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Subject Exposure in Aggregate Safety Reports & Common Issues

All new and existing drugs should be safe, effective, and efficacious for the treated populations. Pharma companies must maintain this benefit-risk balance throughout the drug lifecycle.  

The reporting rate of serious adverse events (SAEs) is key to determining overall drug safety. Per the International Council for Harmonisation (ICH) guideline on development safety update reports (DSURs),  

“an estimation of cumulative subject exposure can help provide context for the cumulative summary tabulations of SAEs, and the overall assessment of safety.”1

Aggregate safety reports include DSURs and periodic safety update reports (PSURs). They estimate the population exposed to the drug in clinical trials and post-marketing settings. The latter is based on data relating to the volume of sales and/or prescriptions for marketed products.2

Abbreviations: DSUR=Development Safety Update Report; ICH=International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; IMP=Investigational medicinal product; PBRER/PSUR=Periodic Benefit- Risk Evaluation Reports/Periodic Safety Update Report; RMP=Risk Management Plan; GVP=Good Pharmacovigilance Practices.

These safety reports’ exposure sections should estimate the size and nature of the population exposed to the drug. These sections briefly describe how the subject/patient exposure was estimated and the methods’ limitations.

Who should be included in the reporting of subject exposure?

In general, include anyone who received the drug in any setting when reporting subject/patient exposure. This includes the following:  

Exposure From Clinical Trials

Include subjects/patients exposed in any interventional trial conducted by the Sponsor or any partner companies. To allow for analysis across different demographics, cumulative exposure to the investigational drug from ongoing and completed clinical trials should also be presented by age range, sex, and racial group when these data are available.

DSUR Section 6.1 and PSUR Section 5.1 contain exposure from clinical trials. When the data lock points for the DSUR and PSUR align, the cumulative exposure from clinical trials should be the same.

Post-marketing Exposure:

DSUR Section 6.2 and PSUR Section 5.2 contain an estimate of the interval and cumulative patient exposure in the marketed setting. Sales data from the regions where the drug is marketed helps determine this estimate.

When the data lock points for the DSUR and PSUR are aligned, the cumulative exposure in the marketed setting should be the same. In the PSUR, cumulative exposure should also be presented by

  • indication, sex, age, dose, formulation, and region;
  • by relevant subgroups; and
  • by special populations (e.g., pediatric or elderly use) when applicable.

Other Studies:

In addition, subjects may receive drugs outside of clinical trials. Some scenarios include combination studies, pre-approval access, investigator-initiated trials, compassionate use programs, named‑patient use, or expanded access programs). Present this data in DSUR Sections 8.4, 8.5, or 10 and PSUR Sections 7.4, 7.5, or 9.1, as applicable.

Common Issues with Reporting of Exposure

Obtaining and estimating subject exposure in aggregate safety reports is not always straightforward. We frequently encounter issues when helping our clients with these reports! Table 1 provides examples of common issues and potential solutions.

Table 1 Common Issues with Reporting of Subject Exposure in Safety Aggregate Reports

IssueDescriptionSolution
Duplication of subjectsIt can become challenging to obtain exposure data with complex trial designs. These include crossover studies, different routes of administration/formulation, multiple-phase studies, or multiple indications.
For example, a subject can be exposed to multiple treatment arms, phases, or formulations within the same trial e.g., in crossover trials. Thus, researchers may count that subject more than once when assessing their exposure. Duplicating subject exposure can over-inflate the number of subjects exposed. Thereby, this dilutes the overall reporting rate of SAEs.
Ensure that the overall total exposure reported only includes unique subjects. This will cause a discrepancy between the total exposure and the sum of the individual exposures from the different treatment groups. Explain this discrepancy in table footnotes.

Where possible, the biostatistics team should generate exposure data tables using blinded dummy codes, in place of manual calculations.
Blinded studies in clinical developmentSeveral factors may limit estimating clinical trial exposure. These include the rapidity of subject enrollment and the number of ongoing trials with blinded treatment assignment.

