Overview of Good Clinical Practice care Overview of Good Clinical Practice community Donna W. Dorozinsky, RN, MSN, CCRC research teach

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Essential Study Documents care Essential Study Documents community research teach

Study Documentation DWD & Associates During the conduct of a clinical trial, both the sponsor and the investigator generate large quantities of documentation. These documents permit the evaluation of the conduct of the study and the quality of the data produced. They demonstrate the compliance of the investigator, sponsor, and monitor with GCP and with regulatory requirements. DWD & Associates DWD & Associates

Essential Study Documents Essential Documents are those documents that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. ICH GCP E6 guidance 1997 These are the documents that are usually audited by the sponsor or by regulatory authorities to confirm the validity of the trial and the integrity of the data. DWD & Associates DWD & Associates

Essential Study Documents Purpose: demonstrate the compliance of the investigator, sponsor, and monitor with GCP and applicable regulatory requirements. Assist in the successful management of a trial by the investigator, monitor, and sponsor DWD & Associates DWD & Associates

Essential Study Documents Grouped into 3 sections Before the clinical phase of the trial begins During the clinical conduct of the trial After completion or termination of the trial ICH GCP provides a list of the minimum documents that should be in each study file as well as where they should be maintained—in the files of the sponsor or the investigator (or both). Before the trial begins: These should be generated during the planning stage and be on file before the trial formally starts During the trial: Should be added to the files during the trial as they become available After the trial: All these documents should be in the file at the conclusion of the study along with all the before and during documents. DWD & Associates DWD & Associates

Essential Study Documents Both Sponsor and investigator should establish a study file at the beginning of the trial At close-out of trial Confirm that all necessary documents are in the appropriate files Documents may be subject to an audit Acceptable to combine some of the documents At closeout of trial: go through files to make sure everything is there. Use a checklist. Have different personnel be responsible for different parts of file—e.g. study coordinator responsible for CRF/source documents/screening logs/etc. Pharmacist responsible for drug accountability etc. Investigator retains overall responsibility for the documents and file Audit: at some point the trial may be audited. Ensuring that all documents are present at the end of the trial will help to decrease anxiety at audit time. It is easier to locate everything when the trial has just finished rather than going looking for it months/years later. It is acceptable to combine some of the documents but individual elements must remain easily identifiable. DWD & Associates DWD & Associates

Before The Clinical Phase Of The Trial Document Investigator Sponsor Investigator’s brochure X Signed protocol and amendments, if any, and sample CRFs Information given to trial subjects -Informed consent form -Any other written information Advertisement for recruitment IB—to document that relevant and current scientific information about the investigational product has been provided to the investigator Protocol/CRFs—To document investigator and sponsor agreement to the protocol and CRF Informed Consent —To document the informed consent Written info —to document that subjects will be given appropriate information Advertisement —to document that recruitment measures are appropriate and not coercive. DWD & Associates DWD & Associates

Before The Clinical Phase Of The Trial Document Investigator Sponsor Financial aspects of trial X Insurance statement (where required) Signed agreement between involved parties Dated, documented approval/favorable opinion of IRB/IEC Financial Aspects —document financial agreement Insurance Statement: to document that compensation to subjects for trail-related injury will be available (if applicable) Signed agreement: may be investigator/sponsor, investigator/CRO, sponsor/CRO, IRB approval: approval of protocol and any amendments, CRF (if applicable), informed consent form, written info given to subjects, advertisements, subject compensation if any, any other documents approved. DWD & Associates DWD & Associates

Before The Clinical Phase Of The Trial Document Investigator Sponsor IRB/IEC composition X Where required Regulatory authority authorization/approval/notification of protocol (where required) CV of investigator and sub-investigators Normal values/ranges for medical/lab/tech procedures IRB composition: to document that the IRB is constituted in agreement with GCP Regulatory authority: To document approval prior to initiation of trial where required. For example when you are waiting for IND notification from the FDA. CV: to document qualifications and eligibility to conduct trial and or provide medical supervision of subjects DWD & Associates DWD & Associates

Before The Clinical Phase Of The Trial Document Investigator Sponsor Medical/lab/tech procedures/tests -Certification or accreditation or established quality control or other validation Where required X Sample of labels attached to investigational product containers Instructions for handling of investigational products and trial-related materials Medical/lab: To document competence of facility to perform required tests and support reliability of results. Would be required with an on site lab. Label: To document compliance with applicable labeling regulation and appropriateness of instructions provided to the subjects Instructions: To ensure proper storage, packaging, dispensing, and disposition of investigational products. DWD & Associates DWD & Associates

Before The Clinical Phase Of The Trial Document Investigator Sponsor Shipping records for investigational products X Certificate of analysis of investigational product shipped Decoding procedures for blinded trials (third party if applicable) Master randomization list Shipping records: To document shipment dates, batch numbers, and method of shipment. Allows drug accountability Certificate of analyses: to document identity, purity, and strength of investigational products Decoding: To document how, in case of an emergency, identity of blinded investigational product can be revealed without breaking the blind for the remaining subjects Master Randomization list: To document the method for randomization of trial population. DWD & Associates DWD & Associates

Before The Clinical Phase Of The Trial Document Investigator Sponsor Pretrial monitoring report X Trial initiation monitoring report Pretrial monitoring: To document that the site is suitable for the trial. Review of investigator site facilities, availability of subjects and other study resources Initiation report: To document that trial procedures were reviewed with the investigator and staff. DWD & Associates DWD & Associates

During the Trial Document Investigator Sponsor Investigator’s Brochure Updates X Revisions to protocol/CRF /IC form/ written information /advertisement IRB/IEC approval of any amendments/revisions CVs of any additional investigators/sub-investigators DWD & Associates DWD & Associates

During the Trial Document Investigator Sponsor Updates to normal values/ranges X Updates of medical/lab/tech procedures/tests Where required Documentation of investigational product Certificates of analysis for new batched of investigational product Documentation of investigational product drug accountability. The site must be able to account for all drug product shipped from the sponsor. DWD & Associates DWD & Associates

During the Trial Document Investigator Sponsor Monitoring Visits X Relevant communications other than site visits -letters, meeting notes, telephone calls Signed informed consent forms Source Documents Monitoring visit: To document site visits by and findings of the monitor Communications: To document any agreements or significant discussions regarding trial administration, protocol violations, trial conduct, AE reporting. Often referred to as notes to file. If they are e-mail print-outs, each note should be signed and dated by the person who prints them. This authenticates them as study information. This is because current e-mail systems are not validated. For example, an e-mail could be edited by receiver and no record of the change would be recorded. Your signature confirms that the document is an original. IC forms: To document that consent is obtained in accordance with GCP and is dated prior to participation of each subject in the trial. Source Docs: To document the existence of the subject and substantiate integrity of trial data collected. To include original documents related to the trial, to medical treatment, and history of subject. Likewise, any photocopied document should be signed and dated by the person that is photocopying the information. DWD & Associates DWD & Associates

During the Trial Signed, dated, and completed CRFs Copy Original Document Investigator Sponsor Signed, dated, and completed CRFs Copy Original Documentation of CRF corrections Notification by investigator to sponsor of SAEs and related reports X CRFs: to document that the investigator or designee confirms the observations recorded CRF corrections: to document all changes/additions or corrections made to CRF after initial data were recorded. Data changes should be noted by a single strike through with initials and date along with an explanation for any changes that are not apparent. Notification of SAEs: To document notification of sponsor of SAEs within the required time period. Usually 24 hours. DWD & Associates DWD & Associates

During the Trial Document Investigator Sponsor Notification by sponsor &/or investigator, to regulatory authorities and IRB of unexpected SAEs and other safety info Where required X Interim or annual report to IRB Subject screening log Notification of reg/IRB of SAEs: In accordance with GCP. Investigator must notify IRB of any events related to their site as well as sponsor generated safety summaries. Interim or annual report: To document compliance with GCP Subject screening log: to document identification of subjects who entered pretrial screening. DWD & Associates DWD & Associates

During the Trial Document Investigator Sponsor Subject identification code X Subject enrollment log Investigational product accountability at site Signature sheet Record of retained body fluids/tissue samples Subject ID code: to document that investigator keeps a confidential list of names of all subjects allocated to trial numbers. Allows investigator to reveal the identity of any subject Subject enrollment log: To document chronological enrollment of subjects by trial number Investigational product accountability: To document that investigational products have been used according to the protocol Signature sheet: To document signatures and initials of all persons authorized to make entries and or corrections on CRFs Record of retained body fluids/tissue samples: To document location and identification of retained samples if assays need to be repeated. DWD & Associates DWD & Associates

After Completion or Termination of the Trial Document Investigator Sponsor Investigational product accountability at site X Documentation of investigational product If destroyed at site Completed subject identification code list Audit certificate (if required) Final trial close-out monitoring report Invest Product accountability: To document that the investigational products have been used according to the protocol. To document the final accounting of investigational products received at the site, dispensed to subjects, returned by the subjects, and returned to sponsor. Documentation of Invest products: to document destruction of unused investigational products by sponsor or at site. This would be for dispensation at end of study. Subj ID code list: To permit identification of all subjects enrolled in the trial in case follow-up is required. List should be kept in a confidential manner for agreed upon time. Audit: To document that audit was performed (if required) Final trial monitoring report: To document that all activities required for trial close-outs are completed, and copies of essential documents are held in the appropriate files DWD & Associates DWD & Associates

