14. ICSR processing of Clinical trial cases:

Clinical trials and pharmacovigilance are parallel processes, whenever any adverse event reported from the patient in trial it will be sent to pharmacovigilance team. 

Let us see in detail processing of how events experienced in trails gets submitted to regulatory authority. 

Who share information about adverse event to sponsor/pharmaceutical company? 

The investigators in trials are responsible to report all serious adverse events immediately to the sponsor except for those that the protocol or investigator’s brochure identifies as not requiring immediate reporting. 

Detailed written immediate reports should be made by the investigator within a very short period of time and under no circumstances should this exceed 24 hours following knowledge of the serious adverse event. 

The follow-up report should allow the sponsor to determine whether the serious adverse event requires a reassessment of the benefit-risk balance of the clinical trial, if the relevant information was not already available and provided in the initial report. 

In cases where reporting is not required immediately, the investigator shall report within the appropriate time frame, taking account of the specificities of the trial and of the serious adverse event, as well as possible guidance in the protocol or the IB.

Non serious adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations shall be reported to the sponsor according to the reporting requirements and within the time periods specified in the protocol. 

Processing and submission of case: 

Once sponsor receive the reports it will be sent to case receipt team of pharmacovigilance. 

Case receipt team and triage team perform primary analysis of the received report to ensure all the required information received or not. If any information is missing then follow up will be sent immediately. Case validity check will be done and primary analysis of seriousness, causality and listedness will be assessed and case sent to global team for further processing and submission of report. 

Global team perform case validity check again which is important as it is final check to confirm if case requires regulatory submission. Once the case confirmed as valid then duplicate check will be done to check if it is new report or already received information and case will be created in database. From the report the details will be entered into database by case processor and perform coding of events and products. The case will be assessed for seriousness, causality, expectedness and writes narrative and SUA summary (when necessary, refer below). 

For blinded trials involving a placebo and an active drug, seriousness, causality and expectedness should be evaluated as though the subject was on active drug. Break the blind in the company (or CRO) drug safety group for every case that could be expedited (that is, serious, possibly related, unlabeled/unexpected). Scroll down for more information on unblinding.

Seriousness: The judgement as to whether the event is serious is usually made by the reporting investigator 

Causality: The assessment of whether there is a reasonable possi­bility of a causal relationship is usually made by the investigator. In the absence of information on causality from the reporting investigator, the sponsor should consult the reporting investigator and encourage him to express an opinion on this aspect. The causality assessment given by the investigator should not be downgraded by the sponsor. If the sponsor disagrees with the investigator’s causality assessment, the opinion of both the investigator and the sponsor should be provided with the report. 

In placebo controlled studies, all AEs will be assessed for causality against active IMP. If an SAE is considered to be related to any IMP, an expectedness assessment will be required. In blinded studies without a placebo, or with multiple controls the investigator will carry out a separate causality assessment for each active IMP. 

Expectedness: Assessment of expectedness is usually done by the sponsor. The expectedness assessment will be performed against the Reference Safety Information (RSI) for each IMP to which the event is suspected to be related. If the SAR is considered expected, the treatment allocation will not need to be revealed and the report will simply be filed as a serious adverse reaction until such a time as the treatment allocation for all participants will be revealed. All assessments will be documented on the relevant SAE form. 

If the SAR is considered unexpected, the following process for expedited unblinded SUSAR reporting will be followed: 

• The designated individual responsible for unblinded safety reporting will follow the study-specific unblinding process to reveal the treatment allocation for the relevant participant (note that this may be separate from the emergency unblinding procedure). Unblinded data must not be revealed to any member of the blinded team. 
• If the treatment is revealed to be placebo, no expedited reporting is required, (unless the SAR is believed to be related to the placebo or one of its excipients). However all required information to complete the report, including follow-up to resolution of the event must be obtained. Queries should continue to be raised with the team to follow-up the event, regardless of whether the patient was on active IMP or placebo. 
• If the treatment is revealed to be active IMP, the delegated individual responsible for unblinded safety reporting will complete the e-SUSAR report form based on the completed SUSAR / SAE report with the addition of the unblinded information. When submitting the form, it is important to clearly identify that the report contains unblinded information, and that confirmation of receipt should NOT be sent to blinded members of the study team. 
• The delegated individual will forward the completed e-SUSAR form and associated documentation to the REC. Again, blinded members of the study team must not be copied in, and the REC should be asked NOT to provide confirmation of receipt to any blinded member of the study team
• If further information is required to follow-up the event, the blinded study team will collect this and forward to the designated unblinded individual.
• Once the event has fully resolved and all follow-up has been completed, finalised SAE & SUSAR reports and all associated correspondence will be retained by the designated unblinded individual until the study is unblinded, at which point all relevant documentation will be filed in the TMF. A file note will be added to the TMF to indicate that unblinded information is held separately.

