The Drug Information Association / American Statistical Association Interdisciplinary Safety Evaluation working group has proposed an Aggregate Safety Assessment Plan (ASAP). The ASAP promotes a consistent approach to safety data collection and analyses across studies. The ASAP is a valuable tool for sponsors to enhance characterisation of the emerging product safety profile
Recently, a Drug Information Association / American Statistical Association-sponsored Interdisciplinary Safety Evaluation working group published a recommended approach to the aggregate assessment of clinical trial safety data. The proposed Aggregate Safety Assessment Plan (ASAP) has several components including identification of the safety topics of interest, how the safety data will be pooled across clinical studies and the data analysis standards that will be employed. In addition, the ASAP delineates how the safety data will be reviewed in aggregate to enable earlier signal detection as well as to promote consistent messaging regarding the emerging safety profile of the product. Lastly, the ASAP prompts a clinical trial sponsor to consider what key gaps in safety knowledge will remain at the time of product filing and potentially require further data collection or safety studies.
The ASAP is an internal document compiled by a clinical trial sponsor early in the investigation of a product. The ASAP is meant to be a ‘living’ document that evolves over the different phases of clinical development. At a minimum, clinical scientists familiar with the product and disease under study in conjunction with safety scientists and statisticians with expertise in the analysis of safety data should collaborate on the creation of the ASAP. Ideally, the ASAP effort should also be supported by an epidemiologist. This team starts by reviewing what is known about the mechanism of action of the product, pre-clinical study results, drug-related adverse events reported in early human studies and, if applicable, available safety information from related products. This information, coupled with knowledge about the epidemiology of the study population (such as associated co-morbidities), forms the basis for the selection of the safety topics of interest. The safety topics of interest require collection and analysis of data beyond that which is routine for a clinical study. Creation of an ASAP should prompt team members to consider questions about the safety topics of interest that will be posed by regulatory authorities, healthcare providers and patients. These questions drive decisions about the data, which will be needed at regulatory submission. In addition, team members should research how the safety topics of interest have been assessed in the past by other clinical trial sponsors. Pre-emptive and thoughtful aggregate safety evaluation is critical in order to thoroughly characterise a product’s safety profile and important product risks.
A comprehensive understanding of the safety data from completed and ongoing clinical trials is critical to understanding the benefit: risk profile of a product. A common objection to devoting resources to more in-depth safety planning earlier is doubt about whether a product will progress into later stages of development. However, formation of an ASAP may improve efficiency by serving as the reference point for the safety standards used in individual study statistical analysis plans. In addition, a proactive dialogue regarding the statistical outputs needed by the clinical team for documents such as the Investigator Brochure or Development Safety Update Report can minimise the need for ad hoc requests and missed timelines. Lastly, even if a programme does not advance into late-stage development, the learning gained from populating an ASAP is carried over to work on the next project which may be successful.
In addition, over the past 10 years, health authority expectations have risen regarding the quality of clinical trial safety data. As more therapies become available for specific diseases, the focus progressively shifts to how the safety of various products is differentiated. Product approvals may be denied or delayed due to safety concerns or an uncertain benefit: risk profile for the drug doses studied in the pivotal trials. Moreover, a lack of safety planning may lead to less favourable labelling than anticipated. Consequently, devoting resources to the characterisation of a product’s ‘safety story’ is just as important as to its ‘efficacy story’.
Nonetheless, clinical trial sponsors may not concentrate closely on the safety package until after the registrational studies have started. The dangers of this approach are important missing data, challenges in data integration due to lack of standardisation across studies, and concerns arising about the adequacy of the safety data. For example, regulatory authorities may expect expert adjudication of designated adverse events or request specific statistical analyses, both of which may not have been considered or planned before the start of the clinical trials. Once the pivotal studies have begun, the case report forms would have been finalised and the initial patients enrolled. At that point, a course correction of the study can be problematic and costly. In addition, often there is a lack of foresight as to how the safety information will be put into the appropriate context at the time of product submission. For instance, the observation of certain adverse events during the clinical studies may raise concerns, particularly if there is a higher number of events in the active drug treatment group versus the control arm. While such an imbalance may be a chance occurrence, without information about the event background rate in the study population, this possibility cannot be assessed. An example is the surprisingly increased incidence of melanoma in patients with Parkinson’s Disease (PD). Although the underlying basis for this finding is not clear, a mutation or other alteration in a gene or protein conferring an increased risk for both PD and melanoma is possible. Knowing this association between PD and melanoma is critical to understanding an observation of a higher than anticipated rate of melanoma in PD clinical trials.
