Show Me Your Docs! A REVIEW OF UNIVERSITY OF PITTSBURGH GUIDELINE: STUDY DOCUMENTATION FOR FDA REGULATED RESEARCH

Transcription

1 Show Me Your Docs! A REVIEW OF UNIVERSITY OF PITTSBURGH GUIDELINE: STUDY DOCUMENTATION FOR FDA REGULATED RESEARCH

2 Speakers Kelly Dornin-Koss, MPPM, RN, CCRC Director Education and Compliance for Human Subject Research Cynthia Kern, RN, CIP, CCRC Director, Office for Investigator Sponsored IND and IDE Support

3 Objectives To review regulatory requirements for study documentation To discuss The University of Pittsburgh Guideline for Study Documentation for FDA Regulated Research To discuss FDA Inspectional Findings and Warning Letters

4 Regulatory Requirements for Documentation

5

6 Federal Policy Regulations FDA Regulations Title 21 CFR 11- Electronic records; electronic signature Title 21 CFR 50 - Protection of Human Subjects Title 21 CFR 56 - Institutional Review Boards Title 45 CFR 46 Title 21 CFR 54 - Financial Disclosure by Clinical Investigators Title 21 CFR Investigational New Drugs Title 21 CFR FDA approval to market a new drug Title 21 CFR Biological Products Title 21 CFR Licensing Title 21 CFR Investigational Devices Title 21 CFR 814 Pre-market approvals (PMAs) of medical devices

7 45 CFR 46 Addresses IRB Records Adequate documentation of IRB activities and meeting minutes (45 CFR & 21 CFR ) Written notifications to investigators of IRB decisions and for studies disapproved a statement of the reasons for its decision (21 CFR (e) Specifications for registering IRBs (45 CFR Subpart E & 21 CFR Subpart B)

8 Federal Policy 45 CFR 46 Address Content of Assurance Agreements A list of IRB members Written procedures for conducting initial and continuing IRB reviews Written procedures for ensuring prompt reporting of unanticipated problems involving risks to human subjects or others, serious or continuing noncompliance and study suspensions or terminations

9 Closer Examination of FDA Regulations 21 CFR 312 Responsibilities of Sponsors & Investigators Content of IND Application (312.20) Protocol Amendments (312.30) Information Amendments (312.31) Safety Reporting (312.32) Annual Reports (312.33) Labeling of Drug (312.6) 21 CFR 812 Responsibilities of Sponsors & Investigators Content of IDE Application (812.20) Supplemental Applications (812.35) Reports ( ) Unanticipated Device Effects Progress Reports, Investigator Lists Labeling of Device (812.5)

10 Record Keeping & Disposition of Drug / Device Case Histories Investigators are required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation (exposure to device). Case histories include the case report forms and supporting data including, e.g. signed and dated consent forms and medical records including e.g. progress notes of the physician, the individual s hospital chart(s), and the nurses notes. The case history shall document that informed consent was obtained prior to participation in the study.

11 Supplement the FDA and Federal Policy Regulations but do not replace them

12 ICH 8.1 Essential Documents Before During After

13 ICH - Contains multiple extensive definitions beyond those captured in our regulations Good Clinical Practice Compliance (In relation to trials) Documentation Case report form Essential documents Source document

14 University of Pittsburgh Guideline: Study Documentation for FDA Regulated Research INFORMED CONSENT

15 Documentation of Informed Consent 45 CFR Informed consent shall be documented by the use of a written consent form approved by the IRB and signed by the subject or their LAR A copy shall be given to the person signing the form 21 CFR Informed consent shall be documented by the use of a written consent form approved by the IRB and signed and dated by the subject or their LAR A copy shall be given to the person signing the form. ICH Prior to a subject s participation in the trial, the written informed consent forms should be signed and personally dated by the subject or the subject s LAR and by the person who conducted the informed consent discussion..receive a signed copy.

16 Consent Recommendations Narrative Note - Regulatory Requirement Who was present during the informed consent discussion; The fact that risks were presented; A notation, if applicable, that significant issues of concern to the subject were addressed; A statement that all questions were answered to the satisfaction of the subject. Narrative notes should also be present for addendum consents

17 IRB # PI: Subject ID: Points Discussed Comments List the persons present during the informed consent discussion Who explained the details of study participation? Note approximate length of time of discussion. Were all risks and benefits of study participation presented to the subject (and family)? Were all questions answered to the subject s (and family s) satisfaction? Does the subject appear to understand all terms of participation and agree to enrollment? How was comprehension assessed? Was the consent document signed by all parties prior to the performance of any study related procedures? Was a copy of the signed consent document provided to the subject?

