Periodic Safety Report: DSUR, PSUR, PBRER, ASR, IB, Orphan Designation Annual Report

During the drug development and after the drug is on the market, the sponsor or market authorization holder has obligations to submit the safety information to regulatory agencies periodically. These periodic reports have different requirements and sometimes are confusing. While these reports may be prepared by the regulatory affairs department or pharmacovigilence department, biostatistics group may often be asked to provide the information for these periodic reports.

These reports and their abbreviations could be very confusing especially for those who are not working in the pharmacovigilence department: DSUR, IND Annual Report, ASR, IB, PSUR, and PBRER… If we take a close look at these reports, they may be considered as four types:

• DSUR (replacing IND Annual Report and Annual Safety Report) for drugs under developments
• PBRER (replacing PSUR) for drugs already on the market
• IB is required whenever there is a clinical trial
• Orphan Designation Annual Report is required for the developing product with orphan designation - for rare disease

DSUR:  Development Safety Update Report

According to ICH E2F “Development Safety Update Report”,

The Development Safety Update Report (DSUR) proposed in this guideline is intended to be a common standard for periodic reporting on drugs under development (including marketed drugs that are under further study) among the ICH regions. US and EU regulators consider that the DSUR, submitted annually, would meet national and regional requirements currently met by the US IND Annual Report and the EU Annual Safety Report, respectively, and can therefore take the place of these existing reports

ICH E2F Guideline is finalized in August 2010 and is replacing the previous IND (investigational new drug) Annual Report (in US) and Annual Safety Report (in EU). Other documents regarding DSUR can be found at ICH.org website

• Concept Paper
• Business Plan
• DSUR Examples Commercial Sponsors
• DSUR Examples non-Commercial Sponsors
• Presentation on E2F

IB: Investigator Brochure

According to ICH E6 “Good Clinical Practice”,

The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety monitoring procedures. The IB also provides insight to support the clinical management of the study subjects during the course of the clinical trial.

For post marketing commitment clinical trials, the product label (package insert) may be used in place of the investigator brochure since the package insert includes the contents required in the investigator brochure.

Orphan Drug Designation Annual Report 

21CFR Part 316 (Orphan Drugs) contains the specific section (section 316.30) requiring the annual reports of holder of orphan drug designation:

§ 316.30 Annual reports of holder of orphan-drug designation.
Within 14 months after the date on which a drug was designated as an orphan drug and annually thereafter until marketing approval, the sponsor of a designated drug shall submit a brief progress report to the FDA Office of Orphan Products Development on the drug that includes:
(a) A short account of the progress of drug development including a review of preclinical and clinical studies initiated, ongoing, and completed and a short summary of the status or results of such studies.
(b) A description of the investigational plan for the coming year, as well as any anticipated difficulties in development, testing, and marketing; and
(c) A brief discussion of any changes that may affect the orphan-drug status of the product. For example, for products nearing the end of the approval process, sponsors should discuss any disparity between the probable marketing indication and the designated indication as related to the need for an amendment to the orphan-drug designation pursuant to § 316.26.

EU has the similar requirement and sponsors are required to submit to the European Medicines Agency (EMA) every year after their medicine has been granted orphan designation. See EMA Orphan Designation Annual Report.

PSUR: Periodic Safety Update Reports

The term PSUR comes from the previous ICH E2C (R1) “Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs”. ICH guideline E2C has been subsequently revised and renames as Periodic Benefit-Risk Evaluation Report (PBRER) (see below). However, the term PSUR is still used by EMA. See EMA's 'Periodic safety update reports: questions and answers'

PBRER: Periodic Benefit-Risk Evaluation Report

According to the ICH E2C (R2) “PERIODIC BENEFIT-RISK EVALUATION REPORT (PBRER)”,

The Periodic Benefit-Risk Evaluation Report (PBRER) described in this Guideline is intended to be a common standard for periodic benefit-risk evaluation reporting on marketed products (including approved drugs that are under further study) among the ICH regions.

Other supporting documents regarding PBRER are:

• Concept Paper
• Business Plan
• Contribute to the E2C(R2) IWG

E2C (R2) is finalized at November 2012 and is supposed to replace the PSUR. However, EMA has not fully adopted the PBRER and continues to use the term PSUR as defined in its recent guideline “Guideline on good pharmacovigilance practices (GVP) 4 Module VII – Periodic safety update report (Rev 1)”

FDA fully endorsed E2C (R2) and PBRER and issued its guidance “Providing Postmarket Periodic Safety Reports in the ICH E2C(R2) Format (Periodic Benefit-Risk Evaluation Report”

A paper EMA’S NEW PSUR-PBRER from Sentrx.com discussed this confusion.

