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Clinipace Business Continuity: GCP Compliant Clinical Trials


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Clinipace's Jan Holladay Pierre's presentation on Business Continuity Considerations for Clinical Trial Sites during the COVID-19 Pandemic. Jan presented on Tuesday, March 31, 2020.

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Clinipace Business Continuity: GCP Compliant Clinical Trials

  1. 1. Business Continuity: GCP Compliant Clinical Trials Jan Holladay Pierre, MPH, CMQ/OE Director Quality Assurance
  2. 2. Business Continuity: GCP Compliant Clinical Trials Global Considerations Towards COVID-19 Pandemic
  3. 3. Global Regulatory Guidance’s for Business Continuity Resources ▸FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic: Guidance for Industry, Investigators, and Institutional Review Boards – updated 27Mar2020 with Q&A ▸EMA Guidance on the Management of Clinical Trials during the COVID-19 Pandemic ▸MHRA Guidance Managing Clinical Trials During Coronavirus (COVID- 19) ▸Other country-specific guidance © Clinipace 2020 3
  4. 4. Business Continuity (BC) and Resilience Planning ▸Is the process of creating systems of prevention and recovery to deal with potential threats to an organization. In addition to prevention, the goal is to enable ongoing operations before and during execution of disaster recovery. ▸An organization's resistance to failure is "the ability ... to withstand changes in its environment and still function". Often called resilience, it is a capability that enables organizations to either endure environmental changes without having to permanently adapt, or the organization is forced to adapt a new way of working that better suits the new environmental conditions. © Clinipace 2020 4
  5. 5. Adapt & Innovate
  6. 6. Goals and Opportunities ▸Ensure general public health safety for all ▸Assure the safety and welfare of trial participants ▸Maintain compliance with good clinical practice (GCP) ▸Minimize risks to trial integrity during the COVID-19 pandemic ▸Retool “business as usual activities” and reallocate resources towards QC and FDA/Competent Authority (CA) inspection readiness activities ▸Cross-train for continuity in skills and abilities for all employees © Clinipace 2020 6
  7. 7. COVID-19 PANDEMIC - Activities ▸General Safety and Social Distancing ▸Trial Participant communications and awareness of BC activities ▸Ongoing clinical risk-benefit considerations with FDA/Competent Authority and IRB/IEC notification ▸CRO, vendor, site capabilities assessment ▸Contingency planning affecting protocol implementation with updates/revisions towards existing plans and procedures ▸Ramp-down opportunities © Clinipace 2020 7
  8. 8. Outline BC Activities Employee Safety and Social Distancing © Clinipace 2020 8 Activities ‣ All employees should practice social distancing. ‣ Work from home. Compliance Check ‣ Ensure VPN use and good practices for downloading any sensitive data.
  9. 9. Telemedicine Considerations ▸HITECH Act, which will allow HIPAA covered health care providers to use audio or video communication technology to provide telehealth to patients during the COVID-19 pandemic. © Clinipace 2020 9
  10. 10. Outline BC Activities Trial Participant communications and awareness of BC activities © Clinipace 2020 10 Activities ‣ Trial Participants who no longer have access to IP or the investigational site may need additional safety monitoring through phone contact, virtual visit, alternative location for assessment (i.e., local labs or imaging centers) ‣ Consider any alternative shipping and storage arrangements at the Trial Participant’s home. Compliance Check ‣ ICH E6(R2) 4.3.3 if subject consented contact PCP for follow up ‣ IMP accountability and stability requirements remain the same per ICH E6(R2)5.14.5/21CFR312.61/62 and the Investigational Brochure (IB) ‣ Document how the stability of the product will be maintained during transit (especially for cold chain product), how safe custody of product will be ensured.
  11. 11. Telephone/Video Conference: Standardized IC Process ▸Identification of who is on the call ▸Review of the IC with the trial participant by the investigator and response to any questions they may have ▸Confirmation by the witness that the patient’s questions have been answered ▸Confirmation by the investigator that the patient is will to participate in the trial and sign the ICD while the witness is listening on the phone ▸Verbal confirmation by the patient they would like to participate in the trial and that they have signed and dated the ICD that is in their possession ▸If the signed ICD can not be collected from the patient’s location, FDA has the following two options: • Attestations by the witness who participated in the call and by the investigator that the patient confirmed that they agreed to participate and signed the ICD • A photograph of the ICD with attestation by the person entering the photograph into the study records that states how that photograph was obtained and that it is a photograph of the IC signed by the patient © Clinipace 2020 11
  12. 12. Outline BC Activities Trial Participant communications and awareness of BC activities © Clinipace 2020 12 Activities ‣ Trial Participants should be kept informed of changes to the study and study personnel. ‣ Consider eConsent option ‣ An unsigned consent form provided to the trial participant in isolation by a health care worker who has entered the room ‣ Consider phone and/or video conference with the trial participant and an impartial witness and if desired and feasible a family member. Compliance Check ‣ Document telephone contact in source record ‣ Document changes in manner of obtaining consent to include possible eConsent options ‣ Standardize across sites new IC process.
