FDA, EMA Issue Guidance on Conducting Trials During COVID-19 Pandemic
Recognizing that the COVID-19 pandemic could affect the conduct of clinical trials, the FDA issued a final guidance March 18 to aid in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during the COVID-19 pandemic. The FDA issued an updated guidance on March 30, which added the answers to 10 questions.
The European Medicines Agency (EMA) also issued guidance March 20.
“With this guidance issued today, the FDA is helping industry and investigators navigate the COVID-19 pandemic and help assess how to move forward with critical clinical trials,” said Anand Shah, the FDA’s Deputy Commissioner for Medical and Scientific Affairs. “The FDA released this guidance to emphasize that at all times, patients’ safety should continue to be at the forefront of considerations. We want to support the continuance of these clinical trials in compliance with good clinical practice and minimizing risks to trial integrity, while also safeguarding the health and well-being of study participants.”
“Challenges may arise, for example, from quarantines, site closures, travel limitations, interruptions to the supply chain for the investigational product, or other considerations if site personnel or trial subjects become infected with COVID-19,” the guidance said. “These challenges may lead to difficulties in meeting protocol-specified procedures, including administering or using the investigational product or adhering to protocol-mandated visits and laboratory/diagnostic testing.”
The guidance acknowledged that protocol modifications may be required, and that there may be unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 control measures. “Although the necessity for, and impact of, COVID-19 control measures on trials will vary depending on many factors, including the nature of disease under study, the trial design, and in what region(s) the study is being conducted,” the guidance provided general considerations to assure the safety of trial participants, maintain GCP compliance and minimize trial integrity risks.
The guidance said the considerations for ongoing trials are:
- Sponsors should consider each circumstance, focusing on the potential impact on the safety of trial participants, and modify study conduct accordingly. “Ensuring the safety of trial participants is paramount,” the guidance said. “Study decisions may include those regarding continuing trial recruitment, continuing use of the investigational product for patients already participating in the trial, and the need to change patient monitoring during the trial. In all cases, it is critical that trial participants are kept informed of changes to the study and monitoring plans that could impact them.”
- Sponsors, in consultation with clinical investigators and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs), may determine that the protection of a participant’s safety, welfare and rights is best served by continuing a study participant in the trial as per the protocol or by discontinuing the administration or use of the investigational product or even participation in the trial. Such decisions will depend on specific circumstances, including the nature of the investigational product, the ability to conduct appropriate safety monitoring, the potential impact on the investigational product supply chain, and the nature of the disease under study in the trial.
- Since trial participants may not be able to come to the investigational site for protocol-specified visits, sponsors should evaluate whether alternative methods for safety assessments, such as phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers, could be implemented when necessary and feasible, and would be sufficient to assure the safety of trial participants. Sponsors should determine if in-person visits are necessary to fully assure the safety of trial participants (for example to carry out procedures necessary to assess safety or the safe use of the investigational product appropriately); in making the decision to continue use or administration of the investigational product, the sponsor should consider whether the safety of trial participants can be assured with the implementation of the altered monitoring approach.
- In some cases, trial participants who no longer have access to the investigational product or the investigational site may need additional safety monitoring (e.g., withdrawal of an active investigational treatment).
- The need to put new processes in place or to modify existing processes will vary by the protocol and local situation. For example, this assessment could include consideration of whether it is appropriate to delay some assessments for ongoing trials, or, if the study cannot be properly conducted under the existing protocol, whether to stop ongoing recruitment, or even withdraw trial participants.
- COVID-19 screening procedures that may be mandated by the health care system in which a clinical trial is being conducted do not need to be reported as an amendment to the protocol even if done during clinical study visits unless the sponsor is incorporating the data collected as part of a new research objective.
- Changes in a protocol are typically not implemented before review and approval by the IRB/IEC, and in some cases, by the FDA. Sponsors and clinical investigators are encouraged to engage with IRBs/IEC as early as possible when urgent or emergent changes to the protocol or informed consent are anticipated as a result of COVID-19. Such changes to the protocol or investigational plan to minimize or eliminate immediate hazards or to protect the life and well-being of research participants, such as to limit exposure to COVID-19, may be implemented without IRB approval or before filing an amendment to the IND or IDE but are required to be reported afterwards. FDA encourages sponsors and investigators to work with their IRBs to prospectively define procedures to prioritize reporting of deviations that may impact the safety of trial participants.