18 Case Report Forms Per ICH: A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject

19 Source Documents What are they? Records on which clinical observations are first recorded The original recording of any observations made or data generated about a study subject during her/his participation in a clinical trial. Source documents confirm the completeness and accuracy of data collection and show evidence that the study was conducted not only according to the protocol, but also ethically.

20 ICH GCP 1.52 Source documents are the original documents, data and records (e.g., hospital records; clinical and office charts; laboratory notes; memoranda; subjects diaries or evaluation checklist; pharmacy dispensing records; recorded data from automated instruments; etc)

21 Follow Minimum General Standards Keep handwritten notes and signatures legible. If necessary, the individual s name may be printed underneath the signature. Sign and date all entries in real time (including late entries) Only use dark ink (no pencil) Never obscure entries that require correction (no whiteout)

22 Case Report Forms as Source Documents May serve as source documents if they represent where data was originally recorded. If using CRFs as source, maintain a list of which ones are source.

23 Computer Records Used as a Source When data is entered directly into a computer system that is 21 CFR Part 11 compliant, the electronic data system is your original source. Regardless of the type of system used, the principles are the same: Data must be reliable and usable for evaluating the safety and effectiveness of FDA regulated products

24 FDA Guidance specifies Data element = the smallest unit of observation captured for a subject, e.g race, H&H, pain severity measurement Each data element is associated with a data originator example of source data originators, include: investigators, study staff, subjects, medical devices, electronic health records For each protocol, a list of data originators should be maintained. The list should be maintained to reflect authorized users and staff changes that occur during the conduct of an investigation The list should identify the systems, devices, and instruments that transmit data directly into the ecrf

25 Source Documents Data collection forms should be developed and in place BEFORE the first study subject is enrolled.

26 What to document Data collection forms should address all study activities Eligibility criteria / screening Procedures at each study visit Drug/device dispensing Follow-up procedures All contacts with study participants Adverse events Concomitant medications Log to reflect collection and disposition of blood or tissue samples

27 Source Document Reminders Subject identifiers On all data collection forms Communications All contacts / attempts to contact study participants Laboratory test results Document review and address out of range values Questionnaires Subject ID and date of completion

28 Source Documents Entry criteria Checklist, address presence of inclusion criteria and absence of exclusion criteria

29 Eligibility Criteria Subject ID Criteria Yes No Comments Age years Scheduled to have orthopaedic surgery No history of alcohol abuse No alcoholic beverage in last 24 hours No recreational drug use in the last 6 months Not currently taking phenothiazines or NSAIDS No history of hepatitis No history of renal failure (creatinine > 1.3mg/dL) No history of diabetes No history of neurologic conditions such as stroke, head injury, spinal cord injury or intracerebral hemorrhage Not pregnant Signature Date

30 Protocol Subject ID Reproductive Potential: If you choose to be sexually active during this study, you must accept the risk that pregnancy could still result, exposing you or your partner to potential loss of pregnancy as well as other unknown effects on the developing fetus. ******************************************************************************** If you or your partner are of childbearing potential, please indicate method of contraception: Hormonal contraceptive (oral, depo, patch, injectable or vaginal ring Intrauterine device Double barrier (e.g., condoms, diaphragm with spermicidal gel or foam) Other, please specify Signature Date Please sign and acknowledge that you and your partner will be using an acceptable method of birth control during your participation in this study

31 Laboratory and other test results Documentation should reflect investigator review of results in a timely manner. Documentation should also address any necessary actions and reporting with respect to out of range results.

32 Questionnaires Study ID and Date If not personally completed by the subject, then identify who completed the form

33 Notes to File An entry, normally in the form of a document, in the regulatory binder that makes a correction to another entry or document, or explains something.

