Automated Lab Surveillance and Event Adjudication in an Outcomes Study.

Adopting eClinical Systems for Safety Surveillance: A Case Study

One leading Pharmaceutical company is utilising ICON’s electronic lab reporting tool, ICONIK Labs in its post-marketing trial for a drug that treats a chronic condition. And, it is once again using ICON’s electronic adjudication system, MIRA™, as it had in Phase III trials for two other in-market drugs in the same franchise.

Identifying the pain point Preparing and analysing clinical data, always a monumental task, has become extremely complex as clinical trials have grown larger and longer with the goal of improving risk management and patient safety. At the same time, R&D organisations are under continuous pressure to improve their productivity, as manufacturers face external constraints on their profitability. The confluence of growing volumes of clinical data, the need for analytical speed, and a business mandate for greater efficiency calls for the development of better technology solutions.

Conducting post-marketing surveillance

The company’s product is marketed in more than 60 countries and used daily by more than 700,000 patients. While the product is not the first in its class, the U.S. Food and Drug Administration (FDA) mandated that the company study several primary and secondary outcomes as a condition of approval.

Consequently, the company launched a multi-year, event-driven non-inferiority study of the product across more than 30 countries. The study’s two-arm design compares the compound added to the standard of care in one treatment arm, versus the standard of care in the other through a randomised, double-blind, placebo-controlled study design to test non-inferiority and potentially, superiority. The time from randomisation to first occurrence of any of the primary or secondary outcomes will be adjudicated and compared between treatment groups.

Monitoring lab values with a dynamic visualisation tool

A call for innovation

The company found an answer in ICONIK Labs from ICON plc. They began using the web-based technology to manage, visualise, analyse, and report on the 25-30 lab variables being monitored in the outcomes study. Through the system, data from ICON’s Central Laboratories are made available to the company’s medical and safety surveillance teams via an Internet portal. There, they enter a work environment hosted by ICON that gives them access to lab values via a series of pre-built reports and visualisations. With these reports as a starting point, they can then drill further into the database using any of the variables as filters. Instant graphic results make trends and outliers obvious. The pre-built visualisation template provides, among other views:

The pre-built visualisation template provides, among other views:

• Labs Overview: a cross table of study-wide lab metrics that the user can manipulate to display the study data of interest. • Alert Overview: an overall picture of the lab test results across the study showing the counts and percentages of low/normal/high lab values. Visualisations can be adjusted to give various presentations of the data. (See Figure 1.) • Lab Trends: an overall view of the trends emerging from the study’s lab data.• Patient Profile: an “at-a-glance” view of individual patient’s lab test results, specifically highlighting those that fall outside of the reference ranges as well as indicating the relative change in each lab test over time. (See Figure 2.) • Hy’s Law: a display of lab values that assists with the detection of subjects who may be suffering from Drug Induced Liver Injury (DILI).

The company’s established process for reviewing laboratory results was adequate to support Phase I-II studies that involved up to 500 patients for six months, but additional functionality and a more robust solution was required for a trial of this scope. With smaller, more manageable trials, customised listings would be created to sort the data, which were then furnished to the study’s medical director. The Medical Monitor would review the data tables manually; looking for trends and outliers, request reports, and graphs from statisticians—a long and laborious process that often took several weeks. “It was obvious that we could not do a proper job of monitoring the battery of lab parameters in such a broad post-marketing trial using a largely manual, paper-based process,” noted the company’s project director. “With each of the 9,340 patients in the study having eight to fifteen scheduled medical visits and multiple lab parameters measured per visit, the volume of information would explode very quickly. It would become impossible to make sense of it all without the aid of interactive analytical tools.”

Figure 1: Sample Alert Overview, providing a picture of test results across an entire study.

HBA1C_BLOOD

CREATININE_SERUM

LIPASE_SERUM

AMYLASE_SERUM

ALT_SERUM

BILIRUBIN_SERUM

CALCITONIN_SERUM

ALBUMIN_CREAT_URINE

DIREC_LDL_CHOL_SERUM

HDL_CHOL_SERUM

T_CHOL_SERUM

TRIGLYCERIDES_SERUM

LDL_CHOL_SERUM

POTASSIUM_SERUM

CALCIUM_SERUM

SODIUM_SERUM

ERCS_BLOOD

HAEMATOCRIT_BLOOD

HAEMOGLOBIN_BLOOD

T_LEUCOCYTES_C_BLOOD

THROMBOCYTES_BLOOD

MDRD_EGFR_SERUM

HCG_C_SERUM

0 5000 10000 15000 20000 25000 30000 35000 40000 45000

Colour by Alert Flag H N L (Empty)

Lab

Tes

t Nam

e

Alert Count

Intuitive Prebuilt Report Templates Members of the medical team working on the trial had the opportunity to customise the views, but found that the pre-built templates were exactly what they needed. They access the system several times a week to track the overall study progress and to identify possible trends in a blinded fashion. And, very important, they also use it to retrieve all lab values for a specific patient with a reported adverse event. Data will be part of the safety evaluation for the specific patient and can easily be compared to the rest of the population. The medical team can also notify the safety committee of the potential need to intervene in a particular patient’s treatment, and they can identify sites that have an unusual number of values outside of the normal range; allowing them to address any operational issues that may be affecting results.

A Catalyst for a New Approach to Surveillance The team is finding that the dynamic nature of the tool is changing their overall approach to surveillance. The company’s medical director commented, “With it, you can get involved in a discussion that inspires a scientific line of inquiry and then instantly have the answers. I can challenge the data, looking at combinations of lab parameters and searching for trends in a way that I could never do if I had to wait three weeks for a statistician to produce a graph for me. It matches the way I think about data.”

