Good Clinical Practice Standards

1. Good Clinical Practice Standards • This educational module comprising of 22 slides describes the standards on “Good Clinical Practice” (GCP) developed by the ICH (International Conference on Harmonization) as an international ethical and scientific quality standard. These standards are affirmed by the investigator in filling out FDA Form 1572 for designing, conducting, recording and reporting of clinical trials that involve human research subjects. • These slides provide a summary of instructions to an investigator, sub-investigator(s) and investigator’s designate in performing a clinical trial involving a drug, biologic or device in accordance with the “Good Clinical Practice” standard • Adherence to this standard assures credibility of the data, and well-being, safety and protection of the rights of research subjects engaged in clinical trials consistent with the Declaration of Helsinki

2. Good Clinical PracticeInvestigator – Role and Responsibilities • Qualification: Appropriate education, training and experience to assume responsibility and should provide evidence of such qualifications. • Familiarity with the Test Article:Should be thoroughly familiar with the test article described in the investigators brochure. • Compliance:Should comply with GCP procedures and applicable regulations • Monitoring: Should permit monitoring and auditing by the sponsor and appropriate regulatory agencies • Delegating Responsibility: Maintain a list of appropriately qualified persons who have delegated trial-related responsibilities

3. Good Clinical Practice Investigator - Resources • Demonstrate potential for recruiting required number of subjects • Have sufficient time to properly conduct and complete the trial within the agreed period • Must have adequate number of qualified personnel and facilities to conduct the trial properly and safely • Investigator must make sure personnel assisting in the study are adequately informed about the protocol, investigational products(s) and trial-related duties and functions

4. Good Clinical Practice Investigator – Medical Care of Trial Subjects • A qualified physician, who is an investigator or sub-investigator for the trial must be responsible for all trial-related medical decisions. • During and following subject’s participation in a trial, the investigator should ensure that adequate medical care is provided to a subject for any adverse events (including lab values). • The investigator must inform the subject when medical care is needed for inter-current illness(es) of which investigator becomes aware. • It is recommended that the investigator inform subject’s primary physician about subject’s participation (subject ‘s agreement to this requirement is required) • If subject wishes to withdraw from the study, the investigator should make reasonable effort to ascertain the reasons – while fully respecting the subject’s rights.

5. Good Clinical Practice Investigator – Communication with IRB • Before Initiating a trial the investigator must have in his/her position: • Written date approval letter for the trial period • Written and approved informed consent form • Consent form updates (if any) • Subject recruitment procedures (e.g., advertisements) • Any other information to be provided to the subjects • Provide a current copy of the Investigator’s brochure • If the Investigator’s Brochure is updated, the investigator must supply a copy of the updated brochure to the IRB • Any other documents that are subject to review by the IRB

6. Good Clinical Practice Investigator – Compliance with Protocol • The investigator should conduct the trial in compliance with: • The protocol agreed to by the sponsor • If required, protocol agreed to by the regulatory authority(ies) • Ultimately given approval by the IRB • The investigator/institution should sign the protocol, or an alternative contract, to confirm the agreement • The investigator should not implement any deviation from, or changes of the protocol without: • Agreement by the sponsor • Prior review and documented approval from the IRB of an amendment except where necessary to eliminate an immediate hazard (s) to trial subjects or when the changes involve only logistical or administrative aspects of the trial (e.g, change in the monitor(s), change of telephone number without IRB approval. However, as soon as possible, the implemented deviation or change, the reason for it, and, if appropriate, the proposed protocol amendment(s) should be submitted to: • The IRB for review and approval • To the sponsor for agreement • If required, to the regulatory authorities

7. Good Clinical Practice Investigator – Investigational Products • It is the investigator’s responsibility for investigational product(s) accountability at the trial site • The investigator or person who is designated by the investigator should maintain records of: • The product(s) delivery to the site • The inventory at the site • The use by each subject • The return to the sponsor or disposition of unused products • The records should include: • Date, quantities, batch/serial numbers, expiration dates and the unique code numbers assigned to the product(s) and subjects • Maintain records that document adequately: • Doses provided to subjects as specified in the protocol • Reconcile all investigational product(s) received from the sponsor

8. Good Clinical Practice Investigator – Investigational Products (Cont.d) • Products should be stored as specified by the sponsor and in accordance with applicable regulatory requirements • Products should be used only in accordance with the approved protocol • Should explain to the subject: • Correct use of the product • Should check at appropriate intervals that the subject is following the instructions properly to use the product