After Completion or Termination of the Trial Document Investigator Sponsor Treatment allocation and decoding documentation X Final repot by investigator to IRB and to regulatory authority where applicable Clinical Study Report If applicable Treatment allocation: Returned to sponsor to document any decoding that may have occurred Final report to IRB: To document completion of the trial Clinical Study Report: To document results and interpretation of trial DWD & Associates DWD & Associates

Regulatory Binders CV and current medical licensesw for the PI, all sub-I, and any others listed on Form FDA 1572 A completed, signed and dated copy of Form FDA 1572, plus completed and signed copies of any amended Form FDA 1572 Asigned, dated copy of the official study protocol, plus signed dated copies of any subsequent amendments IRB approval letter for protocol and consent and any approved advertisement for subject recruitment. IRB membership roster Investigator’s Brochure Lab CAP and CLIA certifications. CV and license for lab director, reference ranges for lab tests Drug inventory

Regulatory Binders Correspondence to or from sponsor, PI, IRB, Investigational Drug, Pharmacy and subjects Screening log Patient log Monitoring reports Signature log and delegation sheets SAE reports and supporting documents IRB notification of IND safety reports All correspondence should be stamped with date of receipt Drexel University College of Medicine, Guidelines for the conduct of Clinical Trials, Regulatory Documents 4/27/2004.

Source Documentation

Source Documentation Importance of Documentation Necessary for the reconstruction, evaluation, and validation of clinical findings, observations, and other activities during a clinical trial –ICH 1.52 Substantiates the integrity of trial data, confirm observations that are recorded and confirm the existence of subjects.

Source Documentation Purpose: To record a subject’s history, diagnosis, and medical management Enable monitors to verify that trial data are accurate, complete, and verifiable Permit a reconstruction of the trial

Examples of Source Documents Past Medical History Patient medication record Admission assessment Nursing records Vital signs Lab report that physician initials and dates ECG Consultant reports

What is not considered source data? Lab print-out X-ray report Others?

The Electronic Medical Record 21 CFR, Part 11 Applies to records in electronic form that are created, modified, maintained, archived, or retrieved for FDA regulated purposes. Validation Limited access Secure, computer-generated time stamped audit trails.

The Electronic Medical Record Treated same as paper with regards to documentation. Available to the FDA for audit. Password and username security.

Source Documentation Apply ALCOA to achieve data quality Attributable Legible Contemporaneous Original Accurate Attributable: Is it obvious who wrote it? Is the data signed? Does the data correspond to actual subjects? Legible: Can the data be read? Contemporaneous: Is the information current and in the correct time frame? Is the information dated? Does the date correspond with the rest of the documents? Original: Is it the original data or a copy? Has the data been altered? Accurate: Are conflicting data recorded elsewhere? Does the data make sense?

Source Documentation Source documents should be the original document. If a copy is used as a source document, it should be certified that it was verified to be an exact copy of the original, having all of the same attributes and information as the original. If the original document is retained elsewhere in the study file, the copy does not need to be certified. This is a recommendation per FDA guidance documents, but it is not required per federal regulation. This helps provide an audit trail in the event that the copy appears to have been altered. E.g. If the original lab data are retained in the laboratory, a printout does not need to be certified.

Source Documentation Must have: Subject number or identifier Date/time of collected data point Data Signature of person making observation Unless data is automated (e.g. Dinamapp printout)

Recording of Source Data Must be permanent Black ink or typed Protected from unauthorized change Nothing that can be erased Sequence should be chronological If additions need to be made, they need to be signed and dated. Original entry must be visible if corrections are done. (audit trail)

Recording of Source Data Corrections should be made according to GCP Draw a single line through data to be corrected, record new data, initial and date correction. If reason for change is not obvious, it should be explained. If data are transcribed (e.g. lab data), the source data is the original laboratory report. Corrections: Never completely obscure old data. Never use whiteout. Never do writeovers. If corrections are not done correctly it is a red flag for an auditor and makes them suspect fraud.

Recording of Source Data Source documents should not be removed from the investigator’s site. Source documents should never be destroyed. The first place the data is recorded is the source document. Since the first place the data is recorded is the source documents, it helps to have proper forms readily available to avoid scraps of paper or post-its becoming the source documents.

Recording of Source Data CRF as source document Data may be recorded directly onto a CRF with no prior written or electronic record. Any data that is to be recorded directly onto a CRF should be identified in the protocol as per ICH GCP.

Recording of Source Data When a subject drops out of a study Document the reason for dropping out Keep a record of attempted and actual patient contacts Obtain all follow-up information where possible If unable to obtain follow-up, document the subject as lost to follow-up.

Source Documentation Do’s and Don’ts Do print legibly. Do use a black ballpoint pen. Do make sure your letters and numbers are legible and easy to read. Do complete all sections of each page as requested. Always use a 24 hour clock. Dates should be recorded in the day, month, year format (dd/mmm/yyyy).

Source Documentation Do’s and Don’ts Checkboxes should be marked with a checkmark or an X Do use only accepted medical abbreviations.

Source Documentation Do’s and Don’ts Don’t add information at a later date without indicating that you did so. Don’t date the entry so that it appears to have been written at an earlier time. Don’t add inaccurate information. Don’t destroy original documents even if they require error correction. Don’t alter information. Don’t double document paper and electronic.

Source Documentation Do’s and Don’ts Don’t leave empty lines or spaces. Draw a line through the empty line or space to prevent charting by someone else. Don’t write in the margins If you need to record additional information, use a progress notes page or use a comments space. Don’t predate or postdate information.

Case Report Forms

Where can data be found? It continues with the Case Report Form or data collection form CRFs provide the means to collect S/E data required by the protocol which is then transferred to a data base to ensure quality and integrity of the trial Why are there so many CRFs? The shoe box and the IRS audit phenomenon Attestation to credibility, veracity, compliance, etc. Organization of forms Amount of data to be collected Grouping of forms by visit

Special Considerations: The eCRF The computerized eCRF replaces the paper CRF. Sponsor provided computers used only for eCRF entry. Computers should be secured within the office. Password and username security is critical.

Investigator-Initiated Clinical Research In collaboration with your statistician, develop case report forms to accurately collect data Why? Record of participant safety Record of compliance Record of procedures carried out Facilitates analysis of the data and writing the paper(s) What else???

CRF Recording Practices Do not use records from one subject’s book for another subject. Do not use photocopies of a CRF as a source doc or as a replacement for a CRF. If data are not available, record NA. If a test or item was not done, indicate ND If no data for a particular CRF is collected, complete the header of the CRF and draw a diagonal line across the entire page to indicate not done. Do not obscure the header section.

CRF Recording Practices Do not write in the margins. Do not write on the pink or yellow copies of the CRF. Only write on the white page. Use only black ballpoint pen. Place cardboard or a similar insert beneath the record on which entries are being made. Use only standard medical terminology and abbreviations. If changes need to be made after the white portion of the CRF has been submitted, it needs to be done through a formal data clarification process.

CRF Recording Practices Numeric values Must correspond to source documents. Must be positioned using the printed decimal where applicable. It is not necessary to enter zeros in each box. Times must be recorded using a 24 hour clock. Complete dates/times should be provided. When dates/times are unknown, record UNK If exact date/time is not known, give the best estimate based on records &/or the subjects recollection. Indicate on the SD when times are estimated.

CRF Recording Practices Investigator must sign and date the Conclusion of Subject Participation record to certify that he/she has examined all the pages of the CRF and that all data recorded are accurate and complete. Date of review must reflect review of corrected information. AE record and Death Report record require a signature also.

Source Data Verification

Source Data Verification What is it? Procedures carried out to ensure that the data contained in the CRF is consistent with that in the source documents. Why do it? Establish the existence of the research participant in the trial and his/her eligibility Ensure that source data exists for all participants Ensure protocol compliance Systems with procedures should be implemented that assure the quality of every aspect of the trial. ICH – 2.13

Source Data Verification Objectives: To prove the existence of the subjects To prove their eligibility to participate in the study To confirm that they gave consent To confirm that relevant data have been accurately transferred from the source document to the CRF To ensure that there is no bias caused by omitting data

Source Data Verification If the study is going to be monitored anyway, why should we spend the time to double check it too?????

Source Data Verification Site monitors review of CRFs is not always timely or comprehensive. Improve quality of data collected. By verifying your own data, you can recognize trends or areas that need to be improved. Monitor: Because there may be a lapse of time before the monitor reviews the CRFs, queries may result in a significant amount of rework for the staff. Because the study may not be fresh in their minds, the rework may be more time consuming or less accurate. Also, the monitor does not always review all the documents but just key CRFs—inclusion/exclusion, AEs, dosing, etc. Quality: Better quality data means fewer queries from the monitor. Fewer queries from the monitor means better quality data to the sponsor. This may equal more studies! If similar errors are found across different studies, it may indicate a process or form that needs to be reworked. It helps to ensure a continuing process improvement.