- The implementation of alternative processes should be consistent with the protocol to the extent possible, and sponsors and clinical investigators should document the reason for any contingency measures implemented. Sponsors and clinical investigators should 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 those trial participants were impacted.
- Changes in study visit schedules, missed visits, or patient discontinuations may lead to missing information (e.g., for protocol-specified procedures). It will be important to capture specific information in the case report form that explains the basis of the missing data, including the relationship to COVID-19 for missing protocol-specified information, such as 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 the FDA.
- If scheduled visits at clinical sites will be significantly impacted, certain investigational products, such as those that are typically distributed for self-administration, may be amenable to alternative secure delivery methods. For other investigational products that are normally administered in a health care setting, consulting FDA review divisions on plans for alternative administration, such as home nursing or alternative sites by trained but non-study personnel, is recommended. In all cases, existing regulatory requirements for maintaining investigational product accountability remain and should be addressed and documented.
- With respect to efficacy assessments, the FDA recommended consultation with the appropriate review division regarding protocol modifications for the collection of efficacy endpoints, such as use of virtual assessments, delays in assessments, and alternative collection of research-specific specimens, if feasible. For individual instances where efficacy endpoints are not collected, the reasons for failing to obtain the 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).
- If changes in the protocol will lead to amending data management and/or statistical analysis plans, the sponsor should consider doing so in consultation with the applicable FDA review division. Prior to locking the database, sponsors should address in the statistical analysis plan how protocol deviations related to COVID-19 will be handled for the prespecified analyses.
- If planned on-site monitoring visits are no longer possible, sponsors should consider optimizing use of central and remote monitoring programs to maintain oversight of clinical sites.
The guidance added that if policies and procedures are not already in place for applicable trials:
- Sponsors, clinical investigators, and IRBs should consider establishing and implementing policy and procedures, or revise existing policy and procedures, to describe approaches to be used to protect trial participants and manage study conduct during possible disruption of the study as a result of COVID-19 control measures at study sites.
- Changes to policy and procedures could address, but not be limited to, impact on the informed consent process, study visits and procedures, data collection, study monitoring, adverse event reporting, and changes in investigator(s), site staff, and/or monitor(s) secondary to travel restrictions, quarantine measures, or COVID-19 illness itself.
- Policy and procedures should be compliant with applicable (regional or national) policy for the management and control of COVID-19. Depending upon the nature of the changes, a protocol amendment may be required under the applicable regulations.
For all trials that are affected by the COVID-19 pandemic, sponsors should describe in appropriate sections of the clinical study report or in a separate study-specific document:
- Contingency measures implemented to manage study conduct during disruption of the study as a result of COVID-19 control measures.
- A listing of all participants affected by the COVID-19 related study disruption by unique subject number identifier and by investigational site, and a description of how the individual’s participation was altered.
- Analyses and corresponding discussions that address the impact of implemented contingency measures (e.g., trial participant discontinuation from investigational product and/or study, alternative procedures used to collect critical safety and/or efficacy data) on the safety and efficacy results reported for the study.
“Robust efforts by sponsors, investigators, and IRBs/IECs to maintain the safety of trial participants and study data integrity are expected, and such efforts should be documented,” the guidance concluded. “FDA recognizes that protocol modifications may be required, including unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 control measures. Efforts to minimize impacts on trial integrity, and to document the reasons for protocol deviations, will be important.”
FDA Adds Appendix with 10 Questions
At the end of March, the FDA added an appendix to the guidance that included 10 frequently asked questions:
- What are some of the key factors that a sponsor should consider when deciding whether to suspend or continue an ongoing study or to initiate a new study during the COVID-19 pandemic?
- What key factors should sponsors consider when deciding whether to continue administering or using an investigational product that appears to be providing benefit to the trial participant during the COVID-19 pandemic?
- How should sponsors manage protocol deviations and amendments to ongoing trials during the COVID-19 pandemic?
- How should a sponsor submit a change in protocol that results from challenges related to the COVID-19 pandemic?
- 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?
- With the rapid changes in clinical trial conduct that may occur due to the COVID-19 pandemic, including multiple deviations to address patient safety, what is the best way for sponsors and investigators to capture these data?
- If patients are currently dispensed investigational product through a pharmacy for self-administration at home, can a sponsor switch that to home delivery without amending the protocol?
- If patients are currently receiving an investigational product infusion at the clinical trial site, can a sponsor switch to home infusion?
- Considering that there will be likely delays to on-site monitoring of clinical trials during the COVID-19 pandemic, what are FDA’s expectations in such circumstances?
