Adverse event reporting requirements

This section contains the following:


Introduction

During the course of a clinical trial, the occurrence of adverse events must be carefully monitored and recorded.  For this process, special forms to report trial-related adverse events should be developed. Serious adverse events must be notified to the data monitoring office and the trial team promptly.  It is important that a system for prompt and efficient notification of any unexpected or serious adverse event be set up.


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Illustrative example -WHO pre-eclampsia trial

Data management

Data will be collected prospectively by the researcher responsible at the local collaborating centre and forms will be sent to the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP) at WHO headquarters in Geneva monthly following the standard data management procedure of HRP.  Side effects will be recorded by the researcher.

Although it is very unlikely that serious adverse events will occur, these will be recorded in special forms and will be returned by the local investigators to the Trial Coordination Unit (HRP/WHO in Geneva) by facsimile within 24 hours of the event.  These procedures have been used in multiple multicentre trials and proven to be very efficient and compliant with the GCP principles and data management.

Data entry will be done centrally in Geneva.

Unblinding

The need for unblinding should be extremely rare as the trial intervention is not associated with severe side effects and it will not delay or prevent standard management of the patient in the case of a complication such as renal calculi. If the woman develops pre-eclampsia or eclampsia, she will be treated according to routine treatment protocols regardless of the supplementation status. If, however, unblinding is needed for any reason the principal investigator will be informed and, if necessary, the trial coordinator will be contacted to reveal the code. (WHO Multicentre Randomised Trial of Calcium Supplementation for the Prevention of Pre-eclampsia - go to protocol)


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Illustrative example - CRASH trial

Unexpected adverse events
Anaphylactic reactions to intravenous corticosteroids are extremely rare, but should be treated in whatever way the responsible doctor prefers (one possibility being intra-muscular adrenaline 0.5 mg, i.e. 0.5 mL of 1 in 1,000 (1 mg/mL) solution) [14]. It would be expected that 24-hour anaesthetic cover would be available in all hospitals participating in CRASH. If a serious and unexpected adverse drug reaction occurs and is suspected to be related to the study medicine, this should be logged by calling the 24-hour randomisation service, who will inform the CRASH co-ordinating Centre in London.

In general, gastro-intestinal bleeds and infections do not need to be reported in this way because some increase in their incidence might be expected with steroids. Likewise, the various medical events that are to be expected in head injured patients do not need to be reported by telephone. All such events are, however, routinely monitored among all patients on the outcome form.

'Unblinding' the allocated treatment in an emergency
In general there should be no need to unblind the allocated treatment. If some contra-indication to corticosteroids develops after randomisation (e.g. severe gastrointestinal bleeding), the trial treatment should simply be stopped. Unblinding was never found to be necessary in the NASCIS trial of MP in spinal cord injury [4], and should be done only in those rare cases when the doctor believes that clinical management depends importantly upon knowledge of whether the patient received corticosteroid or placebo (e.g. suspected anaphylaxis). In those few cases when urgent unblinding is considered necessary, the randomisation service should be telephoned, giving the name of the doctor authorising unblinding and the CRASH treatment pack number (if available), and the caller will then be told whether the patient received corticosteroid or placebo.  ( CRASH Trial - go to protocol)


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Illustrative example - Perinatal care trial

Adverse Events
Adverse events in health providers (study subjects)

Although we do not expect adverse events in the study subjects, it might be possible that the active participation (or not participation) of the health providers in the intervention could originate conflicts among some of them, or with the hospital authorities, related to the implementation of the new guidelines in clinical care. It also might be possible that some women had conflicts with the birth attendants related to the use (or non-use) of the practices recommended in the new guidelines. These kinds of conflicts could be interpreted as adverse events if they led to:
loss of job positions or
malpractice lawsuits.

CLAP study coordination will monitor the changes in the health providers’ staff composition on a weekly basis. If any health provider resigned or was fired, a specific questionnaire will be completed considering the motives (from the hospital and the subject’s point of view). Reports will be sent to the corresponding staff at the Data Center and National Institute of Child Health and Human Development (NICHD) within 7 days of identification. CLAP study coordination will ask the Head of the Obstetric Department in each hospital to report all malpractice lawsuits directed toward the department’s health providers. The coordinators will also specifically address this issue with the Head of the Department on a quarterly basis. If any health provider received a malpractice lawsuit, resigned or was fired, a specific questionnaire will be completed considering the terms of the suit and the time period of the event that originated it. Reports will be sent to the corresponding staff at the Data Center and NICHD within 7 days of identification.

Adverse events in women and children
Although women and their offspring are not subjects in this study, they are the ultimate beneficiaries of the health practices promoted in the intervention. We do not expect adverse events associated with the behavioral intervention on health providers. However, we will continously monitor in-hospital maternal deaths and early neonatal deaths up to discharge from hospital. The routine data forms of the PIS include maternal and neonatal status at discharge (alive, death), and they will be monitored on daily basis through the data collectors during all the study period. To be able to assess women who are readmitted, the Head of the Department will be be instructed to report any maternal death occurring in the hospital, also on a daily basis.

In case of a maternal death, a specific case report form will be completed with the following information: date, time of onset; clinical history; medical management, including rationale; pertinent laboratory tests; relevant past medical history; autopsy report or expectation of an autopsy; location/study center; reporting physician; verification of notification to IRB, Data Safety and Monitoring Board (DSMB), and the Data Center (see appendix 3 for the form).

The death will be reported to the corresponding staff at the Data Center, NICHD, and IRB within 2 days of the occurrence.

To monitor neonatal deaths, monthly monitoring reports on the number of in-hospital early neonatal death (up to 7 days of life) and number of live births in the same period will be produced and sent to the DSMB.  (CLAP Trial - go to protocol)


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Additional resources

Trial Protocol Tool resource icon Events Checklist

This checklist has been contributed by Dave Sackett, who prepared it for the forthcoming 3rd edition of Clinical Epidemiology; A Basic Science for Answering Questions about Health Care, to be published by Lippincott, Williams & Wilkins in 2005.


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Trial Protocol Tool resource icon Checklist for adverse event reporting

This checklist has been contributed by Barbara Farrell who prepared it for the second version of the Trial Management Guide.


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Trial Protocol Tool resource icon Sample form for reporting serious adverse events

This is a sample form for reporting serious adverse events.


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Trial Protocol Tool resource icon Sample form for reporting adverse events

This is a sample form for reporting adverse events.


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Further reading

WHO GCP Guidelines on the Reporting of Adverse Events. In: Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products. WHO Technical Report Series, No. 850, (pages 97-137). World Health Organization, Geneva, Switzerland, 1995. Chapter 7

Duley L & Farrell B.  Clinical Trials. London, BMJ Books, 2002.

Meinert CL & Tonascia S.  Clinical Trials. Design, Conduct, and Analysis. Oxford, Oxford University Press, 1986.

Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. 3rd edition New York, Springer-Verlag, 1998.

Shapiro SH, Louis TA.  Clinical Trials, Issues and Approaches. New York, Marcel Dekker, Inc., 1983.

Smith PG & Morrow RH. Methods for Field Trials of Interventions against Tropical Diseases: a ‘Toolbox’. Oxford, Oxford University Press, 1991.


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This page was last updated 19th October 2004.