34 Notes to File Are not a substitute for good, prospective, and complete source documents. Don t simply point out the error. Include: Why this happened Actions that were taken/will be taken to address the deficiency Steps to prevent recurrence

35 Notes to File Should also contain the following: Date Protocol number and title Subject ID (if appropriate) Signature and printed name of person generating the note and date next to signature

36 Protocol Deviations Determine the cause Is it necessary to report to IRB, FDA, etc? Methods to prevent recurrence

37 Other Essential Documents Regulatory files FDA protocol or investigational plan Informed consent document IRB correspondence IRB Documentation Investigator s Brochure or Report of Prior Investigations

38 Regulatory Files Qualification Documentation Financial interest forms Conflict of Interest Management Plan and Notifications of Significant Financial Interest Signature and Delegation of Authority Log Training study-specific

39 Regulatory Files Form FDA 1572 or Investigator s Agreement Office for Investigator Sponsored IND and IDE Support Correspondence FDA Correspondence Form FDA 3674 Screening/enrollment log Lab certifications and normal ranges

40 Regulatory Files Accountability Records Specimen Tracking Log Serious Adverse events / unanticipated device effects Reportable Events Monitoring Visits Sponsor Correspondence Data and Safety Monitoring Documents Case Report Form templates

41 SIGNATURES AND DELEGATED RESPONSIBILITIES Investigator Project Name Title or Position Task Codes* Signature Initials Dates of Work on Study Delegated Responsibilities A=Make eligibility/termination decisions B=Obtain informed consent C=Label and dispense study drug D=Make data entries and corrections on CRF s E=Evaluate adverse events F=History & Physical Exam G=Scheduling study visits H=Maintain drug/device accountability records I confirm that this list accurately reflects the delegation of responsibilities during the trial Principal Investigator Date

42 Telephone conversations, s Document all telephone conversations with the sponsor or regulatory agency. Include who initiated the call, the topic of discussion and the resolution. These notes should be maintained in the regulatory files. Also, print and file all relevant correspondence regarding the study in the regulatory files.

43 TELEPHONE COMMUNICATIONS LOG Investigator: Project: Study Site: Sponsor: All contacts with Sponsor representatives concerning patient management or study conduct should be documented. This cumulative listing of phone calls and other non-printed communications between site and Sponsor provides a brief record of such contacts supplemented as necessary by additional details filed elsewhere in the Investigator File, e.g., in files of specific patients, notes-to-file in the Essential Documents Binder, conference call notebook, etc Date Person Topic and Discussion

44 Adverse Events An unfavorable medical occurrence, which may include abnormal signs (e.g., abnormal physical exam or laboratory finding), symptoms, or disease temporally associated with, but not necessarily related to, the subject s participation in the research.

45 Adverse Event Reports All adverse event reports should be sent to the appropriate agencies and copies should be maintained in the regulatory files.

46 Adverse Events Evaluate the subject with respect to the event Document and follow to resolution Report to appropriate parties Does the occurrence necessitate additional actions?

47 Reporting to FDA The sponsor of an investigational drug, device or biologic study is responsible for notifying FDA of adverse events. In cases where an investigator also acts as the sponsor, this individual assumes the responsibility for directly notifying FDA of adverse events.

48 Adverse Events Tracking Log Adverse Event Start Date Severity Relationship to Study Intervention End Date Outcome Therapy Given None Resolved Possible Continuing Probable Continuing Definite None Resolved Possible Continuing Probable Continuing Definite Investigator signature Date

49 Record Storage and Retention Double-lock Locked file cabinet in secured room

50 Record Retention Time Limits Pitt IRB: 7 years FDA: 2 years after FDA approval of drug or device or study is abandoned and 5 years after biologic is manufactured ICH: 2 years after approval from last ICH region (European Union, Japan, USA) or 2 years after study abandoned Pediatric research 2 years after the age of majority (Pennsylvania age yrs)

51 Investigational Product Accountability

52 Investigational Product Life Cycle Sponsor Assessment Investigative site Participant IDS or secure storage

53 Managing the Investigational Product

54 Accountability and Storage Secure location, limited access Investigational Drug Service drugs Devices secure area, appropriate environment

55 Dispensing and Documentation Written physician s order Use by the subject Dose modifications Adverse events

56 Labeling - Drugs Caution: New Drug Limited by Federal law to investigational use Shall not bear any statement that is false or misleading in any particular and shall not represent that the investigational new drug is safe or effective for the purposes for which it is being investigated.