Source Data Verification What should be verified? Research sites should compare source documents to the protocol and to the CRFs before starting the study to make sure they are gathering the correct information at the correct timepoints. After the study, the source documents should be compared to the CRFs to verify all data. Verification procedures should be outlined in an SOP. During the study, the source documents are often used as the guide to what data to collect and at what timepoints. If the source documents are incorrect, the correct data will not be generated. This may render the study ineligible and the data unusable. CRF data that is not supported by source documentation is not valid or verifiable. This data may eventually be audited by the FDA. If significant errors are found at that point, it could prevent or delay an investigational drug’s approval. Data verification should occur before it is forwarded to data management. Whether the data is reviewed on an on-going basis or at the conclusion of the study, may be dependent on the duration of the study and the volume of data collected. It is usually advantageous to conduct data verification on an ongoing basis so that problems can be resolved before they have a significant impact.

Source Document Verification All verification needs to be documented. Checklist form Signatures/dates of verification Different person who verifies than who recorded data. System for correcting error Checklist form Needs to include each subject/each CRF Checklist form needs to include area for signature/date It is better to have a someone verify who did not record the data. Often, if you have recorded the data, you may not recognize inconsistencies of data. System for correcting error—flag pages that need to be corrected. Corrections should be made by the person who originally recorded and signed the data.

Source Document Verification What do I look for?

CRF vs. SD Review Demography Informed Consent Eligibility Medical History Study Medication Concomitant Medication Lab & Diagnostic test results Adverse Events All subjects accounted for Demography: Does each patient exist. Informed Consent: Was informed consent obtained before any study procedures were done. Is the informed consent signed/dated? Is it the correct version of the informed consent? Eligibility: Does the subject meet the criteria for the study? All inclusion and exclusion criteria should be double checked. If a subject does not meet the incl/excl criteria, it is possible that his data will need to be excluded from the statistical analyses. Medical History: Everything recorded on the medical history/progress notes is recorded onto the CRF Study Medication: Does the dosage/time/route agree. Was the correct regimen followed? Concomitant Medications: Does it agree with the raw data—patient diary or source doc. Does it make sense with AE form or prior medical history. Lab & Diagnostic test results: These are often printouts. Is it for the correct patient. Are the dates/times correct. AEs: Are they properly recorded. To they agree with data and other CRF fields. Are there any notations in the patient diary or progress notes that were not picked up as an AE. All subjects accounted for: Are there CRFs for all patients including those that have dropped out or that were lost to follow up.

CRF vs. SD Review Protocol Adherence Protocol Deviation An incident involving noncompliance with the protocol but does not affect the subject’s rights, safety, welfare, or the integrity of the resultant data. Protocol Violation More serious, may involve critical study parameters. May render a subject ineligible Affects the subject rights, safety, welfare or data integrity. Protocol Adherence: Was the protocol followed? Any protocol deviations or violations need to be reported. Protocol Deviation: e.g. protocol required test was completed one day outside of the allowed window. A follow up that was supposed to be done at 7-10 days was done on day 11. Protocol Violation: E.g. enrollment of a subject who doesn’t meet incl/excl criteria without sponsor permission. Failure to do a protocol required test.

Archiving DWD & Associates DWD & Associates

Archiving Requirements If an archive is not up to standard it will have a negative impact on the outcome of a study audit. Archives may be kept on site or may be contracted out to an archiving service. It does not matter where documents are kept only that they are secure and available whenever needed by the sponsor. DWD & Associates DWD & Associates

Archiving Responsibilities Sponsor Retain all sponsor specific essential documents Retain according to regulatory requirement of the countries where the product is approved Retain for 2 years after discontinuation of the clinical development of a product. Transference of ownership of the compound and documents must be reported to appropriate authorities. Archiving responsibilities are spelled out in the ICG GCP E6 document. Much of this was covered in the Essential Study Document section of this module. These will be the documents that we are referring to. DWD & Associates DWD & Associates

Archiving Responsibilities Sponsor Essential documents should be retained until at least 2 years after the last approval of a marketing application (NDA) in an ICH region and until there are no pending or contemplated marketing applications in an ICH region. Inform the investigator in writing of the need for record retention and when the records can be destroyed. These time periods must be interpreted as minimum periods. Sponsors may require investigators to keep the documents for longer than the minimum period. DWD & Associates DWD & Associates

Archiving Responsibilities Investigators Maintain all essential documents as per GCP Prevent destruction of essential documents Retain documents until sponsor notification that documents can be destroyed Have documents available for access by monitor, auditor, IRB, or regulatory authority as requested. DWD & Associates DWD & Associates

care Adverse Events community research teach

Evaluating Safety Adverse Events Serious Adverse Events Devices Federally Funded Research Adverse Drug Experiences Protocol Violations/Deviations

When a proposed drug’s benefits outweigh known risks, the FDA’s Center for Drug Evaluation and Research considers it safe enough to approve. Benefit vs. Risk: How CDER approves new drugs

ADVERSE EVENTS

Adverse Events Definition: (from ICH GCP 1997) Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Interpretation: AEs are illnesses, objective signs, or subjective symptoms that have appeared or worsened during the courses of a study. They do not have to be related to the study drug. All events that occur during a study need to be evaluated regardless of what regimen the subject is receiving, including placebo.

Interpretation Changes in the clinical condition or worsening of conditions present at the onset of the study Patient deterioration due to the primary illness Inter-current illness Drug interactions Events related or possibly related to concomitant medication Important abnormal laboratory values which the clinician considers clinically relevant

Adverse Events Primary role of the Investigator Challenges in identifying and reporting

SERIOUS ADVERSE EVENTS

Serious Adverse Event (SAE) Definition (from ICH GCP 1997) Any untoward medical occurrence that at any dose: Results in death Is life-threatening Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect It is important not to confuse the term serious with severe. Severe describes the intensity of the AE (e.g. mild, moderate, severe) not the medical significance of it. Serious is based on the patient/event outcome or action criteria of the event. Life-threatening: This means that the subject was at immediate risk of death at the time of the event. It does not include a reaction that, had it occurred in a more severe form, might have caused death. Disability: If the AE resulted in a significant, persistent, or permanent change, impairment, damage or disruption in the patient’s body function/structure, physical activities, or quality of life.

Additional FDA Description Based upon appropriate medical judgment, jeopardize the patient or subject and may require medical or surgical intervention without hospitalization. 21 CFR Part 312.32 In addition to those listed on previous slide 21 CFR, Part 312.32 adds situations that based upon……..

Responsibilities of Sponsors The sponsor is responsible for the ongoing safety evaluation of the investigational product. Must notify the FDA and all participating investigators of Any AE that is both serious and unexpected. Any finding from tests in animals that suggest a significant risk for humans. The sponsor is responsible for ensuring that systems exist to record, document and report AEs and SAEs. The sponsor is expected to promptly review all information relevant to the safety of the drug obtained by the sponsor from any source, foreign or domestic. Sponsors must expedite the reporting of SAEs that are unexpected and may be related to the study drug. There are additional incidents that may be expedited at the judgment of the sponsor: an expected SAE that has an increased rate of occurrence or a significant hazard to the patient population, such as lack of efficacy with a medicinal product used in a life-threatening disease. In addition to expedited reporting, the sponsor must also submit to the regulatory authorities all safety updates and periodic reports.

Responsibilities of Investigators Know the definitions of an AE/SAE for the individual protocol and IRB. Report all unexpected SAEs to the sponsor except those that the protocol identifies as not needing immediate reporting. Report to the sponsor any AEs and/or laboratory abnormalities identified in the protocol as critical to safety evaluations. Supply sponsor and IRB/IEC with information regarding serious adverse events Per ICH GCP The immediate report should be followed promptly by detailed, written reports. The reports should identify the subject by their unique code number assigned to study subjects.

Responsibilities of Investigators Ensure that members of staff are aware of the procedure for reporting AE/SAE Ensure that all AE/SAE documentation are included in the study file AE/SAE to be followed up until outcome is known Assign causality Review IND Safety Updates received from sponsor and forward to IRB

Serious vs. Severity Serious patient outcome Severity ADL

Reporting Serious Adverse Events Investigator Established procedure for reporting Report to Sponsor and IRB immediately Sponsor Notify the FDA no later than 7 calendar days after Sponsor’s initial receipt of information. FDA Form 3500A Notify Investigators through IND Safety Updates

FDA Guidance – IND Studies What is an unanticipated problem? AE represents a serious unexpected event that is rare in absence of drug exposure. Signal that events were not isolated occurrence Expected event that occurs with greater frequency Event that results in modified IB Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting – Improving Human Subject Protection, Draft. April, 2007

Reporting to IRB – FDA Guidance IND Studies Sponsor is in best position to review and analyze AE information Investigator may rely on sponsor’s assessment and provide to the IRB a report prepared by the sponsor If sponsor reports directly to the IRB, the investigator is not expected to duplicate reporting.

DEVICE RELATED EVENTS

Device Regulation 21 CFR 814 PMA: any premarket approval application for a class II medical device.

