6.1 Introduction

In addition to the multiplicity of mandated periodic pharmacovigilance documents required for investigational and authorized medicinal products, documents submitted at the time of application for marketing authorization, and those required for risk evaluation and management, the PV Medical Writer will be required to prepare ad-hoc safety reviews and the Response to Questions Documents, at the behest of regulatory authorities.

If new safety data from the marketplace raises concern for a particular safety issue that may indicate inconsistency with the medicinal product’s prevailing safety profile as described in the product labeling, regulators may request the Marketing Authorization Holder (MAH) or New Drug Application (NDA)/Biologic License Application (BLA) holder to prepare a safety review (either cumulative or covering a defined time period). In some cases, the MAH or NDA/BLA holder may prepare such safety reviews on their own volition, as formal documentation of an internal safety assessment exercise, undertaken proactively to review safety data suggestive of a new or altered safety issue.

When requested by a regulatory authority, the parameters of the safety review are usually defined by them as in, for example: ‘A cumulative review of all case reports describing serious nervous system disorders and allergic reactions from the International Birth Date (IBD) up to the cut-off date of 30 June 2012.’ The request for preparation of the safety review may be a one-off requirement. However, it has been known for the regulators to ask for annual or even semi-annual reviews on a particular safety issue. Such a condition would emanate from the regulators’ consideration that periodic long-term monitoring of the issue is warranted to fully assess the nature of the risk and determine definitively, causality with respect to the medicinal treatment. Such periodic long-term monitoring of a safety issue may be expected with certain safety concerns, such as the development of malignancies that, by their very nature, require long-term surveillance and follow-up to assess causality. It is common practice for the regulators to ask that the annual or semi-annual safety reviews be submitted at the same time as the Periodic Safety Update Report (PSUR), if the medicinal product is still on a 6-monthly and 1-year cycle.

In addition to requests for ad-hoc safety reviews, it is also commonplace for the regulators to compile a list of questions, requesting additional data or clarification of submitted data, at the time of the initial application for marketing authorization/approval or license renewal. In these settings, the MAH or NDA/BLA holder (for authorized products) or applicant (in the case of initial applications), is expected to provide responses to the regulators’ questions in the form of a Response to Questions Document.

In contrast to the ad-hoc safety review, which is generally a ‘safety only affair,’ the content of the Response to Questions Document will vary depending on the questions posed by the regulators, and may comprise only safety-related questions, as well as on occasion, non-clinical-, efficacy-, and product quality-related questions.

6.2 The Ad-hoc Safety Review

The preparation of each safety review, the required source data, and participants, will be largely driven by the details of the requested review. However, as a general rule, the following data types are prescribed for a typical safety review and summarized in Table 6.1.

Table 6.1 Source data for the Ad-hoc Safety Review.

6.2.2 Review of the Ad-hoc Safety Document

The team participating in the preparation of ad-hoc safety reviews is generally identical to that involved in the preparation of the PSURs, including the assigned roles or areas of responsibility. As such, this information is not repeated here and the PV Medical Writer is instead referred to Section 5.2 of Chapter 5 (Pharmacovigilance Medical Writing for Marketed Products), where details of appropriate reviewers for the safety review can be found.

6.2.3 A Timeline – Planning for the Ad-hoc Safety Review

Preparation of the ad-hoc safety review is usually undertaken in 60 days and follows a timeline similar to that applied to preparation of the EU RMP. For this reason, the applicable timeline is not re-created here and the PV Medical Writer is referred to Section 4.2 of Chapter 4 (Pharmacovigilance Medical Writing in Risk Evaluation and Management) for details of a suitable timeline for completion of the ad-hoc safety review.

6.2.4 Generic Model of an Ad-hoc Safety Review

A generic model template for the ad-hoc safety review, which can be modified to fit the purpose of the required safety assessment, is presented below.

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