Per ICH guidance, for blinded trials, an exposure estimate based on the randomization scheme should be provided.1 What if they aren’t evenly randomized e.g., 15 subjects exposed in a 1:1 randomization scheme active drug: placebo? In this case, should the extra subject be in the active drug or placebo counts? Furthermore, blinded data can also limit the ability to sub-group exposure data by age range, sex, and race.
In general, use a more conservative approach. Place the extra subject in the placebo counts to not dilute the SAE reporting rate.

Where possible, the biostatistics team should generate exposure data tables using blinded dummy codes, in place of manual calculations.
Limitations of the study/post-marketing population (i.e., rare diseases)Sardella and Belcher3 state that rare disease patients have low exposure to treatments for rare diseases. Therefore, they also experience infrequent spontaneous suspect adverse drug reactions. This combined with the likelihood of rare but often common concomitant pathologies, particularly in many rare genetic diseases (confounding by indication), makes identifying possible adverse reactions inefficient and insensitive.Use qualitative and alternative proactive approaches (e.g., noninterventional safety studies to collect data during the post-marketing period). This approach is better at defining the safety profile and monitoring the benefit-risk profile of drugs for rare diseases.3
Obtaining post-marketing dataFor marketed products, obtaining the estimated exposure data presents additional challenges. Several methods are used to determine the estimated exposure. Surveys, studies, or data collection by healthcare providers, health authorities, or government agencies are often used to determine how many patients are taking a drug in a particular country or region. Another method is through sales data provided by the marketing authorization holder.

It may be difficult to determine the daily dose and hence patient-year exposure from sales or survey data. Also, sales data may not capture off‑label use or compassionate use in countries without marketing authorization.

Assessing if the number of units sold was used is difficult as sales data don’t always equate to the number of patients exposed.
Reporting post-marketing exposure is challenging. Thus, estimate the exposure from post-marketing sources. Describe the methods used to calculate post-marketing exposure plus all the assumptions made. Review these regularly for changes.

How can we help you maintain compliance with regulatory authorities?

Certara safety/pharmacovigilance writers have extensive ‘exposure’ to exposure data. We’re well-positioned to help you develop the best exposure reporting strategy for your drug. Read this white paper to learn key information concerning aggregate safety reports and how they’re linked.

References:

  1. ICH guideline E2F on development safety update report Step 5. European Medicines Agency. September 2011. EMA/CHMP/ICH/309348/2008.
  2. Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report (Rev 1). 9 December 2013. EMA/816292/2011 Rev 1
  3. Sardella M, Belcher G. Pharmacovigilance of medicines for rare and ultrarare diseases. Ther Adv Drug Saf. 2018;9(11): 631–638.

About the authors

Mary Pilkington, PhD
By: Mary Pilkington, PhD

Mary Pilkington, PhD, has over 20 years of experience in regulatory writing. She is an expert in writing pharmacovigilance documents, including development safety update reports, periodic benefit-risk evaluation reports, periodic adverse drug experience reports, and risk management plans. She is process-driven, having created standard operating procedures and working instructions for pharmacovigilance documents, and is client-oriented, developing long-term governance relationships. She also has proven skills in training and developing junior writers to become pharmacovigilance document subject matter experts. She is an associate director and the service line head for safety/PV at Certara.

Dr. Nicholas Churton
By: Dr. Nicholas Churton

Dr. Nicholas Churton is a principal regulatory writer with over 10 years of experience working in a clinical research organization. He has authored multiple regulatory documents across various therapeutic areas and multiple phases, specializing in aggregate safety reporting documents such as development safety update reports (DSURs), periodic benefit-risk evaluation reports (PBRERs), risk management plans (RMPs), periodic adverse drug experience reports (PADERs), and responses to health authority queries. He has experience in managing large cross-functional teams on pivotal projects in addition to developing training resources and providing oversight of junior writers.

Manisha Chakov
By: Manisha Chakov

Manisha Chakov has over 16 years of regulatory writing experience and 7 years of experience with laboratory processes and compilation of information necessary to meet regulatory standards. Her areas of expertise include writing safety documents (such as development safety update reports and periodic benefit-risk evaluation reports), study reports, and responses to health authority queries, as well as data analysis, research, and analytical method development and validation.

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