WHITE PAPER

Literature Surveillance

Increasing Precision and Reducing Recall with Robust Strategies and Technology Platforms

Author

Andrew PurchaseDirector of Patient Safety OperationsPharmacovigilance & Patient Safety PRA Health Sciences

The author wishes to acknowledge the contributions of Senior Leadership from PRA Pharmacovigilance & Patient Safety (PVS).

White Paper | Literature Surveillance

Executive SummaryLiterature surveillance is an important tool in the suite of monitoring activities to ensure the safety of medicinal products. The

success of published literature surveillance is measured by precision and sensitivity. Pharmaceutical and biotech companies

must screen and analyze published literature from the clinical development stage, through post-marketing, as part of their

pharmacovigilance obligations. It is critical to detect safety signals as soon as possible to affect appropriate measures and

protect patient safety.

PRA Health Sciences has established consistent processes and clear accountabilities for literature surveillance to identify adverse

drug reactions, assess the expeditability of adverse reactions, review aggregate safety reports, and perform signal detection and

assessment. To ensure precision, PRA monitors global scientific and medical publications using large databases such as Medline

and Embase, as well as country-level journals.

An Introduction to Literature Surveillance During clinical development, it is mandated that drug

developers perform literature surveillance in accordance with

and in support of other surveillance activities, such as ongoing

safety evaluation or annual safety reporting (ie, Development

Safety Update Reports, or DSURs). This obligation intensifies

when the developer submits a New Drug Application (NDA)

or Marketing Authorization Application (MAA) and receives

authorization to market its product, as it then becomes a

requirement to perform a systematic literature review no less

than once a week. It is also expected that NDA and Marketing

Authorization Holders (MAHs) have procedures for monitoring

local publications in countries where the product has been

authorized for marketing.

Given the amount of available literature and the number of

potential sources (eg, Embase, Medline, Reactions Weekly,

Biosis), it is optimistic to expect to find every piece of literature

that may be published. Conducting a literature search requires

a realistic, pragmatic, and objective approach along with

targeted search strategies. These planning elements ensure

that the recall representing the number of results considered

relevant is as precise as possible.

Building a Robust Literature Surveillance Strategy It is essential that the development of the search strategy is

driven by the purpose of the search. Is the objective to look for

general safety information or Individual Case Safety Reports

(ICSRs), to identify new information about the medicinal

product, or to monitor a particular safety signal? In the clinical

development setting, exposure to the medicinal product

happens in a controlled environment and can be limited to a

certain patient population. When the medicinal product moves

to market, exposure widens to other patient populations, and

new or emerging safety information may be found. To build a

robust and targeted strategy, it is critical that it can evolve as

more is learned about the medicinal product and the objective

of the search changes.

Safety signals can arise from different sources of data,

including scientific literature. Scientific articles may describe

case reports with the use of a medicinal product or results

from studies conducted with the concerned product.

Monitoring the scientific literature can therefore provide

additional insight into the safety profile of a medicinal product.

When a safety signal is detected, the next step is to confirm

the causal association between the medicinal product and the

safety concern. This is achieved by looking at the strength of

the evidence, the clinical relevance, and previous awareness.

Reviewing scientific literature can help identify any similar

White Paper | Literature Surveillance

Figure 1:

safety concerns reported with the medicinal product in focus

or with products from the same pharmacological class. In

some circumstances, systematic literature reviews and meta-

analyses can be performed to further assess a safety signal

and support a more comprehensive analysis. In this scenario,

the research question should be clearly formulated, and the

selection of relevant publications, assessment of study quality,

summary, and interpretation of the findings should follow a

rigorous methodology.

Figure 1 offers a search strategy example to help visualize

how changes in the search strategy can impact the amount of

recall. Subsequently, Figure 2 provides insight into potential

time savings that can be realized.

Comparing Literature Recall

For this example, a search of PubMed was performed on

07 January 2021. The first search included the medical product

“Ibuprofen” and a publication date range of “01 January 2020

to 31 December 2020”. The second search included the

medical product “Ibuprofen” AND the event “Headache”

and a publication date range of “01 January 2020 to 31

December 2020”.

1200

0

200

400

600

800

1000

1016

19

Ibuprofen Ibuprofen AND Headache

Search Strategy (01Jan2020 to 21Dec2020)

Rec

all

In this example, you will note a 98% reduction in the amount

of recall when comparing the first and second searches.

Reducing the amount of recall may, in turn, increase the

precision, but some additional selection considerations

should be made.

Figure 2

Time Commitment/Recall

If we assume that each recall took an average of 4 minutes to

review, this figure represents the overall time commitment

to review the recall from the first and second searches

discussed in Figure 1.

Considerations to ensure recalls are not missed:

Databases: Consider which scientific databases and journals to search

Product terms: Think about factors such as alternative names, different spellings, and active substances of an indexed term

Search Terms: Consider the following search terms, which are often noted by regulators as being deficient in literature strategies:

• Outcome Terms (eg, Death)

• Pregnancy Terms (including uneventful pregnancies)

• Special Types of Reports (eg, Asymptomatic Overdose, Medication Errors, Misuse, Abuse, Occupational Exposure)

Time to Review

First Search = 68 hours

Second Search=1.3 hours

White Paper | Literature Surveillance

Automation of Literature Surveillance Despite the best efforts and most sophisticated strategies,

the amount of literature recalled can still be overwhelming,

particularly for companies with hundreds of products in

development and on the market. This is one of many similar

instances where technology and automation offer a solution.