  13. 13. If patients are currently receiving an investigational product infusion at the clinical trial site, can a sponsor switch to home infusion? Sponsors should consider the safety risk to trial participants who would miss an investigational product infusion because of the inability to come to the clinical trial site. In general, for investigational product that is usually administered in a health care setting, consulting the appropriate FDA review divisions is recommended regarding plans for alternative sites for administration (e.g., home nursing or alternative sites by trained but non-study personnel). For example, consulting FDA would be strongly advised for complex investigational products (e.g. cellular therapy and gene therapy products) where potentially altered storage and handling conditions could adversely affect product stability. © Clinipace 2020 13
  14. 14. Outline BC Activities Ongoing clinical risk-benefit considerations with FDA/Competent Authority and IRB/IEC notification © Clinipace 2020 14 Activities ‣ On-going clinical trials with direct potential benefit to Trial Participant may continue for enrolled Trial Participants. ‣ Discontinuing clinical trials for which there is little to no prospect of direct benefit to Trial Participant should be considered. Compliance Check ‣ Ethical principles of research and federal regulations for HSP regulations require an acceptable risk-benefit rationale. ‣ All decisions to adjust clinical trial conduct should be based on a risk assessment by the sponsor(ICH GCP section 5.0).
  15. 15. Outline BC Activities Ongoing clinical risk-benefit considerations with FDA/Competent Authority and IRB/IEC notification © Clinipace 2020 15 Activities ‣ Study decisions may include the nature of the disease, continuing trial, use of the investigational product for trial participants already participating in the trial, and monitoring during the clinical trial. ‣ Assess whether the limitations imposed by COVID-19 pandemic on protocol implementation pose new safety risks to trial participants. Compliance Check ‣ If risk assessment leads to actions that affect the clinical trial relevant regulatory/competent authority and IRB/IEC must be informed. ‣ Is it feasible to mitigate these risks by amending study processes and/or procedures.
  16. 16. Outline BC Activities Ongoing clinical risk-benefit considerations with FDA/ Competent Authority and IRB/ IEC notification © Clinipace 2020 16 Activities ‣ Sponsors should evaluate alternative methods for safety assessments (e.g., phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers) ‣ Assess continued availability of clinical investigator/sub- investigators to provide trial oversight and whether sufficient clinical trial support staff and equipment remain. Compliance Check ‣ Ensure sensitive and PHI not shared inadvertently when contacting the Trial Participant and that a process of authenticating the Trial Participant identity is practiced and that voice messages are not left at the Trial Participant’s home. ‣ Alternate locations for assessments could be identified on the 1572 or documented in other clinical trial document with requisite PI oversight.
  17. 17. Outline BC Activities Ongoing clinical risk-benefit considerations with FDA/Competent Authority and IRB/IEC notification © Clinipace 2020 17 Activities ‣ Sponsors should determine if in-person visits are necessary to fully assure the safety of Trial Participant ‣ The sponsor should consider whether the safety of Trial Participants can be assured with the implementation of the altered monitoring approach. ‣ The sponsor may ask PIs to voluntarily suspend their trials if they can do so safely Compliance Check ‣ ICHE6(R2) Adaptive and Risk- Based Monitoring
  18. 18. Outline BC Activities © Clinipace 2020 18 Activities Compliance Check
  19. 19. Technology: Centralized and Remote Monitoring ‣ CDMS ‣ Pharmacovigilance (PV) Safety Database ‣ CTMS ‣ IRT/IVRS/IWRS ‣ EMR systems ‣ ERDM systems ‣ eCOA/ePRO ‣ Telemedicine ‣ Virtual platforms ‣ Other eSource platforms (e.g., BYOD) © Clinipace 2020 19
  20. 20. “Trust but Verify” Definition: Verify: To prove the truth of, as be evidence or testimony; confirm; substantiate.
  21. 21. Risks: Virtual and Remote Applications ‣ Trusting the remote or virtual activity without physical access to evidential documentation. ‣ Virtual applications used must be validated and the method of use standardized and tested for variability between onsite versus virtual visits. ‣ Removes the subjective nature of monitoring ‣ Reliability and Authentication Assurances eSource records ‣ ALCOA-CCEA Test © Clinipace 2020 21
  22. 22. Outline BC Activities Sponsor/CRO, vendor and site capabilities assessment © Clinipace 2020 22 Activities ‣ Identify clinical trial sites by region/local areas to best prioritize site management and monitoring activities ‣ Identify vendors supporting ongoing clinical trials in these regions/areas for their capabilities to deliver services. ‣ Regions/local areas most affected should consider restricting Trial Participant - site as well as CRA- site onsite interactions and consider virtual and remote activities. Compliance Check ‣ QRM – risk-based decisions ‣ The mechanism for confirming Trial Participant has been seen at an alternate lab should be documented ‣ Confirm the IP was delivered and received by the Trial Participant. ‣ Site follow-up call to the Trial Participant confirming alternate activities.