SUA Summary/Analysis of similar events (AOSE):

As per 21 CFR 312.32the sponsor must identify in each IND safety report all IND safety reports previously submitted to FDA concerning a similar suspected adverse reaction and must analyze the significance of the suspected adverse reaction in light of previous, similar reports or any other relevant information (21 CFR 312.32(c)(1)). The analysis must include similar reports from all INDs held by the sponsor and any other relevant information known to the sponsor (21 CFR 312.32(c)(1)). Sponsors should evaluate a suspected adverse reaction in the context of other related reports or adverse events, including those that occurred in the placebo or active comparator group and those that occurred in pre- and postmarketing studies. For example, if there are, a dozen other myocardial infarctions in patients taking the study drug in other INDs but also in the comparators, this should be noted.

https://www.govregs.com/regulations/expand/title21_chapterI_part312_subpartB_section312.32#title21_chapterI_part312_subpartB_section312.32

Submission to regulatory authority: 

Once the case is completely processed, reviewed and confirmed by medical reviewers with detailed written narratives, cases shall be submitted to regulatory authority in standard format as per regulatory requirement (ex; E2B format for EMA, MedWatch format for USFDA, CIOMS for other authorities, etc..).

For blinded trials, if the drug is the placebo, then no expedited report in the US or in the EU. If the comparator, choice of reporting to the manufacturer of the comparator or (most common) report to the health agency as an expedited report without notifying the other manufacturer. If it is the sponsor’s study drug, expedited report with notification to all “concerned” investigators (this is defined in various ways in each company) and some or all IRBs (usually all). In general, all investigators and IRBs are informed.

The sponsor shall ensure that all relevant information about suspected serious unexpected adverse reactions that are fatal or life-threatening is recorded and reported as soon as possible to the competent authorities in all the Member States concerned, and to the Ethics Committee, and in any case no later than seven days after knowledge by the sponsor of such a case, and that relevant follow-up information is subsequently communicated within an additional eight days. All other suspected serious unexpected adverse reactions shall be reported to the competent authorities concerned and to the Ethics Committee concerned as soon as possible but within a maximum of 15 days of first knowledge by the sponsor. The sponsor shall also inform all investigators who involved in trial. 

Unblinding:

Unblinding means revealing the arm or some component of an arm to which an individual participant has been assigned. This may include any or all site staff, participant, protocol chair(s), and/or other team members. 

Types of unblinding:

• Full unblinding at completion of the study: Under normal circumstances, all participants will be unblinded simultaneously once the data are complete per instructions in the protocol document. Full unblinding also occurs when sudden (or unplanned) unblinding of a study is required due to interim results of the study or results of another trial. 
• Partial unblinding: When not all arms on a study are unblinded or when one or more drugs are unblinded across arms but others remain blinded. Thus, some aspect of the treatment of some participants is still blinded. 
• Urgent unblinding of individual participants during study conduct: Urgent, unplanned unblinding prior to the conventional unblinding date is done to protect participant safety, e.g., for drug identity during an acute reaction. The unblinding information is shared only on a need-to-know basis. 

Unblinding regulatory requirements:

For the FDA, the blind should be broken and the case reported unblinded to FDA if it meets the expediting criteria (serious, unexpected, possible relation to the study drug). However, as FDA notes in 21CFR312.32, if patient safety can be assured without breaking the blind, FDA encourages sponsors to discuss alternative reporting arrangements with FDA and described in the protocol. That is, if the company anticipates the need to break the blind frequently, a mechanism to keep the blind in place or to have very limited unblinding and safety analysis (e.g. by a DMC) should be put in the protocol before starting the study.

In the EU the regulations are explicit:

• Treatment codes should be broken by the sponsor before reporting a SUSAR to the competent authority (that is, the health agency) and the Ethics Committee/IRB.
• When a serious AE comes in and if it might be a SUSAR, the blind should be broken only for that patient by the sponsor even if the investigator has not broken the blind. Then 3 possibilities occur:
  • 1. The patient took the test product: this is an expedited report.
  • 2. The patient took a marketed comparator: the SAE should be assessed for expectedness according to the labeling (IB or SPC as appropriate) for that product. If it is unexpected then the SUSAR is expedited; otherwise it is an expected SAR and not expedited.
  • 3. The patient took placebo: Events associated with placebo will usually not satisfy the criteria for a SAR and therefore are not expeditable.

• Types of blinded trials:
• Single-blinded study: The treating physician is aware of which treatment the participant is receiving, but the participant is not, or vice versa
• Double-blinded study: The participant, treating physician, site staff, and study team are unaware of the treatment assignment
• Partial-blinded study: Within a study arm, some of the study drugs are blinded and others are open- label (e.g., ZDV + 3TC [open] plus nelfinavir or nelfinavir-placebo [blinded]) 
• Open-label or Unblinded Study: Both the participant and the treating clinician responsible for the participant (including site staff) are aware of the participant’s treatment assignment. 

Impact of unblinding:

If you unblind too many cases and if these cases become invalid for the statistical efficacy analysis in the clinical trial and NDA/MA, the entire trial and NDA/MA may lose statistical significance and fail. Companies should thus be very sure that the case must be unblinded for reporting purposes before unblinding.

Accidental Unblinding

If blinded members of the team obtain access to information which could reveal the treatment allocation of any participants in the trial, this will be treated as a protocol deviation and a potentially serious breach of GCP. 

Details of any such incident must be reported to the Investigator (CI), the trial manager and the ICRF Quality Assurance & Governance Manager in the first instance for evaluation and assessment. The CI will be responsible for onward reporting if required. Details of the error and any corrective and preventative actions implemented will be documented in the TMF, and will be provided to the statistician at the time of final analysis for consideration as to whether inclusion in the clinical study report is required.