Robust platforms can significantly reduce effort and improve

efficiency for literature surveillance activities. Technology

facilitates standardized, automated workflows that maximize

literature operations and provides a single platform/repository

for storing surveillance data. When searching multiple data

sources, such technology also performs de-duplication by

flagging duplicate results and highlights keywords to expedite

literature reviews and shorten the time for locating relevant

information. It is well documented that the deployment of

such literature platforms can reduce review times by 20-40%,

as shown in Figure 3.

The Impact of Automation

If we refer back to Figure 2, where we presented the time

commitment/recall, we can conclude that the literature

platform can reduce the review time by up to 40%.

Time to Review:First Search

Without Literature Platform= 68 hours

With Literature Platform= 32.8 hours

Time to Review:Second Search

Without Literature Platform= 1.3 hours

With Literature Platform= 0.78 hours

Implementation of these platforms streamlines oversight and

coordination of literature surveillance activities and ensures

inspection readiness. Such systems also enable ongoing

monitoring of the performance of the process and literature

strategy by providing access to on-demand reports.

Figure 3

PRA's Standalone Literature Surveillance Platform Features Include:

Detection and Removal of Duplicates (ie, De-Duplication)

Creation of Standardized Review Workflows

Keyword Highlighting

Reference and User Permissions Management

Central Storage of Articles

Creation of On-Demand Reports for Key Performance Indicators

Literature Surveillance of VaccinesOnce a new medicinal product is approved, a certain level of

scrutiny to the product’s safety should always be expected.

A public health emergency such as the COVID-19 pandemic

calls for a global effort to develop safe and effective treatments/

vaccines to combat the disease. While the timeframe for the

development of such treatments/vaccines may be shorter, there

can be no compromise in patient safety. That being said, the

shortened timeframes can increase the level of scrutiny that

these treatments/vaccines may face. Of course, routine

literature surveillance is a mandated requirement for a newly

approved medicinal product; however, we should be prepared

for a significant increase in the amount of recall when performing

literature surveillance during a public health emergency.

If we continue with the example of COVID-19, the development

of a robust literature strategy is more critical than ever. As part

of the literature strategy, it might be important to consider, for

example, the development of the vaccines, the evolution of the

disease, and the available treatment options. In addition, since

the landscape of such public health emergencies is constantly

White Paper | Literature Surveillance

PRA and Literature Surveillance PRA has the resources, processes, and technologies to support

effective literature surveillance. Our team of experienced

information specialists has backgrounds in the medical,

healthcare, scientific, and information technology industries.

PRA employs subject matter experts (SMEs) to manage

literature surveillance, as detailed in Figure 4.

evolving, it is essential to continually monitor the effectiveness

of the literature strategy and revise it with increased frequency.

Otherwise, it might be expected to recall between 500 to 1000

results per day.

When performing literature surveillance under an increased

level of scrutiny and with a likelihood for a high volume of

information, having a literature platform is more important

than ever.

PRA is a leader in all aspects of literature surveillance for

pharmaceutical and biotech companies, both in the clinical

development and post-approval environments.

Library Technicians• Develop, validate, and revise literature strategies

Drug Safety Associates (DSAs)• Execute searches, review abstracts, and procure selected articles

Safety Scientists

• Provide oversight of the process, review abstracts and articles

Safety Physicians

• Assess articles and summarize the review results

Qualified Person for Pharmacovigilance (QPPV)/Local Person of Pharmacovigilance (LPPV)

• May also be involved in the review of the search results (ie, in a post-approval environment)

Pharmacoepidemiologists

• Support with systematic literature reviews and meta-analysis

Figure 4

PRA supports the following type of literature surveillance activities:

Routine Pharmacovigilance

Aggregate Safety Analysis (DSUR, Risk Management, Signal Detection)

Adhoc Literature Reviews (support of Adhoc Signal Detection)

Local Literature Surveillance

Systematic Literature Reviews and Meta-Analysis (Real World Information)

White Paper | Literature Surveillance

References1. https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-good-pharmacovigi-

lance-practices-gvp-module-vi-collection-management-submission-reports_en.pdf

PRA Health Sciences conducts comprehensive Phase I-IV biopharmaceutical drug development. To learn more about our solutions, please visit us at prahs.com or email us at prahealthsciences@prahs.com.

White Paper | Literature Surveillance

Contact Information

For further information regarding PRA’s approach to literature surveillance or to discuss any aspect of PRA’s services, please contact your PRA account director or the PRA employee below:

Andrew Purchase

Director, Patient Safety Operations

Pharmacovigilance & Patient Safety

Phone: +44 (0) 1792 525 623

PurchaseAndrew@prahs.com

World Headquarters

4130 ParkLake Avenue, Suite 400

Raleigh, North Carolina 27612 USA

Phone: +1 (919) 786 8200

Fax: +1 (919) 786 8201

www.prahs.com

MA

R 2021