  23. 23. Can a sponsor initiate virtual clinical trial visits for monitoring patients without contacting FDA if there is an assessment by the sponsor and investigator that these visits are necessary for the safety of the trial participant and it will not impact data integrity? • FDA regulations allow for changes to be made to the investigational plan or protocol without prior FDA review or approval, if the change is intended to eliminate an apparent immediate hazard or to protect the life and well-being of subjects. • Therefore, changes in protocol conduct necessary to immediately assure patient safety, such as conducting telephone or video contact visits for safety monitoring rather than on-site visits, can be immediately implemented with subsequent review by the IRB and notification to FDA. © Clinipace 2020 23
  24. 24. Outline BC Activities Sponsor/CRO, vendor and site capabilities assessment © Clinipace 2020 24 Activities ‣ Sponsor/CRO should consider sites with direct EMR access for SDV. ‣ CRA’s should request through institution’s legal department direct access to EMR system study portals for secure, online access to PHI. ‣ CRA access to site’s electronic regulatory document management (ERDM) system for remote regulatory document review. Compliance Check ‣ ICH E6 1.21 defines direct access as “Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial”. ICH E6 5.15.1 directs sponsors to ensure “that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial- related monitoring, audits, IRB/IEC review, and regulatory inspection”
  25. 25. Adequate Source Data Verification (SDV) ▸Monitors assure the site is maintaining complete Trial Participant source records. ▸FDA guidance on risk-based monitoring discusses remote review of electronic medical records via the EMRS. ▸FDA also suggests that critical data and processes surrounding the collection of critical data be identified and indicated in the clinical monitoring plan (CMP) ▸FDA COVID-19 guidance does not include recommendations towards remote review of source data ▸Can SDV be done remotely if appropriate security and processes are established? • We do not want to over-burden the site nor do we want any HIPAA or data breaches if we ask the site to redaction original source • Have we determined that there is a process for certifying copies (i.e., verification of the original by signature or validating the process for producing an exact copy) prior to redaction and delivery (i.e., mail, email) © Clinipace 2020 25
  26. 26. Outline BC Activities Sponsor/CRO, vendor and site capabilities assessment © Clinipace 2020 26 Activities ‣ Remote IMV and activities such as IP accountability through video- conferencing can be considered. ‣ Frequency IMV should consider stability of the IP and margin of safety and expiry of the IP which would require less monitoring Compliance Check ‣ HIPAA/GDPR and sharing PHI/PII is still in effect so consider how to safeguard employee privacy, maintain the blind and de- identification PHI identifiers during video-conferencing. ‣ The IP accountability procedure should still be followed and therefore the IMV should document compliance with this procedure. ‣ Lastly the actual video process should be validated if you are capturing source information (IP accountability).
  27. 27. Adaptive Monitoring Strategies: Remote and Centralized Activities ‣ Changes to monitoring approach should not increase site burden. ‣ How do we ensure continued adequacy facilities and resources through remote monitoring? ‣ How do we ensure continued filing for required regulatory documents? ‣ How do we ensure the site is maintaining complete Trial Participant source records? © Clinipace 2020 27
  28. 28. Outline BC Activities Contingency planning affecting protocol implementation should be fully documented © Clinipace 2020 28 Activities ‣ Implementation of alternative processes should be consistent with the protocol to the extent possible. ‣ Document how restrictions related to COVID-19 led to the changes in study conduct and duration of those changes and indicate which Trial Participants were impacted and how they were impacted as protocol deviations until the amendment is approved. ‣ No need to update patient Information Sheet can use separate information sheet Compliance Check ‣ TMF should include a note that the clinical trial was discontinued/paused and the reason. ‣ If the restart of the study does not involve any substantial changes to the IND/IDE and Clinical Trial Authorization (CTA), then a substantial amendment notification to FDA/MHRA will not be necessary. ‣ If screening for COVID-19 is mandated locally do not need to be reported as a protocol amendment (FDA)
  29. 29. Delay Identification Protocol Deviations and/or GCP Violations Sponsors should carefully document situations where monitors were unable to access, or had to delay, monitoring of a clinical site due to the COVID-19 control measures as protocol deviations. © Clinipace 2020 29
  30. 30. Outline BC Activities Updates/revisions towards existing case report forms (CRFs), plans, procedures, 1572s, DOAL and regulatory reporting should occur. © Clinipace 2020 30 Activities ‣ CRFs should explain the basis of missing data related missed visits and any other protocol deviations including the relationship to COVID-19. ‣ Data Management Plan (DMP) to include procedures for handling missing information should be developed with these deviations summarized in the clinical study report (CSR) and reflective in the Statistical Analysis Plan (SAP). Compliance Check ‣ If amending the DMP and/or SAP to reflect protocol changes, consider consulting with the regulatory/competent authority prior to database lock.