9. Good Clinical Practice Investigator – Randomization Procedures and Unblinding • The investigator should follow trial’s randomization procedure • Ensure that the code is broken only in accordance with protocol • If trial is blinded, the investigator should promptly document and explain to the sponsor any: • Premature unblinding • Accidental unbliniding • Unblinding due to serious adverse events

10. Good Clinical Practice Investigator – Informed Consent of Trial Subjects • Obtaining Informed Consent: • Investigator should comply with regulatory requirements • Should adhere to GCP and ethical principles (Declaration of Helsinki) • Should have approved consent form • Informed Consent Document • Should follow the guidelines of informed consent document provided by the university • Should be revised whenever important new information becomes available that may be relevant to the subject’s consent • All revised consent forms must be approved by the IRB in advance of use • The subject or subject’s legally authorized representative should be informed in a timely manner should new information become available and communication of this information should be documented

11. Good Clinical Practice Investigator – Informed Consent of Trial Subjects • Subject Consent and Participation Avoid coercion or unduly influence a subject to participate or continue to participate in a trial • Consent Language and Information to the subject or subject’s LAR • Oral and written information pertaining to the trial, including the written consent form should contain any language that waive or appear to waive the subject or subject’s LAR any legal rights or liability for negligence • The investigator or his/her designate should fully inform the subject or if the subject is unable to provide informed consent, the subject’s LAR of all pertinent aspects of trial including the written information that has been approved by the IRB. • If subject/LAR is unable to read, an impartial witness must be present during the entire informed consent discussion • The information language should be non-technical and understandable to the subject/LAR/impartial witness • Provide ample time and opportunity to inquire about details of the trial and all questions about the trial should be answered • Once the subject/LAAR has signed the consent, the witness should sign the consent form. This attests that the subject/LAR has freely given the consent to participate in a trial

12. Good Clinical Practice Investigator – Records and Reports • Records should be accurate, complete, legible and timely pertinent to the data reported to the sponsor in the CRFs (Case Report Forms) and other required reports • Data reported on the CRFs should be derived from the source document. It should be consistent with the source documents and all discrepancies from the source documents must be clearly explained • All corrections to a CRF should be dated, initialed, explained and should not obscure the original entry whether the entry is written or electronic changes or corrections. • Sponsors are required to provide guidance to the investigators on procedures to assure that changes and corrections in CRFs made by sponsor’s designated representatives are documented, are necessary and are endorsed by the investigator. The investigator should retain records of the changes and corrections. • The investigator should maintain the trail documentation as specified under Essential Documents to be kept before, during and after completion or termination of trial (please refer to slides 17 – 22)

13. Good Clinical Practice Investigator – Records and Reports Records Retention Requirements • Essential documents should be retained until at least two (2) years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing application in an ICH region or at least two (2) years have elapsed since the formal documentation of clinical development of the investigational product. • These documents should be retained, however, if required by the applicable regulatory requirements (state or federal) or by an agreement with the sponsor. • It is the responsibility of the sponsor to inform the investigator as to when these documents no longer need to be retained • The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution • Upon request of the monitor, auditor, IRB or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records

14. Good Clinical Practice Investigator – Progress Reports • The investigator should submit written summaries (where required by applicable regulatory requirements) of the trial’s status to the institution. • The investigator should submit written summaries of the status of the trial to the IRB annually or more frequently, if requested by the IRB • The investigator should promptly provide written reports to the sponsor and the IRB and where required by the regulatory authorities, the institution on any changes significantly affecting the trial and/or increasing the risk to subjects

15. Good Clinical Practice Investigator – Safety Reporting • All serious adverse events (SAE) should be reported immediately to the sponsor except for those SAEs that the protocol or other document identifies as not needing immediate reporting • The immediate reports should be followed promptly by detailed, written reports • The immediate and follow up reports should identify Subjects by unique code numbers assigned to trial, but not with identifiers (name, address, identification numbers) • The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected SAEs to the regulatory authority(ies) and the IRB • Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor within the time periods specified by the sponsor in the protocol • For reported deaths, the investigator should supply the sponsor and the IRB with any additional requested information (e.g., autopsy reports and terminal medical reports)