57 FDA Inspections

58 FDA Inspections Center for Bioresearch Monitoring units issue inspection assignments The program assignment code and Field Accomplishments and Compliance Tracking System number The name, address and phone number of the clinical investigator or sponsor-investigator Type and purpose of inspection Background materials Specific issues or concerns

59 FDA Inspections Due date for Center contact to receive completed Establishment Inspection Report (EIR) The headquarters address where the EIR should be sent The name, telephone number and fax number of Center contact

60 Communication Prior to inspection Center issues assignment Field investigator contacts BIMO reviewer Notification of inspection date Obtain information that may change the focus of the inspection To coordinate inspections arrangements if Center personnel will participate in the inspection

61 Communication During an inspection BIMO reviewer contacts the field investigator if significant new information becomes available Field investigator contacts BIMO reviewer if needs: Advice or clarification Uncovers other evidence of concern warranting discussion with Center staff

62 Communication After Inspection Within three business days of conclusion, field investigator forwards to BIMO reviewer any 483 and Establishment Inspection Report (EIR) Field investigator forwards as soon as possible to BIMO reviewer any response to 483 by inspected party BIMO reviewer consults with field investigator as needed when reviewing EIR

63 The FDA Inspection Process 482 Notice of Inspection

64 The FDA Inspection Process Interviews and review of study documentation

65 The FDA Inspection Process End of visit review of findings with investigator and study team

66 The FDA Inspection Process When the FDA inspector finds objectionable conditions (significant violations of federal regulations, they will issue a 483. This form is used to record significant observations and to discuss with the investigator at the conclusion of the inspection.

67 The FDA Inspection Process 483 Investigator should respond in writing within 15 days The field inspector will issue an Establishment Inspection Report (EIR)

68 The FDA Inspection Process The 483, EIR and any associated documents and the Investigator response are sent to the FDA District Office and to the appropriate FDA BIMO reviewer. A classification is assigned NAI No action indicated VAI Voluntary action indicated OAI Official action indicated

69 The FDA Inspection Process Written response to 483 should include the following: Address each specific finding Describe corrective actions Now Continuing Assessment of implementation of corrective actions and plans for continuing evaluation

70 FDA Inspections USEACTION=SEARCH.SHOWADVANCEDSEARCHFORM

71 FDA Inspections

72 The FDA Inspection Process If FDA is not satisfied with the Investigator s response, then a FDA Warning letter will be issued.

73 FDA Warning Letters Most common deficiencies Clinical Investigator Failure to follow the investigational plan and/or regulations Protocol deviations Ineligible subjects Errors in dosing Inadequate recordkeeping Inadequate accountability for the investigational product

74 FDA Warning Letters Most common sponsor-investigator deficiencies: Inadequate monitoring Failure to bring investigators into compliance Inadequate accountability for investigational product Failure to obtain Financial disclosures Investigator agreement / 1572

75 483 FDA Findings Failure to conduct the investigation according to the signed agreement, the investigational plan, and applicable FDA regulations The protocol required post-surgical functional assessments, however, there is no documentation of this for any of the subjects enrolled in this study.

76 Response from PI Deviations were reported to the IRB and FDA Corrective action weekly meetings by a steering committee with review of potential deviations and recommendations for protocol amendments

77 FDA Warning Letter You may delegate some of your clinical investigator duties to others, but you remain responsible for the conduct of the studies You did not describe corrective actions to prevent protocol deviations

78 FDA Findings 483 You failed to ensure that the investigation was conducted according to the investigational plan Five of eleven subjects at your site were randomized without having met the protocol requirement for being at high cardiovascular risk

79 Response from PI Acknowledged that the subjects described were not eligible Will follow protocol eligibility criteria

80 FDA Warning Letter You have not provided sufficient information to enable FDA to evaluate the adequacy of your corrective plan You did not provide any details describing how you plan to prevent recurrence of similar violations in the future

81 FDA Findings 483 You failed to obtain Institutional Review Board approval for changes in the research prior to implementing the changes Your site implemented changes contained in Protocol Version XX, dated XX, before you received IRB approval for this protocol version.

82 Response from PI The monitor failed to inform and educate site about submitting the amendment for IRB review and approval

83 FDA Warning Letter It is your responsibility as the investigator to ensure that the IRB has approved any changes in the research prior to implementing those changes Your response is inadequate because you failed to provide evidence of IRB approval or a corrective action plan to prevent recurrence

84 Recommendations for Response Focus on regulatory requirements associated with each observation Perform root-cause analysis Be specific, complete and realistic Provide corrective action plan Provide method of verification and/or monitoring of corrections timeline

85 Questions???