Device Related Serious Illness/Injury Life threatening Results in permanent impairment/damage to body function or structure Necessitates medical/surgical intervention to prevent permanent impairment, damage of body function/structure

Caused or Contributed Device failure Manufacturer defect Malfunction Improper/inadequate design Improper/inadequate labeling Use error

Medical Device Reporting Reported within 10 working days of learning of it Sponsor immediately conducts evaluation and reports to FDA, all reviewing IRBs and Investigators Reported through Center For Devices And Radiological Health Suspected medical device related deaths need to be reported to both FDA and manufacturer. Use form MEDWATCH Form 3500A

FEDERALLY FUNDED RESEARCH

45 CFR part 46 Reporting Requirement Unanticipated Adverse Event Unanticipated problem involving risks to subjects or others

Unanticipated Problems Unexpected Related or possibly related to participation in research Increased concern about risk of harm

HHS Definition of AE Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign, symptom or disease, temporally associated with the subject’s participation whether or not related to subjects participation.

AE is Reported if… Unexpected given protocol-related documents and the characteristics of the subject population being studied Related or possibly related to participation in the research Places subjects or others at a greater risk of harm Unexpected in terms of nature, severity or frequency Harm is defined as physical, psychological, economic or social harm than was previously recognized This would suggest that modifications are required as corrective actions changes to protocol modification to inclusion exclusion criteria additional procedures to monitor safety of subjects suspension of enrollment of new subjects

Examples of AEs that are Unexpected Liver Failure due to diffuse hepatic necrosis if protocol documents do not identify liver disease as a potential adverse event Liver failure due to hepatic necrosis even if protocol information refers to elevated hepatic enzymes

Unanticipated Problems that are Not AEs An investigator’s laptop is stolen with identifiable data regarding illicit drug use. Dosing error where subject receives a dose 10 times higher than dose indicated by IRB approved consent.

HHS Guidance January 15, 2007 Provides greater clarity of reporting requirements and definitions Provides guidance to IRB procedural requirements Reporting requirements related to external adverse events

POST-MARKETING EVENTS

Reporting Requirements Serious Unlabeled Related to use of drug

Adverse Drug Experiences AE associated with the use of a drug in humans, whether or not considered related including: AE used in course of professional practice AE occurring from drug overdose AE occurring from drug abuse AE occurring from drug withdrawal Failure of expected pharmacological action

Review of ADE Applicants with approved applications must promptly review all ADEs Commercial marketing Experience Post marketing clinical investigations Post marketing epidemiological/surveillance studies Scientific literature Unpublished scientific papers Written procedures for surveillance, receipt, evaluation, and reporting of post marketing ADEs to FDA

Examples IND study with marketed interacting drug Sponsor funded, Investigator Initiated study using a marketed drug Investigator initiated study for off label use

Sponsor Reporting Requirements Post marketing studies 15-day alert report only if there is reasonable possibility that it is related to the drug. Complete FDA Form 3500A for each patient IND # NDA #

ADE Reporting Process for Investigator Print report Documentation is part of the study file When fax document to sponsor, keep fax receipt as part of records. Take the next step and notify sponsor

IN SUMMARY

Best Practices Report it TODAY Processes with documentation of ALL applicable regulations and guidance Awareness of international standards Sponsor has obligation to know what CROs are doing Companies are manufacturers Data FDAAA Clinical Trial Databases FDA Guidance Documents count!!!

Acknowledgement Carol Krueger, CSO, RN – Compliance Officer Food and Drug Administration

Quality Management in Clinical Trials care Quality Management in Clinical Trials community research teach

Course Objectives Discuss key requirements and the purpose of Standard Operating Procedures. Discuss the role of quality assurance in investigator site study conduct. Describe the role of the study monitor in the oversight of sponsor studies.

“Sites have an ethical responsibility to conduct clinical trials with well-trained staff, documented procedural systems, and most importantly, making the time to implement realistic quality assurance processes.” Thomas, Carolynn, Dean, T. Beth, Fowler, Donna,“Quality time: the art of QA program development for research sites” Research Practitioner, Volume 4, number 6, p 219. Quote from Thomas, Carolynn, Dean, T. Beth, Fowler, Donna,“Quality time: the art of QA program development for research sites” Research Practitioner, Volume 4, number 6, p 219.

Challenges for today’s research sites: Competitive enrollment among sites High cost of operations Shortages of qualified staff Increasing trial complexities Decreasing study budgets In order to meet these challenges and to do better than competitors, a site needs to have well-written SOPs which are followed and a quality assurance plan. If work is not done correctly the first time, it is very costly to redo it. When issues are found during monitoring, the resolution of these issues is time-consuming and therefore expensive. In addition, if SOPs and GCP are not being followed, and are discovered during an FDA audit, it could result in the sponsor being unable to use the trial data or even a closure of the site. If problems are found by an internal QA program, they can be resolved quickly.

Quality Management 5 areas Standard Operating Procedures Quality Assurance Monitoring Fraud FDA Inspections

Standard Operating Procedures

Standard Operating Procedures It is a requirement of GCP that during the conduct of a Phase I-IV clinical trial, the responsible organization must employ documented systems of quality control and quality assurance, and ensure that the trial adheres to written SOPs, with the objective that, given the same raw materials, suitably qualified individuals will achieve the same result by following the step-by-step instructions contained within the SOP. SOPs help to document the working procedures for the information of others outside the facility, e.g. regulatory authorities, internal auditors. Also, because old SOPs are maintained, even after updates have been made, when an audit is done, it can be done against the procedures as they were at that time.

Standard Operating Procedures Definition Detailed, written instructions to achieve uniformity of the performance of a specific function. ICH GCP E6 Document A set of written instructions on how to perform a certain task or action.

Standard Operating Procedures Purpose Ensure compliance with GCP and federal regulations Help to achieve maximum effectiveness of clinical operations. Ensure consistency, compliance, and accountability of personnel at all levels of clinical research. Provide structured guidelines for implementing clinical trials. Regulate internal quality Aid in process improvements

Standard Operating Procedures After an SOP is approved All SOPs need to be reevaluated every 2 years at minimum and updated as needed. SOPs need to be filed in a central area. If processes are changed, then the SOP needs to be updated. Each year to two years, the SOP needs to be reviewed. If there are no changes to be made, it can just be re-dated and approved. If the procedure needs to be updated, it must be changed to fit current practice, then approved, and filed. If changes are made, the SOP needs to have a new version number. It is helpful to have a binder of a central location for all SOPs including a table of contents. Prior versions of SOPs need to be archived in a secure area. If the SOPs are to be kept in an electronic archive it must be secure and validated for security. While keeping them in an electronic version is ideal for accessibility, hard copies also need to be kept in a secure location with the appropriate signatures. It doesn't matter if an SOP is not ready for its annual review. Anytime a process changes, the SOP must reflect the way things are currently being done.

Standard Operating Procedures After an SOP is approved All applicable personnel need to be trained on the SOP. Training may be done by: Self-training In-service Hands-on training All training needs to be documented. Any person who will be performing the procedure needs to be trained on the new SOP. Self-training is appropriate for certain SOPs. This may include reading the SOP then answering a few questions about the content of the SOP. Training may be done by in-service. This is an effective means for training a large group of staff at one time. Hands-on training may be done for certain SOPs. This would require a person being an expert on the SOP. This person may be the author or a manager. They would then observe staff members individually completing the procedure. Documentation needs to be done for each staff member for each SOP. The documentation needs to go in their in-service/training file.

Standard Operating Procedures Non-compliance issues Can’t find it! Can’t understand it! Can’t follow it! It’s confusing! That’s how we used to do it! My way is better! Who cares anyway! Who has the time! A centralized electronic file of SOPs should help to alleviate this issue. An SOP needs to be written in user friendly language. The instructions need to be clear and easy to follow. The SOP needs to be written in an organized, standardized format. SOPs need to be current. If your processes change the SOPs need to be updated even if it is before the annual date. If you think your way is better, then maybe you should write the SOP next time or provide input into it. Even if you think your way is better, you must follow the SOP. Deviations from SOPs must be documented and appropriate actions taken. If SOPs aren’t followed in a trial, GCP requires that deviations be documented and actions taken to prevent reoccurrence. If serious or persistent non-compliance continues, the sponsor may terminate the investigator’s involvement in a trial and notify the regulatory authorities. If non-compliance is found during an FDA audit, it is listed as an objectionable condition which is listed on From 483 at the conclusion of the audit. It may cause the data from that site to be rendered unusable. No one thinks they have time to learn new SOPs let alone to write them. Unfortunately, this is not optional. It needs to be included as part of job descriptions and performance evaluations. For certain job levels, it could be mandated to author a set amount of SOPs/year. For all job levels, completion of SOP training needs to be mandatory.

Quality Assurance

Quality Assurance What is it? A comprehensive review of key aspects of a process to assess compliance with standards and systems. Inspection system that checks inputs and outputs. A planned and systematic activity Usually retrospective and sample-based QA is process/systems driven. QA is a means of assessing whether procedures are being done as per their SOPs and GCP. QA follows a plan which is usually a written plan. It is done on a routine basis following the guidelines written the in the plan. Data is not reviewed in a real-time mode or as data is collected. Not 100% of the data is reviewed but a sample size that is determined in the QA plan.