16. Good Clinical Practice Investigator – Premature Termination or Suspension of a Trial • If the trial is suspended or prematurely terminated for any reason the investigator should promptly Inform the trial subjects, should assure appropriate therapy and follow-up and where required, should inform the regulatory authorities and the IRB • If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution, regulatory authorities(if required), the sponsor and the IRB • Provide the sponsor and the IRB a detailed written explanation of the termination or suspension • If the sponsor terminates/suspends a trial, the investigator should promptly inform the the institution (per applicable regulatory requirements) and the IRB and provide written explanation of the termination/suspension • If the IRB terminates/suspends its approval, the investigator should inform the institution and the investigator should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension

17. Good Clinical Practice Investigator –Final Reports • Upon the completion of the trial, the investigator should inform and provide the IRB and the sponsor: • All required reports • Summary of the trial’s outcome • Reports to regulatory authorities if applicable

18. Good Clinical Practice Investigator – Records and ReportsEssential Documents to be Kept before Trial Commences • Investigators Brochure • Signed protocols, amendments (if any) and sample CRF • Information given to the trial subjects • Informed Consent • Applicable translations of informed consent (if any) • Any other written information • Advertisements for subject recruitment • Subject compensation • Financial aspects of the trial • Compensation document for trial-related injury • Signed agreements of all involved parties • Investigator and sponsor • Investigator and CRO (if any) • Investigator/institution and regulatory authorities (if any) • Approval letter from the IRB • IRB Composition • Authorization or notification from the regulatory agencies (where required)

19. Good Clinical Practice Investigator – Records and ReportsEssential Documents to be Kept before Trial Commences • CV of investigator and sub-investigators evidencing qualifications • Normal values of labs /technical procedures included in the protocol • Medical/laboratory and technical procedures of tests • Certification • Accreditation • Established Quality control (QC assessments) • Other validations • Sample labels attached to investigational product containers • Instructions for handling investigational products and trial-related materials (sometimes this information is included in the investigator’s brochure) • Shipping records of investigational products and trial-related materials • Certificates of analysis of investigational products shipped • Decoding procedures for blinded trials • Master randomization list • Pretrial monitoring report • Trail initiation monitoring report

20. Good Clinical Practice Investigator – Records and ReportsEssential Documents to be Kept During the Trial • Investigator’s brochure updates • Any revisions to: • Protocol, amendments and CRF • Informed consent form • Written information provided to subjects/LAR • Advertisement • Dated, IRB approved documents of: • Protocol amendments • Revisions of informed consent, information to subjects/LAR • Advertisements and any other documents given • Continuing review of trial • Dated Regulatory approved documents of: • Authorizations and notifications • Protocol amendments and other documents

21. Good Clinical Practice Investigator – Records and ReportsEssential Documents to be Kept During the Trial • Curriculum Vitae of new investigators and sub-investigators • Updates to normal value(s) range(s) for medical lab technical procedure(s), test(s) included in the protocol • Updates on medical/laboratory/technical procedure tests • Certificates • Accreditation • Established quality control/external quality assessment • Other validations • Documentation of investigational products and trial-related materials shipment • Certificate(s) of analysis for new batches of investigational products • Monitoring visit reports • Relevant communications other than site visits (Letters, meeting notes and notes of telephone calls) • Signed informed consent forms • Source documents • Signed, dated and completed CRF • Documentation of CRF Corrections

22. Good Clinical Practice Investigator – Records and ReportsEssential Documents to be Kept During the Trial • Notification by the originating investigator to sponsor of serious adverse evens and related reports • Notification by investigator (if applicable) to regulatory authorities and IRB of unexpected serious adverse reactions and of other safety information • Notification by sponsor to investigators of safety information • Subject screening log • Subject identification code list • Subject enrolling log • Investigational product(s) accountability at the sire • Signature sheet • Record of retained body fluids/tissue samples (if any)

23. Good Clinical Practice Investigator – Records and ReportsEssential Documents to be Kept After Completion or Termination of the Trial • Investigational product(s) accountability at sire • Documentation of investigational product(s) destruction • Completed subject identification code list (to permit identification of all subjects enrolled in the trial in case of follow up is required – this information should be kept in a confidential manner and for agreed period of time) • Audit certificate (if required) • Final trial close-out monitoring report • Treatment allocation and decoding documentation returned to sponsor to document any decoding that may have occurred • Final report by investigator to IRB where required • Final report by investigator to regulatory authorities where applicable to document completion of the trial • Clinical study report to document results and interpretation