look for?  PI involvement – original and accurate study conduct – 1572  AEs/deviations recorded/reported  Reliable source data transcribed accurately to CRF  Study product secure and stored properly  Dispensed under supervision PI