Quality Assurance Is QA the same as QC? Quality Control is: Usually a 100% review Usually data driven Usually done in real time QC usually is done at the time of data collection or shortly thereafter. Generally the data is reviewed 100% to check for accuracy. It is the data being reviewed, not the processes. An example of this is source data verification.

Quality Assurance Why do QA? Provides assurance that the protocol, SOPs, and GCP are being followed. Ensures the site is ready for an audit. Ensures that data generated are valid and verifiable. Ensures that processes are effective and if not can help to streamline them. Data can be used for business development or recruitment. And also that there are adequate SOPs and systems in place to ensure compliance to GCP.

Quality Assurance The final result: Better end product!

Quality Assurance “Quality cuts out repetition and slices off delays.” Thompson WL. “Clinical trails must be faster, more streamlined”. The Monitor. 1999:13:25-28.

Monitoring

Monitoring Definition: The act of overseeing the progress of a clinical trail, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures, GCP and the applicable regulatory requirements. ICH GCP E6 Document

Monitoring The sponsor shall monitor the progress of all clinical investigations being conducted under its IND. 21 CFR 312 Sec 312.56

Monitoring Purpose: To verify that The rights and well-being of human subjects are protected. The reported trial data are accurate, complete, and verifiable from source documents. The conduct of the trial is in compliance with the currently approved protocol/amendments, with GCP, and with applicable regulatory requirements.

Monitoring Qualifications of monitors: Appointed by the sponsor Appropriately trained with the scientific and/or clinical knowledge needed. Thoroughly familiar with the investigational product, the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and regulatory requirements. Monitors may be performed by the sponsor or its own employees or may be contracted out to a contract research organization.

Monitoring The extent of monitoring of the trial is based on its: Objective Purpose Design Complexity Blinding Size Endpoints Extent is determined by the sponsor Most on-site monitoring should include before, during, and after the trial. In exceptional circumstance the sponsor may determine otherwise. More complicated studies, pivotal studies will be more closely monitored.

Monitor’s Responsibilities Main line of communication between the sponsor and the investigator Verify that the investigator has adequate qualifications and resources. Verify that the staff and facilities are adequate to safely and properly conduct the trial. Verify drug accountability Verify that the protocol is followed The first three are usually done during the pre-study visit and then are followed up on during all subsequent visits. The monitor needs to make sure that the site in adequate not just at the start of the study but as the study progresses. Drug Accountability includes: storage time/conditions are acceptable Only eligible subjects receive it and receive it as per protocol Receipt, use, and return of the drug are controlled and documented Unused products are disposed on in accordance with regulatory requirements

Monitor’s Responsibilities Verify that IRB consent is obtained for protocol and then for any amendments. Verify that informed consent was obtained for each subject Ensure that investigator receives current IB, documents, and supplies Ensure that the investigator and staff are adequately informed about the trial Verify that trial functions are performed as per the protocol

Monitor’s Responsibilities Verify that only eligible subjects are enrolled Report the recruitment rate Verify source data/documents and other trial records Verify that the investigator provides all required reports, notifications, applications, and submissions. Source docs: Makes sure they are accurate, complete, kept up-to-date, and maintained.

Monitor’s Responsibilities Check the accuracy and completeness of the CRF entries, source documents, and trial records against each other. Data required by the protocol are reported accurately on the CRFs and that they are consistent with the source data/documents. Any dose &/or therapy modifications are documented AEs, con meds, & intercurrent illnesses are reported Missed visits, tests, & examinations are clearly reported Withdrawals/dropouts are reported and explained on the CRFs This is a major portion of their job and takes up a lot of their on-site visiting time.

Monitor’s Responsibilities Inform the investigator of any CRF errors, omissions, or illegibility. Determine whether all AEs are reported within the time periods required by GCP, protocol, IRB, sponsor, and regulatory requirements. Communicate deviations from the protocol, SOPs, GCP, or regulatory requirements to the investigator and take appropriate action to prevent recurrence. Should ensure that appropriate corrections, additions, or deletions are made, dated, explained if needed, and initialed by the investigator or authorized staff member.

Monitoring Report A written report should be submitted after each visit or trial-related communication Report should include a summary of what the monitor reviewed and any significant findings, deviations, deficiencies, conclusions, actions taken or to be taken. This enables the FDA to determine that a sponsor’ obligations in monitoring the progress of a clinical investigation are fulfilled.

Monitoring Monitor visits are usually divided into: Pre-study visit/site selection visit Study initiation visit Monitoring visit Study close-out visit Telephone communications Pre-study visit is done prior to signed agreement. It is to determine if the investigator can produce quality work on time. Study initiation visit: done after signed agreement. Telephone communications: may be to answer questions from the site or to communicate new information to the site.

Monitor Visits Pre-study Visit/Site Selection visit Assess the suitability of a site to meet the requirements of a study Investigator issues Study conduct Review of potential subject population Staff Institutional relationships Facilities and equipment Investigator Issues: Interest in study, cooperation, willingness to give study adequate time & staff, acceptance of obligations and GCPs, concern for study rather than personal gains (e.g. money, publications), accessibility, other current studies. Study Conduct: review protocol, AE reporting requirements, record retention, drug accountability. Patient population: size and source of population, enrollment of sufficient subjects in required time, competing studies. Study staff: quality experience, size of staff and current workload, responsibilities of staff, turnover rate, training, familiarity with GCP & SOPs. Institutional relationships: access to IRB Facilities and Equipment: drug storage, record keeping, equipment for procedures/lab tests or other protocol specified needs, space for study.

Monitor Visits Study Initiation Visit Review protocol, informed consent, & CRF in detail with entire staff involved in study Review procedures for study drug dispensing, accountability, and storage Ensure adequate training has been completed This visit is done prior to the study start and is conducted at the site where the study will be done. It should be done as soon as possible after receipt of drug.

Monitor Visits Study Initiation Visit Ensure adequate supplies of clinical trail materials and equipment Review lab schedule and normal ranges Review AE reporting procedures Review contents of the investigator file Review monitoring schedule and procedures Study related materials/supplies include: Current IB, protocol with all revisions, clinical drug supplies, other supplies e.g. blood tubes or specimen kits, blank CRFs.

Monitor Visits Study Initiation Visit Review the QA procedures of site Discuss likely start date Communicate sponsor standards Communicate regulatory requirements/GCPs

Monitor Visits Monitoring visit Check that the facilities/equipment are still adequate Review any staff changes CRF review Current status of study Withdrawn patients AE review Protocol followed Purpose of the visit is to monitor for GCP compliance, protocol adherence, collection of complete, accurate, and valid data, and assessment of study progress. Frequency of these visits is determined by enrollment rate, complexity of study, experience of staff, timelines, and past performance of site. CRF review: check for accuracy and completeness of information and legibility. Verify the data vs. source docs. Bring any discrepancies to the attention of the investigator for correction.

Monitor Visits Monitoring visit Informed consent documentation Drug accountability Lab procedures and review abnormal values Adequate supplies Review any other problems Ensure investigator’s file is up to date IC documentation: ensure that they are using the IRB approved form. It is dated prior to enrollment, signed copy for each patient.

Monitor Visits Study Close-out Visit Review/collect remaining CRFs Verify/collect outstanding edits from prior visits Accountability and return of study drug & clinical supplies Ensure study files are complete Ensure proper secure storage/retention of records Review investigator reporting/study responsibilities Final payment and administrative matters

Questions?

care Compliance and Audit community research teach

Fraud The fabrication or falsification of data or any component of a research trial constitutes fraud and is unquestionably characterized as research misconduct. Completion of a study in a way that compromises the validity or reliability of the findings or violates the rights of the subjects.

Fraud Research Misconduct Falsification of data in proposing, designing, performing, recording, supervising, or reviewing research, or in reporting research results Includes acts of omission and commission

Fraud Acts of omission Acts of commission Deliberately withholding information E.g. Adverse events, con meds Acts of commission Falsification of data Inventing data E.g. Lab values, BP readings Falsification of data: data exists but is changed or modified Inventing data: data do not exist in regards to that subject

Fraud Deliberate or repeated noncompliance with the regulations are considered misconduct Regulations should not be viewed as barriers to the conduct of studies but as tools to well-conducted studies that protect the subjects from harm.

Fraud What is not fraud? It does not include honest error or honest differences of opinion. Lies told by patients/subjects

5 Elements of Fraud Evidence of false presentation of data Prior knowledge that the data was false. Individual promoted the false data claims. Sponsor and/or FDA believed the data to be true within reason. Damage occurred as a result of the data or factual account of the clinical trial.

Fraud What are the consequences of fraud?? Places all subjects in that trial at possible safety risk Jeopardizes the reliability of clinical trial data Breach of medical and scientific ethics

Fraud Data falsification These are just a few examples! Physical or lab exams Biological specimens Subject Identities Drug compliance records Sample collection times These are just a few examples! Physical or lab exams: physicals without any corroborating source documents, bogus lab results reported Biological specimens: samples which are supposed to be from a large number of individuals are actually from only a few different subjects Subject Identities: same subject enrolled more than once under two different names/subject numbers, nonexistent subjects created. Drug compliance records: study drug not taken by subject, discarded, and 100% compliance reported Sample collections times: Sample is due at 9:00, drawn and 9:15, but 9:00 is recorded. Document actually signed on August 17th, but dated August 16th.

