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EU helps ease ambiguity of reporting process with recent published guidance.
When adverse events arise as dramatically as in the clinical trial that went so wrong earlier this year in the United Kingdom, the reporting of what happened presents few conundrums. In fact in that case, the reporting was conducted largely through the mass media, over and above any communication between sponsor, investigator, and regulatory authority.
But most trials, fortunately, do not achieve such spectacular notoriety, and the decisions over what adverse reactions are to be reported, and how, are usually a more discreet matter—often calling for refined judgements by everyone involved in the trial. The European Union has recently issued some advice to help in this decision-making process.
This takes the form of a lengthy document entitled "Detailed guidance on the collection, verification and presentation of adverse event/reaction reports, together with decoding procedures for unexpected serious adverse reactions" (http://
). It should help in interpreting the reporting requirements that are imposed on sponsors and investigators by EU rules on clinical trials (see sidebar), and ease some of the ambiguity that arises in on-the-ground situations.
In the most general terms, the sponsor is responsible for the ongoing safety evaluation of the investigational medicinal product, and consequently for promptly notifying all concerned investigators, the Ethics Committee (EC), and competent authority of each concerned member state of findings that could adversely affect the health of subjects, impact on the conduct of the trial or alter the competent authority's authorization to continue the trial.
It is also the sponsor's responsibility to arrange the systems and written standard operating procedures to ensure quality standards are observed in every step of the case documentation, data collection, validation, evaluation, archiving, and reporting.
More specifically, on the recording and evaluation of adverse events, the guidance says that individual adverse events should be evaluated by the investigator in relation to seriousness and the causality between the trial product and/or concomitant therapy and the adverse event, and where appropriate, reported to the sponsor for further evaluation with respect to seriousness, causality, and expectedness. The sponsor has to retain detailed records of all adverse events reported by investigators and submit them on request to any competent authority where the clinical trial is being conducted.
All adverse events that the investigator or the sponsor judges as having a reasonable suspected causal relationship to a trial product qualify as adverse reactions. The causality assessment given by the investigator should not be downgraded by the sponsor, and in the event of disagreement between sponsor and investigator, the causality assessment from both should be provided with the report.
Adverse reactions should be considered as unexpected if the nature, seriousness, severity or outcome of the reaction is not consistent with the trial product's reference information. The sponsor is to determine expectedness of an adverse reaction on the basis of the investigator's brochure or the summary of product characteristics—whichever is identified in the protocol as the reference document for the entire trial.
One of the most delicate areas in reporting is how to handle SUSARs—suspected unexpected serious adverse reactions—particularly in view of the multiple scenarios in which the sponsor of a trial in Phase I–IV with at least one investigator site in the EU is obliged to report. Expedited reporting is required for all suspected adverse reactions related to an investigational medicinal product (defined here as "the tested investigational medicinal products and comparators") that occur in the trial, and that are both unexpected and serious.
But the requirements are even more onerous. Reporting is also required for SUSARs that occur outside the concerned clinical trial, if the investigational medicinal product has a marketing authorization in a member state and the sponsor is the marketing authorization holder. Even where the sponsor is not the marketing authorization holder for the trial product, any SUSARs associated with it in another trial conducted by the same sponsor in a non-EU country must be reported.
And for investigational products without a marketing authorization in any member state, the sponsor is obliged to provide expedited reporting of any SUSARs associated with it as soon as he/she becomes aware of them. This includes SUSARs that occur in another trial conducted by the same sponsor either in the EU or in Iceland, Norway or Liechtenstein (which are closely linked to the EU via their membership of the 28-nation European Economic Area); those that are identified by spontaneous reports or a publication; or those that are transmitted to the sponsor by another regulatory authority.
Some safety issues also qualify for expedited reporting if they can alter the benefit–risk assessment of a trial product or lead to changes in product administration or trial conduct. Increases in the rate of occurrence of an expected serious adverse reaction or a qualitative change that is considered clinically important as well as SUSARs that occur after the patient has completed a clinical trial and are reported by the investigator to the sponsor are two such situations. Similarly, expedited reporting is required for new events related to the conduct of the trial or the development of the trial products if they are likely to affect the safety of the subjects. These would include a serious adverse event that could be associated with the trial procedures, a significant hazard to the subject population (for instance, lack of efficacy of a trial product used for the treatment of a life-threatening disease), a major safety finding from a newly completed animal study (such as carcinogenicity) or any safety motivated halt of a trial on the same product in another country by the same sponsor.
It is the sponsor's job—and the sponsor's job alone—to report all this information to the competent authorities and to the EC concerned with the trial. The sponsor also has to inform all investigators about SUSARs that could adversely affect the safety of subjects.
Expedited reporting is not, however, usually required for reactions that are serious but expected, or for nonserious adverse reactions, whether they are expected or not. It is also not necessary to report events that are considered unrelated to the trial product.
The sponsor also has to report all SUSARs associated with a comparator product in the clinical trial, even if the product is authorized—not just to the authorities, but also to the marketing authorization holder. Since events associated with placebo will usually not satisfy the criteria for a serious adverse drug reaction—and therefore will not usually require expedited reporting—if SUSARs are associated with placebo because of, for instance, reaction to an excipient, reporting is recommended.
Notification of SUSARs must occur as soon as possible. In the event of fatal or life-threatening SUSARs, it must be no later than seven calendar days after the sponsor becomes aware that the case merits expedited reporting, with a follow-up report submitted within a further eight calendar days. For nonfatal and nonlife-threatening SUSARs, the initial reporting deadline is 15 calendar days.
Information on the final description and evaluation of an adverse reaction report may not be available within the required reporting time frames, but initial expedited reports should be submitted as soon as there is a suspected investigational medicinal product, an identifiable subject (such as a study subject code number), an adverse event assessed as serious and unexpected for which there is a reasonable suspected causal relationship, and an identifiable reporting source. If the information is incomplete when the initial report is made, the sponsor should seek all relevant information for an adequate analysis of causality and provide follow-up reports—with, in appropriate cases, long-term follow-up of a particular reaction.
Usually, treatment codes in a blinded trial should be broken by the sponsor before reporting a SUSAR. Although it is advantageous to retain the blind for all patients prior to final study analysis, when a serious adverse event may be a serious adverse reaction—unexpected or not—that is judged reportable on an expedited basis, the blind should be broken just for specific patients by the sponsor, even if the investigator has not broken it. But as far as possible, the blind should be maintained for biometrics personnel responsible for data-analysis and interpretation of results at the study's conclusion. And investigators should unblind single cases in the course of a trial only if the safety of the trial subject demands it.
It is recommended that in case of a blinded study, the case is assessed for seriousness, expectedness, and causal relationship, assuming that the tested investigational medicinal product caused the reaction. If the case appears to be a SUSAR, then the blinding should be broken. Then, if the product being administered is the tested product, the case would be reported as a SUSAR. If it is a comparator with a marketing authorization, and the adverse reaction is unexpected, then the SUSAR should be reported; otherwise, it is an expected serious adverse reaction and not reportable on an expedited basis. And if, after unblinding, SUSARs are associated with placebo, it is the sponsor's responsibility to report such cases.
The EU guidance also covers many other aspects of reporting, ranging from the management of adverse events in trials with high morbidity and high mortality diseases through to the format and content of the annual safety report of a clinical trial and how to keep investigators informed. There is also a lengthy annex providing comments on the definitions and abbreviations used in relation to safety reporting.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.