  31. 31. What is the best way for sponsors and investigators to capture multiple deviations? • Important to capture specific information for individual participants that explains the basis for missing protocol-specified information that includes the relationship to COVID-19 (e.g., from missed study visits or study discontinuations due to COVID-19). This information, summarized in the clinical study report, will be helpful to the sponsor and FDA. • If it is not possible to capture this information in the case report form(s), sponsors may develop processes that enable systematic capture of these data across the sites in a manner that enables the appropriate analysis when the data are submitted to FDA. • Sponsors may also develop processes to capture site-level status, site-level or vendor- level protocol deviations, and process deviations. © Clinipace 2020 31
  32. 32. Outline BC Activities Updates/revisions towards existing case report forms (CRFs), plans, procedures, 1572s, DOAL and reporting should occur. © Clinipace 2020 32 Activities ‣ IP distribution for self- administration by the Trial Participant may be considered. ‣ Impacted efficacy assessment should be documented (e.g., identifying the specific limitation imposed by COVID- 19 leading to the inability to perform the protocol- specified assessment). Compliance Check ‣ Alternative procedures for IP distribution and administration should be developed in addition to updates in the IP Manual and Safety Management Plan should reflect the impacted efficacy assessment. ‣ CSR should reflect impacted efficacy assessment.
  33. 33. Outline BC Activities Updates/revisions towards existing case report forms (CRFs), plans, procedures, 1572s, DOAL and reporting should occur. © Clinipace 2020 33 Activities ‣ Update 1572 when a new investigator is added to the study. ‣ No need to update 1572 if there are additional labs are added, however, document the changes in the clinical study records and inform the sponsor so that they can update the IND. ‣ Ensure the Delegation of Authority (DOA) Log include additional individuals responsible for protocol- related tasks and required training documented. Compliance Check ‣ 21CFR312.53 ‣ ICH E6(R2) 4.2.3/4.2.4/4.2.5 and 4.2.6
  34. 34. How should a sponsor submit a change in protocol that results from challenges related to the COVID-19 pandemic? • For IND studies, the sponsor should submit a formal amendment to its IND, with the following information added to the cover letter in the subject line: • PROTOCOL AMENDMENT – COVID-19 • TITLE OF PROTOCOL • Sponsors should summarize the major changes made to the protocol related to COVID-19 in the cover letter and should include a tracked changes version of the protocol to facilitate review. As with other protocol amendments, sponsors may implement protocol amendments due to COVID-19 upon submission to FDA if approved by the IRB © Clinipace 2020 34
  35. 35. Outline BC Activities Ramp-Down Opportunities © Clinipace 2020 35 Activities ‣ Sites can use down time for pre-screening activities particularly medical chart/medical record review for Trial Participant eligibility ‣ Rethink recruitment and retention strategies to include adjusted Trial Participant payments based on degree of participation ‣ Site can QC records for those studies currently in maintenance phase Compliance Check ‣ Do not copy (remove) any PHI while performing this pre- screening activity considering the patient has not consented – HIPAA Privacy Rule ‣ Trial Participants should be reasonably reimbursed for costs directly incurred during the research, such as travel costs, and compensated reasonably for their inconvenience and time spent –CIOMS International Ethical Guidelines for Biomedical Research – Guideline 13
  36. 36. Outline BC Activities Ramp-Down Opportunities © Clinipace 2020 36 Activities ‣ CRA’s can reconcile ISF (e.g., deployed ERDM system) with TMF ‣ CRO and Site’s can initiate regulatory inspection readiness activities for closed studies ‣ CROs and Sites can cross train employees for not only career development but for backup potential Compliance Check ‣ Check regulatory inspection program for key areas to consider for inspection readiness.
  37. 37. Records Management Ensure Part 11 assessments performed for those electronic systems supporting the generation of source data © Clinipace 2020 37 Ensure COVID-19 audit trail documentation is in place supporting CSR, regulatory submissions and possible regulatory inspections Agreement with and communication to sites changes to trial conduct should be agreed with and communicated clearly to investigator sites. To support implementation by sites, it is important that changes and local implications are made clear, including marking of changed documents with track changes. Agreements may be documented as e-mail exchange
  38. 38. On a Positive Note – Improvements in How we Run Clinical Trials © Clinipace 2020 38
  39. 39. Thank YouJan Holladay Pierre, MPH, CMQ/OE Director Quality Assurance Clinipace