Fraud Why is data falsified? To qualify ineligible subjects To please the bosses by filling in the blanks and making the source documents match the CRF For fun For profit Pressure on the investigator to publish

Fraud How can we prevent fraud? Ensure that staff have necessary resources and support to follow the protocol and complete the trial Educate staff on protocol, study drug, and CRFs Avoid unreasonable demands on site Ensure adequate education of staff on GCP Develop and implement SOPs Internal monitoring/QA to ensure compliance with regulations and guidelines

Fraud Everyone is responsible for reporting fraud. Therefore, Everyone should be on the lookout for signs of fraud. Fraud should be reported to the FDA. Signs of fraud: frequent changes/mistakes, inconsistencies of data, copies of documents instead of originals, suspicious data, gut feeling.

Fraud Education is the key to improving trial quality. Education must target all who participate in clinical trials. Education must be a continuous process.

Notable Example of Fraud Fiddes, 1999 President of a Clinical Research Co. in California during 1990’s Participated as an investigator in over 200 trials. Involved in 91 submissions with 47 different sponsors.

Notable Example of Fraud Engaged in extensive fabrication and falsification of data. Purchase bacteria from supplier and sent to labs as samples from patients ears. Used one patients urine and submitted for several other patients. Used family members as manufactured research subjects No one suspected him because he was such a well respected investigator.

Notable Example of Fraud Several coordinators reported this to monitor who in turn reported to the Sponsor. When questioned by the sponsor, Fiddes response was one of outrage and requested that a new monitor be assigned. Had it not been for a disgruntled employee, Fiddes would still be operating.

FDA Inspections

FDA Inspections FDA Bioresearch Monitoring Program Performs site visits to clinical investigators, research sponsors, CROs, IRBs, and nonclinical (animal) laboratories Designed to monitor all aspects of the conduct and reporting of FDA regulated research Objective of all inspections is to ensure the quality and integrity of data and information submitted to FDA as well as the protection of human research subjects. This department was formed in 1977.

FDA Inspections Clinical Investigator Inspections 3 Types Study-oriented inspections Investigator-oriented inspections Bioequivalence study inspections We will be looking at the clinical investigator inspections most closely since this will have the greatest impact on your unit.

FDA Inspections Study-oriented inspections Based on studies that are important to product evaluation Pivotal studies for a pending NDA Pivotal studies for product license applications

FDA Inspections Investigator-oriented inspections May be initiated because an investigator conducted a pivotal study May be because the sponsor has reported to the FDA that they are having difficulty getting reports from the investigator or that they have a concern about their work May be based on a subjects complaints May be because they have participated in a large number of studies or have done work outside their specialty area Inconsistent safety or effectiveness findings Too many subjects with a specific disease given the locale of the investigation Pivotal studies: final bioequivalence studies. Single studies in an sNDA file.

FDA Inspections Bioequivalence study inspections Conducted because one study may be the sole basis for a drug’s marketing approval Requires participation by an FDA chemist or an investigator knowledgeable about analytical evaluations We will be discussing the first two types of audits in this presentation—clinical investigator or study oriented inspections. They both follow the same basic procedures.

FDA Inspections Inspection Procedures FDA investigator from district office will contact investigator to arrange a time for the visit. At visit, he will show FDA credentials and present a “Notice of Inspection” form

FDA Inspections Investigation consists of 2 basic parts Determining the facts surrounding the conduct of the study Who did what Delegation of authority Where was the study done How/where the data were recorded Study drug accountability How the monitor communicated and evaluated the study’s progress Who did what: Each data point needs to clearly demonstrate who collected that data point. Delegation of authority: points to criticality of delegation logs. How/where: was EDC involved, paper source documents or a combination of both. Monitor communications: copy of monitoring reports as part of study file.

FDA Inspections Investigation consists of 2 basic parts Study data is audited FDA compares the data submitted to the Agency with all available records that might support the data. In an investigator-oriented inspection, the data audit goes into greater depth, covers more case repots, and may cover more than one study.

What will FDA Inspect? Randomly selected files 100% of informed consent All serious and unexpected AEs Regulatory Binder 100% of investigational drug inventory Source documents vs. CRFs

How Thorough is the Inspection? Expect the FDA Not to Miss ANYTHING! Expect the FDA to Document EVERYTHING!

FDA Inspections After the inspection, the FDA issues its inspection findings. Conduct an exit interview Discuss findings Clarify any misunderstandings May issues a form FDA-483 (Inspectional Observations)

FDA Inspections After the inspection, the FDA issues its inspection findings. FDA issues a letter to the investigator 3 types No Action Indicated (NAI) Voluntary Action Indicated (VAI) Official Action Indicated (OAI) In cases of serious deviations, the FDA may take other courses of action such as regulatory or administrative sanctions. NAI: No objectionable conditions or practices were found during the inspection. Full compliance VAI: Objectionable conditions or practices were found which represented departures from the regulations. Informational letter sent. No response necessary unless indicated. OAI: Objectionable conditions or practices found represented significant departures from the regulations and may require the imposition of administrative/regulatory sanctions.

FDA Inspections http://www.fda.gov/cder/present/dia-62000/woolen1/sld007.htm This chart shows the types of letters received by the investigators post inspection. The majority received letters that had no significant deviations (50%). 45% received letters that were informational but did require response. Only 1% were warning letters that required a response.

FDA Inspections http://www.fda.gov/cder/present/dia-62000/woolen1/sld008.htm Shows the areas where the investigators had deficiencies. Main areas were protocol issues including non-adherence, inadequate and inaccurate records, and AEs. These could include protocol deviations/violations, subjects not meeting inclusion/exclusion criteria, randomization not followed, CRF discrepancies, missing records, and non-reporting of AEs.

FDA Inspections What does the FDA look for: Source of study subjects Inclusion/exclusion criteria Was the protocol followed Adverse events Adequacy of reports Informed consent IRB review obtained CRFs completed Study subjects: Is this a unique populations, do the subjects exist? Is there evidence that they exist? Sign-in logs Inclusion/exclusion criteria: Did they meet the criteria, did they have the disease under study? Compare actually screening data to requirements of the study. Adverse events: were they reported to the sponsor and to the IRB? Are there non reported AE’s in the study documentation. Study logs. Example would be AE documented in progress report, but never shows up on CRF. Reports: CRFs, safety reports, annual reports Informed consent: Was IC obtained, do they have unique signatures?

FDA Inspections What does the FDA look for: Comparison of source data to CRFs to data submitted to FDA Look for adequate documentation to assure that all subject exist Look for any comments in the raw data not reported on the CRF Look for subjective comments such as patient complains Look for concomitant prohibited medications that unrecorded protocol deviations. Data comparison: Look at patient/hospital records, ECGs, x-rays, lab reports.

FDA Inspections What does the FDA look for: Dropouts Who else was involved in the study IRB correspondence SOPs Dropouts: how documented, are the reasons reported, unused study medications accounted for. Who involved in study: who records data in the CRFs, who handles study medications? IRB correspondence: verify date of approval, AEs/deaths reported, protocol changes documented and approved, progress reports sent? SOPs: SOPs that were in existence at the time of the study, not currently. It is critical that SOPs be kept even after outdated.

Preparation for an Inspection Best preparation is before an investigation is even announced! Training programs for all staff including investigators! GCP Regulatory requirements Job responsibilities SOPs Organization and maintenance of regulatory documents Critical that there is clear evidence of all training.

Preparation for an Inspection Gather required documents Signed protocol/amendments Signed FDA form 1572 and accompanying CVs IB IRB documentation Informed consents CRFs Source documents Study drug accountability records SAE reports Site visit log Subject master list

Preparation for an Inspection Notify PI, sponsor or sponsor designee, IRB in the event of an FDA, OHRP or NIH inspection Assure that all records are available for inspection. Selection of a “point person” This person should be available through-out the inspection. Identify an uncluttered room for the Inspector to review records.