- How do I obtain a signed informed consent from a patient who is in isolation and the COVID-19 infection control policy would prevent us from removing a document signed by the patient from their hospital room?
EMA Expects Updates to Guidance
The EMA noted that “due to the rapidly evolving situation further updates to this guidance are possible and likely.”
“Sponsors and investigators need to take into account that there might be specific national legislation and guidance in place, which they should consult and which can be used to complement this guidance, or, with respect to particular matters may take priority over these recommendations,” the guidance said.
EMA said “the feasibility of starting a new clinical trial or including new trial participants in an ongoing trial should be critically assessed by sponsors.”
In regard to changes in ongoing trials, the guidance said the sponsors should consider in their risk assessment whether the following measures could be the most appropriate during COVID-19:
- Conversion of physical visits into phone or video visits, postponement or complete cancellation of visits to ensure that only strictly necessary visits are performed at sites.
- A temporary halt of the trial at some or all trial sites.
- Suspension or slowing down of recruitment of new trial participants.
- Extension of the duration of the trial.
- Postponement of trials or activation of sites that have not yet been initiated.
- Closing sites if it is not feasible for a site to continue participation at all. “The sponsor should consider if the trial site should be closed and how this can be done without compromising safety and well-being of patients already participating and data validity,” the guidance said.
- If unavoidable (it should be justified that this is a truly exceptional situation based on the personal risk-benefit ratio for the individual trial participant), transfer of participants to investigational sites away from risk zones, or closer to their home, to sites already participating in the trial, or new ones could occur. “Initiation of new trial sites is generally not expected in the current situation unless no other solution exists for the trial participant,” the guidance said. “If there is an urgent need to open a new trial site for critical trial visits for example outside the hospital, this may be implemented as an urgent safety measure first, with a substantial amendment application submitted later as for the approval and initiation of an additional site later.” The guidance noted the exceptional situation could involve a trial participant who urgently needs to stay in the trial and for whom no other sites are available. “In such cases, it is important that trial participants as well as investigators (both receiving and sending) are in agreement about the transfer and that the receiving site has the possibility to access previously collected information/collected data for the trial participant and that any eCRF can be adjusted accordingly to allow the receiving site to enter new data. The impact on trial participants should be considered and arrangements made [for] appropriate transport.”
- There may be a need for critical laboratory tests, imaging or other diagnostic test to be performed for patient safety. “In case the trial participant cannot reach the site to have these performed, it is acceptable that laboratory, imaging or other diagnostic tests are done at a local laboratory (or relevant clinical facility for other tests) authorized/certified (as legally required nationally) to perform such tests routinely (e.g. blood cell count, liver function test, X-ray, ECG etc.), if this can be done within local restrictions on social distancing. The sites should inform the sponsor about such cases. Local analysis can be used for safety decisions. If this is a trial endpoint and the samples cannot be shipped to the central lab, analysis should be performed locally and then explained, assessed and reported in the clinical study report following ICH E3,” the guidance said.
The guidance noted that the changes also may be initiated by the investigator sites contacting the sponsor. “There might also be cases where the current principal investigator (PI) of a site is indisposed for a period and may need to delegate parts of his/her duties temporarily to a sub-investigator,” the guidance said. “Any permanent changes in PI should be submitted to the National Competent Authority (NCA) and Ethics Committees as appropriate.”
In addition, “when changes in ongoing trials are considered, the overall well-being and best interests of the participant should be also considered, for example in trials for patients with life-threatening or severely debilitating conditions, when participants require to stay on trial treatment,” the guidance said.
“In cases, when trial halt, even if temporary only, can potentially compromise the overall well-being and best interest of trial participants, all measures need to be considered and taken to avoid this. Changes should be well balanced, taking into account in particular the legitimate interest of trial sites in avoiding further burden in terms of time and staffing during the COVID-19 pandemic,” the guidance said.
The guidance noted “prospective protocol waivers remain unacceptable and that patients should not be included in trials without proper eligibility assessment, including performance of planned tests, and written informed consent according to national laws and regulations. Compliance with the trial protocol should be ensured to such an extent that an ongoing benefit-risk assessment for the clinical trial and its participants is still possible. The impact of protocol changes on clinical data interpretability needs to be properly assessed by the sponsor and the overall evidence generation package could be subsequently discussed within scientific advice with regulatory authorities,” the guidance said.
“Changes to trial conduct should be agreed with and communicated clearly to investigator sites,” the guidance said. “To support implementation by sites, it is important that changes and local implications are made clear, including marking of changed documents with track changes.” In addition, agreements may be documented in an e-mail exchange.