PBRER vs. DSUR

It is often confusing whether or not a PBRER or DSUR or both are needed. It is commonly understood that PBRER is for a marketed products (including approved drugs that are under further study) and DSUR is for drugs under development (including marketed drugs that are under further study). In US, for the marketed products, if IND is still open, the annual safety report (i.e., DSUR) will be required by FDA.

There are some duplications between the DSUR and PBRER. FDA's guidance "PERIODIC BENEFIT-RISK EVALUATION REPORT (PBRER)" intended to provide some clarifications about PBRER and DSUR. In some situations, both PBRER and DSUR are required (to meet different regulatory requirements). in preparation. However, the effort can be made to minimize the duplicate works.

"This guideline aims to address this duplication and facilitate flexibility by encouraging the use of individual modules, where they pertain to more than one report – to be used at different times, for different authorities, and for different purposes. Therefore, the PBRER has been developed in such a way that content of several sections may be used for sections of other documents as a basis for a modular approach (see Section 1.1). "

To some degree, the DSUR can be considered as a subset of PBRER with focus on the ongoing clinical trials.

SOP, WP, MAPP, SOPP for FDA Internal Staff / Reviewers

In an earlier discussion, I compared the differences between SOPs (Standard Operation Procedures) and WPs (Working Procedures). Pharmaceutical companies, Biotechnology companies, Clinical research organizations, and vendors providing services in clinical trials area must have the established SOPs and these SOPs must be followed by their employees. Adequacy of the SOPs and the compliance with the established SOPs are the key targets when there are audits (either from the sponsor or from the regulatory agencies).

As the regulatory agency for drug, biological products, and device clinical trials and market authorization approvals, FDA also has its established working procedures and FDA review staff should be trained on these working procedures and should follow these procedures. I hope that the compliance of these working procedures within FDA is also be monitored or audited.  

Interestingly, different divisions in FDA use different terminologies for their working procedures (see table below).

CDER (Center for Drug Evaluation and Research)	MAPP	Manual of Policies and Procedures
CBER (Center for Biologics Evaluation and Research)	SOPP	Manual of Standard Operating Procedures and Policies
CDRH (Center for Device and Radiological Health)	Guidance Documents (Medical Devices and Radiation-Emitting Products)

FDA also issues a lot of guidances. According to FDA, “Guidance documents represent FDA's current thinking on a topic.  They do not create or confer any rights for or on any person and do not operate to bind FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations.” While these guidances are mainly for industry, some of them are also for FDA Staff and FDA reviewers and perhaps also for investigators, IRB...

To understand what procedures FDA staff / reviewers are following can help the industry in preparing the regulatory submission materials to make sure that the documents FDA reviewers are looking for are included in the submission package.  For example, FDA MAPP 6010.4 “Good Review Practice: Statistical Review Template” can be good reference in preparing the planned analyses and tables. The documents provided “Examples of important statistical issues that may affect the results”

• Breaking the blind
• Unblinded or unplanned interim analyses
• High percentage of dropouts
• Inappropriate imputation for missing values
• Change of primary endpoint during conduct of the trial
• Dropping/adding treatment arms
• Sample size modification
• Inconsistency of results across subgroups
• Type I error inflation due to multiplicity
• Planned and unplanned adaptations
• Non-Inferiority

MAPP 6010.3 Rev. 1 “AttachmentB: Clinical Safety Review of an NDA or BLA” can be a good reference in understanding how the safety data should be presented. The document provides the detail review guidance on safety data including adverse events, vital signs, laboratory data, ECG,… In the section “Standard Analyses and Explorations of Laboratory Data” it specifically discussed what type of laboratory analysis results should be presented and the hypothesis tests for comparing the laboratory results are discouraged.  

In general, this review should include three standard approaches to the analysis of laboratory data, noted as: (1) Analyses Focused on Measures of Central Tendency; (2) Analyses Focused on Outliers or Shifts From Normal to Abnormal; and (3) Marked Outliers and Dropouts for Laboratory Abnormalities. The first two analyses are based on comparative trial data. The third analysis should focus on all subjects in the phase 2 to phase 3 experience. Analyses are intended to be descriptive and should not be thought of as hypothesis testing. P-values or confidence intervals can provide some evidence of the strength of the finding, but unless the trials are designed for hypothesis testing (rarely the case), these data should be thought of as descriptive. Generally, the magnitude of change is more important than the p-value for the difference.