At The Inspection Stay calm Give clear, concise answers to questions asked Do not volunteer additional information Do not speculate Accompany the FDA investigator at all times Have staff available who participated in study Keep an additional copy of each copy that you give to the FDA investigator. A general inspection log should be kept for each day of the inspection. Copies should be marked COPY

At The Inspection Know your job responsibilities If you don’t understand the question, ask for a clarification Answer truthfully If you don’t know the answer, say so Refer to documentation if you need to Do not argue

Recent 483 FDA Findings References: SOPs: ARNOTT P “Standard operating procedures” Clinical Research Manual Euromed Communications Ltd 1996; pp. 13.1-13.12 DUCATE MJ, EYCKEN JP, RIVERA LE and EDMONDS S “A framework for developing global Standard Operating Procedures” Drug Information Journal 1994; 28(4) pp. 937 – 941 GAWADI N “Standard operating procedures” Carson and Dent (Eds) Good Laboratory and Clinical Practices 3rd edition Oxford: Butterworth - Heinemann WILES A, ALEXANDER J, CLARK P, GODLEY M and LENDREM D “Standard Operating Procedures” Drug Information Journal 1995; 29(2) pp. 497 – 502 Zimmerman, Janet F. “Integrating Standard Operating Procedures into GCP Training: The Monitor Fall 1999 “Standard Operating Procedures for Good Clinical Practice by Sponsors” A Publication of the Center for Clinical Research Practice, Inc. 2001 pg. 6 Fries, Ruth Ann “Standard Operating Procedures for Clinical Research Coordinators” Drug Information Journal Apr-Jun 2002 Quality Assurance Low, Mary “Quality Assurance at the Clinical Research Site” Research Nurse September/October 1999 Thomas, Carolynn J., Dean, T. Beth, Fowler, Donna R. “Quality Time: the Art of QA Program Development for Research Sites” Research Practitioner Volume 4 Number 6 pp. 219-225 Verna, LoriAnn, Dorozinsky, Donna “Implementing a Quality Management Program” ACRP presentation Monitoring GEELEN F 1997 “Are Project Trial Nurses more important than Monitors?” Monitor Zentrale Deutschland GEELEN F 1997 “How to select the right monitor” Monitor Zentrale Deutschland ICH Guideline for Good Clinical Practice, ICH Harmonised Tripartite Guideline (CPMP/ICH/135/95), The European Agency for the Evaluation of Medicinal Products (EMEA) 1997 1-58 McFARLAND LV 1996 “Optimising Clinical Site Selection” MEIJER P and GEELEN F 1996 “European survey on GCP” Monitor Zentrale Deutschland SCHUYL ML and ENGEL T 1995 “A Review of the source document verification process in clinical trials” WILDEY S “Trial Monitoring” Clinical Research Manual (11) 1997 Fraud Act 2 of 2000, Promotion of Access to Information Act Republic of South Africa BARQA GCP Committee “Fraud, Misconduct or Simply a Case of Poor Investigating” BARQA Newsletter 1997; 60 pp. 20-22 BARQA GCP Regional Meetings on Fraud Good Clinical Practice Journal 1997; 4 (4) pp. 6-9 BOGAIEVSKY Y “Fraud and Misconduct in Clinical Research: Company Dilemmas and Solutions” Drug Information Journal 1995; 29 pp. 1269-1273 BRACKMAN F “The Consequences of Fraud in Clinical Studies” Good Clinical Practice Journal 1994; 1 (3) pp. 26-27 BROCK P “Suspected Fraud in Clinical Research: Handling the Problem” Good Clinical Practice Journal 1994; 1 (3) pp. 8-14 GNANASAKTHY A and MASIH K “Identifying and Dealing with Protocol Deviations” Good Clinical Practice Journal 1997; 4 (4) pp. 6-9 HUTCHINSON D “How to Minimize the Collection of Unreliable Data in Clinical Trials” Good Clinical Practice Journal 1994; 1 (3) pp. 16-19 JAY P “The Fraud Busters” Good Clinical Practice Journal 1997; 4 (1) pp. 17-18 LOCK S and WELSS F Fraud and Misconduct in Medical Research BMJ Publishing Group 1996 MACKINTOSH D and MOLLOY V “Guarding the Pharmaceutical Chicken Coop: The Case for External Clinical Auditors” Good Clinical Practice Journal 1998; 5 (3) pp. 8-12 MACKINTOSH DR and ZEPP VJ “Detection of Negligence, Fraud, and other Bad Faith Efforts During Field Auditing of Clinical Trial Sites” Drug Information Journal 1996; 30 pp. 645-653 WALSH RC “Systematic Measures for the Prevention and Early Detection of Investigator Fraud” Drug Information Journal 1994; 28 (4) pp. 1161-1165 WELLS F “The Importance of GCP in the Prevention and Detection of Fraud” Good Clinical Practice Journal 1994; 1 (3) pp. 4-7 Sugar, Alan M. “Individuals, Institutions and Research” Research Practitioner from www.researchpractice.com/archive/ind_inst_research.shtml Woollen, Stan, El Hage, Antoine “Scientific Misconduct-The “F” Word” presentation from Oct 2001 Lepay, David, “GCP, Quality Assurance, and FDA” presentation from Fall 2001 FDA Audit El-Hage, Antoine “FDA Oversight of Clinical Trials Policy, Procedures, and Precedents” & “Preparing for FDA Visits” & “Detecting Fraud in Bioresearch Cases for Discussion” presentations Woollen, Stan “Patient Misuse and Investigator Fraud in Clinical Trials: What Can Be Done? Part I” from www.fda.gov/cder/present/dia-62000/woolen1 FDA Information Sheets: FDA Inspections of Clinical Investigators, Updated 9/98 All Topics: ICH GCP E6 Document

Challenges in Recruitment care Challenges in Recruitment community Donna W. Dorozinsky, RN, MSN, CCRC research teach

Current Environment Patient recruitment and retention is the leading bottleneck in studies today Patient recruitment occupies 27% of the cost of clinical development. $5.3billion globally 1 in 20 recruited patients provides data that can be used in the regulatory dossier. >75% of all trials fail to meet their recruitment deadlines.

Current Environment Missed deadlines Phase I last 42% longer Phase II last 31% longer Phase III last 30% longer Of 612 Investigative sites, 45% rate patient recruitment as source of delay

Options Direct to patient advertising Physician practices Television – special interest stories Radio Newspaper Posters in the clinic Physician practices Centralized recruitment

Media Can Work Right vehicle Right patient demography Repetition Targeted strategies to infuse small markets.

Advertising IRB Approval Include: the name and address of the clinical investigator and/or research facility the condition under study and/or the purpose of the research Enrollment criteria Benefits Contact info

Wording State if investigational drug Do not promote “free medical care” Do not emphasize payment

Recruitment Script IRB reviews process IRB reviews info to be collected for database IRB reviews script

Employ Marketing Strategies Product = Protocol design Price = Patient’s benefit of participation Place = Investigator’s site Patient needs to be the focus. Message must target the patient population.

Common Mistakes in Recruitment Failure to consider patient population or physician patient relationship in designing the campaign The site’s capacity Poorly considered media and recruitment tactics Failure to forecast, report and redeploy

Cost of Not Meeting Enrollment $600,000-$8M in lost revenue for every day a drug is delayed to market.

Patient Recruitment Advertising and Marketing Tools

Sources of Patients for Studies Referrals: patients from within practice or from another practice. Direct mailings Health screenings Web – becoming increasingly popular Newspaper advertising Radio and television advertising

Making Physician Referrals Work Dear Dr letters with a new look Coordinator to Coordinator Community networking Presence in the physician’s office during office hours.

Protocol Design and Patient Recruitment Any protocol design should first be based on good science There can be statistical advantages to selecting a narrowly defined patient population There are disadvantages also: DIFFICULT TO RECRUIT!

Elements of a Protocol Which Impact Recruitment Length of study: longer studies are harder to recruit and also to retain. Choice of control group: Placebo controlled often are more difficult to recruit for. Inclusion Exclusion Criteria: new onset Rheumatoid Arthritis (RA) with no use of steroids would be harder to find than RA symptoms for less than 2 years. Degree of Disease: Advanced RA vs. mild RA Concomitant Disease: MI with no hx of HTN vs MI alone Medication exclusions: patient with CHF who are not on an ace inhibitor. Procedures performed: 3 extremity x-rays and 3 MRIs would be a challenge for someone’s schedule.

Elements of a Protocol Which Impact Recruitment Blood draws Invasive diagnostic procedures: tumor staging Biopsies: skin biopsy to dx a derm disorder. Medication withdrawal. Taking someone off of their anti-hypertensive. Availability of open label extension study always enhances subjects because it means if the drug is working they can continue it.

Patient Recruitment Need to focus significant resources on recruitment outside the medical practice Nearly 2/3 or al enrolling patients are self referred. Part-time sites account for nearly 40% of all study conduct dollars and these sites do not the money for full time recruiters or SMOs Professional recruitment groups structure entire recruitment campaigns, including the design and placement of advertising and follow-up. They often have patient databases.

Patient Databases Recent under scrutiny because of HIPAA Databases are often vague and can not identify patients with osteoarthritis vs rheumatoid arthritis. Database should be able to select pre-qualified volunteers given specific set of criteria Should not be the sole source of patient recruitment. Contracts hneed to be created to determine to whom the database belongs. Subjects being pre-screened for studies should be advised of what will be done with this confidential information that they are providing.

Role of a Call Center Patient recruitment Site referral Appointments Retention Compliance Adverse events

Recruiting Patients on the Internet 1999 less than 15% clinical research professionals using the internet for patient recruitment. By 2001 almost 50% use the internet for recruitment.

Using the Internet Need to have good online and offline targets. Advertise website Good presence on search engine

Registering Trial Must be registered at www.clinicaltrials.gov Generally done by sponsor Check anyway!

Other Academic Institutions Harvard: No central recruitment Mayo Clinic University of Wisconsin UCLA FCCC

Other Resources Clinicaltrials Biotrax

Subject Retention Retention is result of various factors that are all directly linked to the human interaction between the site and the potential patient Retention is directly linked to patient satisfaction. Recruitment Precursor to patient retention Advertising that is simple, direct and no n-coercive Informed consent that provides sufficient and understandable information without being so lengthy and highly technical that the patient is too intimidated to sign it. Staff presenting should be caring and willing to answer questions.