If a sponsor plans to initiate a trial aiming to test new treatments for COVID-19, “advice should be sought on alternative procedures to obtain informed consent, as it is likely that the physical consent cannot leave the isolation room, and therefore is not appropriate as trial documentation,” the guidance said.
The guidance added that “certain sponsor oversight responsibilities, such as monitoring and quality assurance activities need to be reassessed and temporary, alternative proportionate mechanisms of oversight may be required.”
The EMA said the extent of on-site monitoring, if it remains feasible, should take into account national and local restrictions, the urgency and the availability of site staff, and should only be performed as agreed with investigator sites. “The burden of the introduction of any alternative measures for the site staff and facilities should also be considered in order to strike an acceptable balance between appropriate oversight and the capacity of and possibilities at the site,” the guidance said.
Possible temporary, alternative measures could include:
- Cancelling on-site monitoring visits and extending the period between monitoring visit.
- Implementing phone and video visits (without unnecessarily increased burden to the investigator site and taking into account trial participant integrity).
- Adapting the on-site monitoring plan when it is impossible to follow, supplementing it with (additional/increased) centralized monitoring and central review of data if possible and meaningful.
“Results of adjusted monitoring/review measures should be reported to the sponsor in monitoring reports and in the clinical study report,” the guidance said. “It is essential that robust follow-up measures are planned and ready to be implemented when the situation is normalized. This should likely include increased on-site monitoring for a period that is sufficient to ensure that the impact of the reduced monitoring could be rectified and problems resolved or properly documented for reporting in the clinical study report.”
The guidance added “remote source data verification (e.g. providing sponsor with copies of medical records or remote access to electronic medical records) is currently not allowed in most member states as it might infringe trial participants’ rights.” In addition, provision of redacted/ de-identified pdfs files will not be acceptable as it puts disproportionate burden on site staff.
The guidance noted several European nations are exploring “possible, temporary solutions related to remote access and conditions for such, providing that methods can be used that restricts access to trial participant records, in line with the principles of necessity and proportionality. This should however also be clarified with other relevant authorities in this area (such as, without limitation, Ethics Committees and data protection agencies) and is consequently not allowed unless a member state has given specific guidance allowing this.”
The EMA also acknowledged that the pandemic “is likely to introduce more protocol deviations than normal. We expect that the sponsor escalates and manages such protocol deviations in accordance with their standard procedures. A proportionate approach will be taken by the GCP inspectors when such deviations are reviewed during inspections, in particular where the best interest of the participant is maintained, and the participant is not put at risk,” the guidance said. EMA added that “an increase in protocol deviations in relation to the COVID-19 situation will in itself not trigger the actions required by GCP §5.20. They will however need to be assessed and reported in the clinical study report, following ICH E3.”
Finally the guidance said that “in order to implement urgent measures for the protection of participants involved in a clinical trial, expenses may arise which may be borne initially by the participants. These should typically be compensated subsequently by the sponsor via the investigator. If additional financial compensation is provided to sites/investigators (e.g. to cover the cost of using couriers for IMP delivery), this needs to be documented and performed according to national legislation. Handling of reimbursement of such expenses should follow national legislation and/or guidance,” the EMA said.
EMA Issues Draft Guidance on COVID-19 Impacts on Methodological Aspects of Trials
EMA also released a draft points to consider guidance on Points to consider on the implications of COVID-19 on the methodological aspects of ongoing clinical trials. The draft is open for comments until April 25.
The guidance noted that “it is foreseeable that the COVID-19 pandemic will interfere with the collection, analysis and the interpretation of clinical trial data.”
“Although it might be desirable from a methodological point of view to continue trials or, in some cases, pause them temporarily, sponsors are strongly recommended to integrate all available knowledge from the ethical, the medical, and the methodological perspective into decision making about the future conduct of a trial while carefully considering advice from regulatory and healthcare authorities responsible for patient and employee safety,” the guidance said.
The guidance added that “the impact on the data collection, analysis and interpretation of results for each trial will need a thorough case-by-case assessment.”
The guidance said sponsors needed to consider:
- Pre-planning how systematic deviations resulting from the measures and individual decisions related to the COVID-19 pandemic are captured. “Such information will prove valuable in the assessment of the potential impact of these decisions on the trial outcome and should help distinguish between ‘affected’ and ‘unaffected’ data,” the guidance said. “In order to assist efficiently with the identification of deviations related to the pandemic that are of major importance for interpretation of trial results, Sponsors are encouraged to define a systematic way to record protocol deviations and capture related reasons.”
