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Pharmaceutical Drug Discovery and Development: Serious Adverse Events

Published: October 18, 2005

This article outlines the reconciliation of serious adverse events (SAE) between segregated clinical data management (CDM) and safety systems.

This article is the third in a series intended to share insight and provide guidance for the pharmaceutical industry. This is done through a proven set of best practices and case studies within the strategic consulting, business intelligence, data warehousing and data management disciplines. The series focuses on Drug Discovery and Development, as the pressure increases for bringing newer, safer, and right drugs to the market — in a cost-efficient, effective and timely manner.  

Drug Discovery and Development is a business process supported by several line functions, including Research, Pre-Clinical Safety, Clinical Pharmacology, Clinical Research and Development, Regulatory Affairs, Clinical Safety & Epidemiology and Marketing. They must continually cooperate with the highest precision in capturing information and sharing results from countless sequential and parallel tasks.  As demanding and sophisticated as this seems, their greatest challenge lies in the application architecture they process the operation on. Drug Discovery and Development architectures consist of numerous applications storing data in different physical formats and diverse DBMS/storage technologies. Although these architectures deliver rich functionality on the front end, they are marred with resulting silos of data on the back end. These silos are neither integrated nor easy to access. This “data rich, but information poor” paradigm is overcome through the determination of highly-motivated team members, who exhaust every option for extracting data, consolidating information and formalizing results for review and distribution. However, it is achieved at a significant cost to the operational environment! Here, the value of data warehousing — with an accompanying self-service analytic and reporting environment — is gaining traction. This approach not only empowers teams with the insight and information needed to manage their areas of responsibility, but serves as the conduit for increasing operational efficiencies, reducing costs and accelerating decision-making processes. 

This article outlines the inherent value of reengineering a critical operating procedure within Drug Discovery and Development. More specifically, it outlines the reconciliation of serious adverse events (SAE) between segregated clinical data management (CDM) and safety systems. In pharmaceutical companies today, this procedure is often accomplished manually by generating paper printouts from each system. After this is done, they cross-reference data and narratives to ensure the events have been recorded accurately and consistently.  
 
Serious Adverse Reactions 
Each year 2.2 million Americans suffer serious adverse reactions to drugs, which is referred to as Adverse Drug Reactions (ADR) or Adverse Events (AE).  Many of these serious reactions result in hospitalization, prolongation of existing hospitalization, permanent disability, birth defects even death. Of these 2.2 million Americans, more than 100,000 will die. Annually, the costs of treating adverse reactions in the U.S. is almost $4 billion. Unmistakably within “pharma,” this is a real business issue. In the case of Vioxx, it can hobble a company for many years.

Collecting SAE Data 
During a clinical trial, thousands of patients will participate in the evaluation of an investigational drug. SAE data is collected using separate processes at different times. It is often stored in different systems. For example:

• When a patient has a serious adverse event, an investigator documents it on an SAE form and transmits it to Clinical Safety and Epidemiology within 24 hours. Data from the form is reviewed, and then entered and stored in the safety system. This system is used to meet legal reporting requirements to health authorities.
• When a patient experiences a serious adverse event, an investigator documents it on a patient’s case report form, which is completed during specified visit intervals. These forms are transmitted to Clinical Research and Development within days, or even weeks! After data from the case report form is reviewed, it is entered and stored in a clinical data management system.
• When Clinical Research and Development reviews and discovers an unreported serious event from transmitted patient case report forms with adverse event data, an investigator must fill out an SAE Form and transmit it to Clinical Safety and Epidemiology. Here, it is reviewed, entered and stored in the safety system. 

Manual Reconciliation of SAE Data
SAE reconciliation between clinical data management and safety systems is continually performed between first patient first visit (FPFV) and last patient last visit (LPLV). This is done because timely, reliable and trusted data guides decision-making processes on the safety profile of a drug and subsequent trial design. It also ensures consistent reporting to health authorities with respect to individual Safety Reports, the annual Investigational New Drug update and New Drug Application. 

Reconciliation is typically achieved through processes that are highly dependent on human communication, sequencing, intervention and analysis. Consider the following: 

• Clinical Safety and Epidemiology requests, receives and forwards all initial, follow-up and final safety system printouts to Clinical Research and Development for review.   
• Clinical Research and Development requests and receives all clinical data management system printouts for review. 
• With respective system printouts in hand and side-by-side, Clinical Research and Development performs two types of reconciliation: standard and detailed. Whereas standard reconciliation is performed on events not caused by the investigational drug, detailed reconciliation is performed on events caused by the investigational drug. Nevertheless, they ensure each SAE is correctly linked to each patient so there is no missing data. Based on the reconciliation type, there must be an exact match between specific variables and a plausible correlation between recorded narratives. When any illogical, missing or inconsistent data is discovered, a complex, corrective and re-verification process is initiated. 

Automated Reconciliation of Serious Adverse Event (SAE) Data
With data warehousing and an accompanying self-service analytic and reporting environment, one global pharmaceutical giant increased the automation of reconciling SAE’s by 90 percent. This company also achieved further efficiencies by enabling automatic alert/notification to support time-based escalation policies. Most importantly, it allowed Clinical Research and Development personnel to focus on other critical sequential and parallel tasks to advance the drug discovery and development process.

After extracting and consolidating data from three clinical data management systems and one safety system into a central repository, an enterprise business intelligence suite was leveraged to: 

• Automatically notify/alert Clinical Research and Development when an initial and follow-up SAE is entered into the Safety System.
• Automatically notify/alert Clinical Safety and Epidemiology when an SAE is entered into the Clinical Data Management System that is not in the Safety System.
• Automatically notify/alert Clinical Research and Development on compromised time-based performance metrics. 
• List SAE’s from either Clinical Data Management Safety System.
• List SAE’s in the Clinical Data Management System that is not in the Safety System and vice versa.  
• List “Reconciled” SAE’s.    
• List “Non-Reconciled” SAE’s with action plans to address missing data, discrepancies between specific variables and non-plausible correlations between recorded narratives.      

The final article in the series will focus on two cases studies that have allowed a global pharmaceutical giant to reduce costs, accelerate decision-making processes and achieve operational efficiencies. These activities have been done for planning, conducting, financing and managing global clinical trials. They have also been accomplished to monitor report and analyze adverse events occurring from initial development throughout the marketing lifetime of the drug.