Possible Predictors of People predisposed to Drop Out of a Study Lower income Lower education level Unstable or high risk phycial status Low levels of social support An ethnic or socio-economic status different from that of the investigator

Retention Drop-out rates vary widely, but range from 15% to 40%, with even higher rates reported. Reasons for patient dropout from a year-long asthma study Tx non compliance 17% Tx adverse event 17% Tx lack of benefit 12% Other medical condition 11% Moved from area 4% Administrative termination 22% Other resons 17%

Subject Compensation: What is Reasonable? How much is the patient inconvenienced? Is the patient hospitalized? How much travel time is involved? How many additional procedures are required for the study? How invasive are the procedures? Cost of living

GCP at Investigator Site care GCP at Investigator Site community Donna W. Dorozinsky, RN, MSN, CCRC research teach

Recruitment All advertising materials must be IRB approved. Any documents given to the subject or seen by the subject must be IRB approved. All scripts must have IRB approval Inability to meet recruitment is #1 cause in delays of study completion

Elements of a Protocol Which Impact Recruitment Length of study: longer studies are harder to recruit and also to retain. Choice of control group: Placebo controlled often are more difficult to recruit for. Inclusion Exclusion Criteria: new onset Rheumatoid Arthritis (RA) with no use of steroids would be harder to find than RA symptoms for less than 2 years. Degree of Disease: Advanced RA vs. mild RA Concomitant Disease: MI with no hx of HTN vs MI alone Medication exclusions: patient with CHF who are not on an ace inhibitor. Procedures performed: 3 extremity x-rays and 3 MRIs would be a challenge for someone’s schedule.

Elements of a Protocol Which Impact Recruitment Blood draws Invasive diagnostic procedures: tumor staging Biopsies: skin biopsy to dx a derm disorder. Medication withdrawal. Taking someone off of their anti-hypertensive. Availability of open label extension study always enhances subjects because it means if the drug is working they can continue it.

Informed Consent Process Includes: Clear discussion of the information in the ICF. Signed and dated ICF. Copy of signed ICF to subject. Documentation of time and date that consent process was conducted. The Nuremburg Code states that: The voluntary consent of the human subject is absolutely essential. This means that the person involved should: have legal capacity to give consent; be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other form of constraint or coercion; and have sufficient knowledge and comprehension of the subject matter and the elements involved as to enable him or her to make an informed and enlightened decision. This latter element requires that all of the following be made known to the subject: the nature of the experiment the duration of the experiment the purpose of the experiment the method and means by which the experiment is to be conducted all inconveniences and hazards reasonably to be expected the effects upon the subject’s health or person which may possibly come from his or her participation in the experiment Generally, documentation is completed by writing a note in the chart confirming that the event took place.

Informed Consent Obtained “prior to” participation in a clinical study. Includes any specific exams or procedures specific to the study (hts, wts, VS, ECGs) Before discontinuing any existing medications the subject is taking for the purpose of determining suitability for the study.

Informed Consent If new information becomes available that may be relevant to the participant’s continued participation, communication of this information must be documented. Updated/amended ICF should be explained and signed by both the consenter and the participant. A copy of signed new consent will be provided.

Informed Consent According to FDA’s Information sheets, the FDA does not require reconsenting of subjects that have completed their active participation or of subjects actively participating when the change will not affect their participation (ex. future cohorts affected). Must reconsent only if they are directly affected (ex. increased drug mutagenecity)

Source Documentation Importance of Documentation Necessary for the reconstruction, evaluation, and validation of clinical findings, observations, and other activities during a clinical trial –ICH 1.52 Substantiates the integrity of trial data, confirm observations that are recorded and confirm the existence of subjects.

Source Documentation Purpose: To record a subject’s history, diagnosis, and medical management Enable monitors to verify that trial data are accurate, complete, and verifiable Permit a reconstruction of the trial

Source Documentation Apply ALCOA to achieve data quality Attributable Legible Contemporaneous Original Accurate Attributable: Is it obvious who wrote it? Is the data signed? Does the data correspond to actual subjects? Legible: Can the data be read? Contemporaneous: Is the information current and in the correct time frame? Is the information dated? Does the date correspond with the rest of the documents? Original: Is it the original data or a copy? Has the data been altered? Accurate: Are conflicting data recorded elsewhere? Does the data make sense?

Source Documentation Source documents should be the original document. If a copy is used as a source document, it should be certified that it was verified to be an exact copy of the original, having all of the same attributes and information as the original. If the original document is retained elsewhere in the study file, the copy does not need to be certified. This is a recommendation per FDA guidance documents, but it is not required per federal regulation. This helps provide an audit trail in the event that the copy appears to have been altered. E.g. If the original lab data are retained in the laboratory, a printout does not need to be certified.

Source Documentation Must have: Subject number or identifier Date/time of collected data point Data Signature of person making observation Unless data is automated (e.g. Dinamapp printout)

Recording of Source Data Must be permanent Black ink or typed Protected from unauthorized change Nothing that can be erased Sequence should be chronological If additions need to be made, they need to be signed and dated. Original entry must be visible if corrections are done. (audit trail)

Recording of Source Data Corrections should be made according to GCP Draw a single line through data to be corrected, record new data, initial and date correction. If reason for change is not obvious, it should be explained. If data are transcribed (e.g. lab data), the source data is the original laboratory report. Corrections: Never completely obscure old data. Never use whiteout. Never do writeovers. If corrections are not done correctly it is a red flag for an auditor and makes them suspect fraud.

Recording of Source Data When a subject drops out of a study Document the reason for dropping out Keep a record of attempted and actual patient contacts Obtain all follow-up information where possible If unable to obtain follow-up, document the subject as lost to follow-up.

Electronic Source Data If there is electronic data as well as printouts, the electronic data is defined as the source data. This will decrease the risk of the data files being changed but the printout remaining unchanged.

Source Documentation Do’s and Don’ts Do print legibly. Do use a black ballpoint pen. Do make sure your letters and numbers are legible and easy to read. Do complete all sections of each page as requested. Always use a 24 hour clock. Dates should be recorded in the day, month, year format (dd/mmm/yyyy).

Source Documentation Do’s and Don’ts Checkboxes should be marked with a checkmark or an X Do use only accepted medical abbreviations.

Source Documentation Do’s and Don’ts Don’t add information at a later date without indicating that you did so. Don’t date the entry so that it appears to have been written at an earlier time. Don’t add inaccurate information. Don’t destroy original documents even if they require error correction. Don’t alter information.

Safety Monitoring Values of Potential Clinical Concern Determined by the physician Labs ECGs Diagnostic findings Clinical Significance – Adverse Events

Adverse Events Monitor at each visit Follow-up on open AEs Continuing at end of study Protocol defined adverse events In early development report everything Open ended questions “how do you feel?”

Adverse Events Assignment of Causality Severity – as observed as well as reported Include an assessment of what you see, contributes to assignment of causality Medical terminology Mapping of terms Consistency in CRF completion

Protocol Adherence Protocol Deviation Protocol Violation An incident involving noncompliance with the protocol but does not affect the subject’s rights, safety, welfare, or the integrity of the resultant data. Protocol Violation More serious, may involve critical study parameters. May render a subject ineligible Affects the subject rights, safety, welfare or data integrity.

Reporting Deviations Violations Document any discussions between sponsor and investigator Submit as a summary to the IRB at time of continuing review Violations Report to IRB immediately Description of event Note any compromise to patient safety Documentation of communication with sponsor Corrective action plan

Site Management Defined process for handling violations/deviations Define responsibilities SOP vs protocol Root cause analysis Communicate to all parties Track trends Corrective actions

Drug Accountability Control of investigational drugs, vaccines, or devices (article) To provide accountability system to address receipt, distribution, and return of all investigational supplies To ensure that supplies are properly stored and accessible only to designated study staff To ensure that investigational materials are used only according to protocol All Clinical Trial Materials (CTM’s) must be accounted for and disposed of per protocol. Pharmacy accounts for all drugs given, returned or destroyed, but investigator retains legal accountability for this.

What does GCP mean to me? Must have Adequate documented training of staff Data handling systems and procedures SOPs!!! Quality Control Processes Computerized systems standards Maintenance of Audit trails Adequate training of staff: staff must be trained on GCPs and SOPs. Training must be documented. Staff must also be educated about each protocol and investigational product they are working with. May be educated by in-service or by self-education e.g. reading protocol, investigators brochure, etc. Individual protocol training must also be documented. Data handling systems and procedures: Every procedure/system must have a Standard Operating Procedure (SOP). This is to guarantee that procedures are done the same way each time so that the results will be reproducible. Each employee must be trained on the SOP and it must be documented. Quality control processes: Must have a system of checks and balances in place. Not only for data review processes. Should do quality assurance on processes and procedures also. Computerized system standards: Systems must be validated and meet federal regulations of 21 CFR Part 11. Audit Trails: All data, both written and electronic, must have an audit trail. You must be able to see what the original data was, what it is corrected to, and who corrected it. E.g. written data is crossed out with one line and initialed and dated. Computer data must retain the original data with a record of who changed it and when in its log even though only the correct data is shown.

????? Evaluations Post Test for CEUs