- Continuing data collection “as long as possible. However, potential risks for study participants when undergoing study-specific procedures, take priority in decisions taken by patients and health institutes. The external validity of trial outcomes may be affected by the presence of different trial populations – some patients were present in the trial before the start of the pandemic; some during the pandemic while possibly exposed to associated measures; and some after the end of the pandemic. Measures taken in relation to the COVID-19 pandemic may interfere with study treatments. In order to be able to identify and address such concerns, sufficient amount of information on pandemic-related measures and whether trial patients or trial conduct were affected, as well as on the subpopulations of exposed/non-exposed, and infected/non-infected patients will be necessary to study the impact on the treatment effect. Sponsors should collect this information to the extent feasible, and in a pragmatic manner,” the guidance said.
Sponsors also should consider conducting a risk-assessment on the impact of COVID-19 potentially affecting trial participants directly and COVID-19-related measures affecting clinical trial conduct on trial integrity and interpretability is recommended. “Sponsors are advised to contemplate an analysis of the accumulating trial data in order to evaluate the implications on recruitment, loss of patients during the trial, ability to record data and ability to interpret the treatment effect in light of the pre-, during and post-pandemic measures phases. It is understood that risk assessment should be part of the trial monitoring activities and could be performed on aggregate and blinded data with the intent to inform the likelihood of the trial to deliver interpretable results, not with the usual intent to confirm the likelihood of the trial being successful. Nevertheless, a more thorough analysis may be warranted. It is recommended that such an analysis of the trial data is conducted by an independent Data Monitoring Committee (DMC), which may already exist for the trial. If not, an independent DMC should preferably be established,” the guidance said.
The guidance noted the potential follow-up considerations or advice of the DMC may include:
- recommendations on how to re-start usual trial operations;
- recommendations of additional measures when completing the trial after the pandemic ;
- the need to adjust the trial sample size;
- additional analyses (to be included in the Statistical Analysis Plan) to investigate the impact of the three COVID-19 phases to understand the treatment effect as estimated in the trial; and
- proposals to deal with any identified potential sources of bias such as missing values, newly identified intercurrent events or other unforeseeable required changes to trial elements.
In addition, “major changes in the conduct of a trial should follow the local regulations and be approved by Ethics Committees. Discussion with relevant competent authorities is encouraged and COVID-19-related guidance should be consulted,” EMA said.
NIH Also Issues Guidance
In addition, the National Institutes of Health also issued guidance on the flexibilities available NIH-funded trials affected by the COVID-19 public health emergency.
“NIH recognizes the significant effects that this emergency is having on NIH-funded clinical trials and other human subjects studies. First and foremost, NIH is concerned about the safety and welfare of human subject participants and research staff. Institutions should take all steps necessary to ensure the safety of all human participants and research staff involved in NIH-funded clinical trials and human subjects studies.”
The guidance encouraged researchers to consult with their IRB and institutions about potential measures to protect participants and research staff. Examples of such measures are:
- limiting study visits to those needed for participant safety or coincident with clinical care;
- conducting virtual study visits;
- arranging flexibilities for required laboratory tests or imaging needed for safety monitoring to occur at local laboratories or clinics;
- canceling large gatherings of 50 or more people;
- limiting or suspending unnecessary travel.
The guidance noted that there are likely to be delays in ongoing research because of the pandemic and that grant recipients may submit late financial and progress reports, if research is delayed due to COVID-19, and may carryover unobligated balances on active grants without requesting prior approval. In addition, recipients may extend the final budget period of the approved project on active grants one time for up to 12 months without requesting prior approval from NIH.
“To support participant health and safety, and continuity of research during this public health emergency, NIH will allow for additional extensions, including mid-project period extensions, for awards supporting NIH-funded clinical trials and human subjects research,” the guidance said. “Recipients should contact the awarding Institute or Center (IC) to provide details on the effects of COVID-19, and the need for an extension. NIH is committed to working with its recipients during this public health emergency.” In addition, NIH will allow project periods to extend beyond the 7-year timeframe for extensions related to COVID-19.
The guidance also noted that due to COVID-19 problems, recipients may incur unanticipated costs, such as:
- costs incurred to arrange for participants to receive care at their local sites or virtually, rather than the study site, for required visits;
- supply chain disruptions;
- personnel disruptions due to illness or closure of facilities;
- additional lab testing (e.g. for COVID-19); and
- increased transportation costs.