The project director concurred, “We now have the freedom to interact with the data in a whole new way. Based on our results, the time to payback for the system is incredibly short.”

Convening the adjudication committee electronicallyBeing able to rapidly and objectively adjudicate cases of possible adverse events in a study of this size and scope also called for innovation. The traditional method of convening the Adjudication Committee (AC) in one location periodically to adjudicate potential outcomes, impractical and slow even for smaller studies was never really an option in this case. Having had success with the adjudication application within ICON’s Medical Information Review and Analysis System (MIRA) in prior studies, the company elected to manage adjudication of outcomes in this study electronically.

The company is using the electronic tool to allow members of the independent AC to review, capture, and archive their assessments of outcomes remotely, from their own computers anywhere in the world. This, at the most basic level, removes the costs and logistical complications of getting the committee members together physically, but more significant, improves data quality and expediates the AC’s determination of primary and secondary trial outcomes.

ALBUMIN_CREAT_URINE

ALT_SERUM

AMYLASE_SERUM

BILIRUBIN_SERUM

CALCITONIN_SERUM

CALCIUM_SERUM

CREATININE_SERUM

DIREC_LDL_CHOL_SERUM

ERCS_BLOOD

HAEMATOCRIT_BLOOD

HAEMOGLOBIN_BLOOD

HBA1C_BLOOD

HCG_C_SERUM

HCG_CHOL_SERUM

LDL_CHOL_SERUM

LIPASE_SERUM

MDRD_EGFR_SERUM

POTASSIUM_SERUM

SODIUM_SERUM

T_CHOL_SERUM

T_LEUCOCYTES_C_BLOOD

THROMBOCYTES_BLOOD

TRIGLYCERIOES_SERUM

Figure 2: Sample Patient Profile, displaying at-a-glance view of a single patient’s lab results.

Lab

Tes

t Nam

e

Date/Time of Collection, Visit Number - Name

001 - V1 003 - V1 005 - V1 006 - V1 007 - V1 008 - V1 009 - V1

16-Sep 21-Oct-2 20-Jan 20-Apr-2 10-Oct-2 19-Apr-2 18-Oct-2

Shape by Reference Range High Low F

H N L (Empty)

Size by Abs (Chg Prev Val (pct))

≥ 80.0% ≤ 0.0%H N L (Empty)

Colour by Reference Range High Low F

A general workflow from identification of potential outcomes and Medical Events of Special Interest (MESIs) to completion of adjudication is presented in Figure 3:

Site Completes

AE/Endpoint EDC Page

ICON NotifiedElectronically Placeholder Created in

MIRA

Source Document

Dossier Collected and Transmitted

to ICON

Source Document

Content and Completeness

QD’d by ICON AM

ICON AM Electronically/

Releases Dossier to AC

for Adjudication

Majority of Time45-70 Days

MIRA™ Tracks Time From Notification of Event to Completion of Adjudication

1. The MIRA system, originally designed for analysis of medical images, has since been expanded to accept any form of clinical data from virtually any source.

Two minds are better than one

Although various adjudication paradigms are possible, this particular trial is using the “two-plus-one” approach (See Figure 4) to adjudication through which:

• Two AC members complete Electronic Case Report Forms (eCRFs) for each case requiring adjudication. Both AC members study the source information and make their independent determinations as to whether the source data support an outcome on a custom designed adjudication eCRF.

• The MIRATM system automatically compares their evaluations, and if they match, the case is considered adjudicated. If, however, there is a discrepancy, the system alerts them of it and prompts them to discuss the case.

• If the two AC members come to an agreement (as they do in about 99 percent of the cases that reach this point), the case is thus considered adjudicated. If they still disagree, the case is escalated to the AC chairperson, who has access to all source information as well as the area where the two AC members disagreed.

• The chairperson completes his or her own adjudication eCRF and the Chair’s adjudication is considered as final.

• Reports can be generated in real time through the MIRATM gateway for all cases that have completed adjudication. Periodic outcome data transfers are also sent electronically to the company’s safety surveillance group and reported to the Data Monitoring Committee and trial steering committee as appropriate.

Figure 4: 2+ 1 Adjudication Paradigm Example

• Case Complete

• Consensus is Sought (Electronic or Live)

• Case Complete

• Case Escalated to EAC Chair for Final Completion

If Agreement

If Discrepancy

If (Electronic or Live) Consensus is Reached

If (Still) No Consensus

2+ 1 Adjudication Paradigm (Example)Primary Adjudicators Review Source and Complete Adjudication eCRF (System Checks Agreement)

Because the client is using both tools from ICON—ICONIK Labs and MIRATM—for the trial, it can take advantage of automation spanning the collection of lab data through to the AC’s evaluation for certain types of outcomes and MESIs. For instance, the ICONIK system flags elevated levels of biomarkers for certain serious conditions, and, based on the outcome of expert review, these cases can automatically be flagged for additional source data collection and submission to the AC for adjudication by the appropriate specialists.

“Establishing the adjudication process in our largest clinical trial has been a major undertaking,” stated the project director. “Without the electronic environment and clearly defined processes it would have been impossible to collect and timely adjudicate all the thousands of cases.”

The outcome

Recognising the magnitude of the task in monitoring outcomes for 9,340 patients across 30+ countries, this leading pharmaceutical company has turned to technology from ICON as a solution. With innovative visualisation software to assist in lab-data surveillance and an automated process for managing case adjudication, the company is reaping the benefits of greater efficiency, more systematic analysis, and stronger compliance.

Benefiting from end-to-end automation

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