While the evaluation of individual case reports remains valuable, regulatory authorities increasingly are focused on the monitoring of clinical trial safety data in aggregate. A single case report can be informative for an adverse event that is typically drug related, temporally associated with experimental product administration and for which there is no clear alternative etiology (e.g., anaphylactic reaction occurring less than 30 minutes after ingestion of a product with no other cause identified). However, aggregate data assessment is needed for adverse events which are anticipated to occur in the patient population regardless of study participation (e.g. stroke in patients with osteoarthritis). For these events, noting that individual subjects have risk factors for the occurrence of an event is insufficient justification for a lack of association with product administration. Instead, the frequency, nature and severity of similar event reports in patients receiving the drug requires scrutiny. The ASAP has a section which is devoted to the description of the methodology for monitoring of aggregate safety data from the ongoing clinical trials, including potentially still blinded studies. Such assessments can support investigational new drug safety reporting decisions. Without a systematic approach to continual safety evaluation, signals may escape early detection and a sponsor could be surprised with an unanticipated safety concern at study completion.
One of the other sections of the ASAP prompts the clinical trial sponsor to consider what key questions about the safety profile of the product will remain unanswered at the time of regulatory submission. The cross-functional team also should be cognisant of the queries from healthcare professionals and patients regarding the safety of the product. More information may be needed regarding the frequency of the event, including in selected patient subpopulations, as well as the adverse event’s range of severity, reversibility and risk factors for occurrence. Another critical question may be how effective proposed measures are in mitigating the risk of an adverse effect of the product. By considering what will be important missing information at product filing, the clinical trial sponsor can proactively plan for how these knowledge gaps will be addressed either in an additional study or sub-study or through postmarketing safety surveillance.
Another valuable aspect of the ASAP is the foundation set for consistent safety messaging. Throughout a product’s lifecycle, communications regarding safety data occur to both internal and external stakeholders. Safety information is transmitted externally to regulatory authorities, clinical trial investigators and participants and more generally via public disclosures such as press releases, meeting presentations and publications. To help direct these communications, the ASAP refers to the concept of a “safety storyboard” which could be a slide deck or a written document. The safety storyboard changes in content over the course of clinical development. Initially the emphasis is on the preclinical safety results and first in human study conclusions. Later as more clinical trial data accumulates, identified risks may emerge for which there is sufficient data to conclude a causal association with product administration. In addition, available data should be described relevant to potential risks for which there is a basis to suspect a link with product use. Other safety topics of interest may also warrant documentation of agreed upon conclusions based on current data. Examples include events of higher regulatory or prescriber interest based on the epidemiology of the patient population (e.g., major cardiovascular events in diabetes) or traditional safety concerns (e.g., drug induced liver injury). In addition, if risk minimisation measures are recommended for certain identified and potential risks, these actions should be part of the key safety messages. The safety storyboard can serve as the source of aligned safety messages which guide communications to various safety stakeholders.
The ASAP puts a clinical trial sponsor in a better position to detect safety risks earlier and to optimally support the benefit:risk profile of the product at submission and in communications to various internal and external stakeholders.
Hendrickson, B.A., Wang, W., Ball, G., et al. (2021) Aggregate Safety Assessment Planning for the Drug Development Life-Cycle. Therapeutic Innovation & Regulatory Science. 55(4): 717-732.
Bose, A., Petsko, G.A., and Eliezer D.(2018) Parkinson’s Disease and Melanoma: Co-occurrence and Mechanisms. Journal of Parkinson’s Disease 8:385-398.