“If unanticipated costs are identified due to impacts of COVID-19, and unobligated balances are not available to re-budget, recipients may request administrative supplements from the funding ICs,” which will make funding decisions on a case-by-case basis in an effort to support the safety and welfare of participants and sustain research during any delays.
In addition, ClinicalTrials.gov posted responses to the top three questions the agency has received from responsible parties related to (COVID-19). They are:
- How do responsible parties update the overall recruitment status of their study records and/or recruitment status of individual sites that close temporarily due to COVID-19?
- How does the sponsor update a study record when a principal investigator designated as the responsible party is not available?
- How can responsible parties for studies related to COVID-19 make their study records easily searchable?
ACRO Offers Guidance on Monitoring
The Association of Clinical Research Organizations (ACRO) also issued a policy statement on dealing with trial monitoring oversight during the pandemic.
ACRO recommended sponsors, clinical research organizations (CROs) and trial sites introduce emergency interim measures so that clinical trial monitoring is maintained during the pandemic. “These guidelines will ensure that data quality is unaffected, clinical trial sites are supported and that the patients enrolled in clinical trials are kept safe. The use of centralized monitoring tools and technologies can supplement and support the recommendations,” the group said.
“Care should be taken that any remote monitoring activities implemented are proportionate to the risks identified,” the policy said. “Further, they should not place any extra burden on clinical trial sites.
ACRO said its recommendations should be considered when:
- sites have suspended or restricted all visitors (including clinical research associates (CRAs)) from accessing medical facilities, but where patient visits are still occurring;
- local health officials have implemented regional quarantines; and
- local CRAs are unable to travel to the sites (for personal health reasons or because of travel restrictions).
- using regular site telephone contacts to monitor the situation and status of patient participation at the sites;
- increasing the frequency of already programmed patient profiles or listing reviews;
- using existing key risk indicators (KRIs) and key performance indicators (KPIs) to assess the impact on early termination, electronic data capture (EDC) data entry backlog, deviations, the volume of missed subject visits, adverse event (AE) reporting cadence, etc. “KRIs and KPIs should be used to identify any trends that may require temporary interventions. Identified trends should be assessed for scale of impacts across sites, which may require discussions across the project team/sponsor to mitigate risks to accommodate investigational product shortages, missed endpoints, alternative methods of monitoring subject safety, etc.,” the policy said.
- in the event that on-site monitoring visits cannot be completed, consider implementing remote review of subject visit data via the EDC system with a focus on data most important to subject safety and data quality. “While this will not cover the review of source documentation, this process can still alert the CRA” to: eligibility violations visible in medical history, scales, ePROs, eDiaries, physical exam findings and concomitant medications; protocol non-compliance with visit windows, gaps in investigational product administration, dose taper and dose titrations, SAE reporting, adherence to withdrawal criteria, etc.; safety concerns through the assessment of labs, AEs and other assessments reported in the EDC system (or lack there-of);
- documenting the results of these remote reviews. Subsequent site follow-up can be managed through remote interim monitoring visit (IMV) reports.
ACRO recommended against accessing electronic health records remotely (unless the process was already established with appropriate privacy and access controls) or requesting that sites fax source documents for remote review.
The policy noted that if companies adopt any of the interim measures they should follow their company’s procedures (e.g., planned deviation or Monitoring Plan addendum) to document the effective date of the interim measure. ACRO also recommended companies document the date of when routine monitoring practices have resumed.
However, before routine monitoring is resumed, strategies on how data is monitored in the interim period should be discussed with the sponsor and then documented. “ACRO’s position is that it will not be necessary to perform 100 percent source document review (SDR) and source data verification (SDV) of all subjects, visits and data. When routine monitoring resumes, a risk-based approach should be applied to subjects monitored using the interim measures,” the policy said.
This may include strategies such as:
- 100 percent SDR/SDV of any screening and/or baseline visits during this time period to confirm consent and eligibility;
- 100 percent SDR/SDV of a percentage of subjects or select critical subject visits (e.g., dose titrations, tapers, where SAEs reported, terminations, etc.)
In addition, “if a database lock is scheduled to occur during the interim period, strategies should be discussed with the sponsor and then documented. “ACRO’s position is that it will not be necessary to ensure 100 percent SDR/SDV of all subjects, visits and data prior to locking. Emphasis should be placed on essential SDR as opposed to SDV. A risk-based approach should be taken when assessing whether the database lock can occur or if it should be delayed,” the policy said.