Why signal detection in clinical development?
Early safety signal detection enables:
Based on several CIOMS Working Group guidelines regulatory bodies mandate robust signal detection systems to be involved as early as possible in the development of medicinal products as part of Good Clinical Practice (GCP). Sponsors must demonstrate that they are actively monitoring for safety issues.
Signal detection and safety monitoring are both critical components of ensuring the safety and efficacy of a drug during clinical trials, but while routine safety monitoring performed by all Sponsors ensures the safety of trial participants by promptly identifying, evaluating, and managing any known or expected risks associated with the study drug, the primary goal of signal detection in clinical studies is to identify unexpected patterns or trends in the data that might suggest new or emerging safety concerns (e.g., a new side effect). It involves the analysis of clinical study data to detect early "signals" that warrant further investigation at a program-wide level. This can occur at any stage of the clinical trial but is often more relevant as data accumulates over time, particularly in later stages or in post-marketing surveillance.
We at ProPharma have implemented and maintained procedural documents and templates for conducting signal detection for developmental products. We work with Sponsors to create a tailored plan to enable the early spotting of signals and significant trends that may represent an unknown risk for their development products based on the design and size of their clinical studies, which can be changed according to the changing characteristics of the study. A core part of the signal detection plan, and what is a challenge for many small to medium-sized clinical Sponsors is the requirement to generate outputs from clinical data that allows easy visualization and hence efficient signal spotting. Our team of signal experts and Clinical Programmers provide the support necessary to generate such reports.
For more information and to get help with signal detection for your development products, contact us today to speak with an expert.
As part of the legal requirements for obtaining the approval of marketing authorizations for post-marketing medicines, applicants must submit to the regulatory authorities and maintain prescribing information on their products regarding the safety and effectiveness of the human prescription drug under the labelled conditions of use.
Prescribing information is intended to provide healthcare professionals, patients and their caregivers with an awareness of how a medicine is intended to be used, which patients should receive the medicine, and the safety of its use in humans. The sources of information used to compile the safety profile of a medicine include overviews of safety data emerging from clinical trials and non-clinical studies conducted during the medicine's development, and data published in public assessment reports. Once an application is approved by an authority, the medicine can be sold and prescribed to patients in the territory.
Once a Marketing Authorization Holder (MAH) has made a product's prescribing information available to the regulatory authorities, prescribers, patients and caregivers and they have been informed of all the risks of using the medicine, job done, right? Wrong.
The understanding of the safety profile of a medicine obtained during its clinical development is derived from its use in a limited number of participants exposed to the drug over relatively short treatment periods. These studies are often underpowered to detect rare adverse events occurring in 1 in 1,000 / 1 in 10,000 patients. Additionally, when selecting a study population, inclusion/exclusion criteria are applied to ensure the participants enrolled are reflective of the treatment population for a products’ intended indication. Often, special populations (i.e., pediatric patients, elderly patients, pregnant patients etc.), patients with significant comorbidities (i.e., renally impaired patients or those with genetic abnormalities), and patients receiving medications that interact with the drug, are excluded from trials. Therefore, the safety of a medicine administered to these types of patients is often unknown at the time an approved product enters the market. It is only during the post-marketed phase of a drugs lifecycle where many more patients are exposed to the medicine, that these aspects of the safety profile may be characterized.
Subsequently, MAHs have legal and ethical obligations to establish a robust pharmacovigilance (PV) system to ensure the continued monitoring of authorized medicinal products for the protection of public health by preventing, detecting and assessing new adverse reactions (or changes to those already known), determining their impact on the benefit / risk to patients and communicating their findings along with mitigation measures to HCPs, patients, caregivers and regulatory authorities. Signal detection is a core component of routine PV and should be conducted throughout a medicine's lifecycle.
A signal is information suggestive of a new potentially causal association, or a new aspect of a known association, between a drug and an outcome, either adverse or beneficial, that is judged to be of sufficient evidence to warrant further investigation. Signals may originate from multiple sources, including spontaneous reports, cases from healthcare and regulatory databases (e.g., the FDA's Adverse Event Reporting System (FAERS), the EudraVigilance Data Analysis System (EVDAS), the World Health Organization's Vigibase), clinical/non-clinical or epidemiological studies, published literature, safety-related publications from regulatory authorities and many other sources (including market research and social media).
Once detected, a signal is taken through a series of phases designed to either confirm or refute the observed association based on the available evidence. The discrete phases of Signal Management of licensed products are summarized in Figure 1.
MAHs are required to use all relevant post-marketing PV data when performing signal detection. In scenarios where the sample of cases reporting a particular association is small, it may be sufficient to conduct signal detection through qualitative analysis, assessing the association case-by-case based on clinical significance of the reported evidence. When the accrual of cases is too large to allow individual scrutiny of all incoming cases, signal detection may be conducted through quantitative analysis of aggregate data using disproportionate statistical methods. In the best examples, signals of disproportionate reporting are further supported by combining with qualitative analysis as much as possible. Selecting the appropriate methodology for signal detection and adhering to regional/international regulations can pose significant challenges to MAHs.
We at ProPharma, with a dedicated team of experts at hand, can work with MAHs in selecting and performing the most effective methodology for signal detection and subsequent management in compliance with legislative requirements.
Once detected, a signal goes through a validation phase, in which the data supporting the detected signal is evaluated to verify whether the available evidence is sufficient to warrant further analysis. In instances of multiple detected signals, analysis and prioritization phases are applied to triage the signals based on the risk to public health and/or the impact on the benefit-risk ratio of the drug. Signals considered to have the greatest impact are prioritized for assessment. During signal assessment, a validated signal is further evaluated using all available sources of information to determine whether there is a causal association between a drug and an outcome. A signal assessment will provide an analysis on the impact of the signal to the benefit-risk ratio of the drug, as well as recommendations for further actions as applicable (e.g., updating the prescribing information to include a description and warning of a newly identified risk of the drug).
Not only does our simple but scalable model allow MAHs to obtain the exact services necessary throughout the entire life cycle of their products, we at ProPharma will also assess the impact of significant findings on other PV-related documents such as Risk Management Plans, PADERs and PBRERs, while supporting MAHs with the compliant communication of significant findings to the relevant regulatory authorities and concerned stakeholders.
For more information and to get help with signal management for your licensed products, contact us today to speak with an expert.