MAPP 6030.9 “Good Review Practice: Good Review Management Principles and Practices for Effective IND Development and Review” discussed the SAP submission during IND:

Statistical analysis plan. Submission of a detailed statistical analysis plan (SAP) in the initial protocol submission for phase 3 protocols is not required by CDER regulations. However, review staff should strongly encourage sponsors to include the SAP in the initial protocol submission, because phase 3 protocols generally include a detailed section devoted to statistical methods that are closely linked to trial design. 

Clinical Trial Regulations in European Union (EU) Countries

For clinical trials in European Union countries, the regulations are mainly based on:

•  European Union (EU) clinical-trial legislation (Directive 2001/20/EC) and EU Legislation – Eudralex Volume 1 “Pharmaceutical Legislation Medicinal Products for Human Use”; Volume 10 “Clinical trials guidelins”
• Regulatory guidelines from The European Medicines Agency (EMA)
• Some guideline documents from The Heads of Medicines Agencies

According to EU Directive 2001/83/EC, “All clinical trials, conducted within the European Community, must comply with the requirements of Directive 2001/20/EC of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. To be taken into account during the assessment of an application, clinical trials, conducted outside the European Community, which relate to medicinal products intended to be used in the European Community, shall be designed, implemented and reported on what good clinical practice and ethical principles are concerned, on the basis of principles, which are equivalent to the provisions of Directive 2001/20/EC. They shall be carried out in accordance with the ethical principles that are reflected, for example, in the Declaration of Helsinki.”

There are two updates to the Directive 2001/20/EC:

• COMMISSION DIRECTIVE 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products
• 2012/0192 (COD)  Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC

The European Medicines Agency (EMA) is the closest counterpart of US FDA and is the main body in EU to provide the regulatory guidelines for conducting clinical trials.

“The European Medicines Agency relies on the results of clinical trials carried out by pharmaceutical companies to reach its opinions on the authorisation of medicines. Although the authorisation of clinical trials occurs at Member State level, the Agency plays a key role in ensuring that the standards of good clinical practice (GCP) are applied across the European Economic Area in cooperation with the Member States. It also manages a database of clinical trials carried out in the European Union.”

The Heads of Medicines Agencies (HMA) is a network of the Heads of the National Competent Authorities whose organisations are responsible for the regulation of Medicinal Products for human and veterinary use in the European Economic Area. The Heads of Medicines Agencies is supported by working groups covering specific areas of responsibility and by the Heads of Medicines Agencies Management Group and Permanent Secretariat.
The Heads of Medicines Agencies co-operates with the European Medicines Agency and the European Commission in the operation of the European Medicines Regulatory Network (“the Network”).

The guidelines related to statistics are mainly under Clinical efficacy and safety: General and Clinical efficacy and safety: Clinical pharmacology and pharmacokinetics

Some of the guidelines are listed below with comparison to the corresponding FDA guidance.

EMA	FDA
Guideline on adjustment for baseline covariates
Guideline on Missing Data in Confirmatory Clinical Trials
Concept paper on the need for a Guideline on the use of Subgroup Analyses in Randomised Controlled Trials
Guideline on Clinical Trials in Small Populations
Reflection Paper on Methodological Issues in Confirmatory Clinical Trials Planned with an Adaptive Design	Adaptive Design Clinical Trials for Drugs and Biologics
Guideline on Data Monitoring Committees	Establishment and Operation of Clinical Trial Data Monitoring Committees
Guideline on the Choice of the Non-Inferiority Margin	Non-Inferiority Clinical Trials
Points to consider on switching between superiority and non-infeirority	Non-Inferiority Clinical Trials
	Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials
Points to Consider on Multiplicity Issues in Clinical Trials Concept paper on the need for a guideline on multiplicity issues in clinical trials
Reflection Paper on the Regulatory Guidance for the Use of Health Related Quality of Life (HRQL) Measures in the Evaluation of Medical Products	Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims
Points to consider on application with 1. Meta-Analyses; 2. One pivotal study	-          Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products -          Integrated Summary of Effectiveness
Guideline on the Investigation of Bioequivalence	Statistical Approaches to Establishing Bioequivalence

Other EU regulatory guidelines that I have been exposed to are:

•  Clinical efficacy and safety: Blood products (including biotech alternatives)
• Guidance for the format and content of the final study report of non-interventional post-authorisation safety studies
• ENCEPP Considerations on the Definition of Non-Interventional Trials Under the Current legislative Framework (“Clinical Trials Directive” 2001/20/EC)
• Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies
• Guidance for Industry on Providing Regulatory Information in Electronic Format: Non-eCTD electronic Submissions (NeeS) for human medicinal products
• TIGes Harmonised Guidance for Non-eCTD electronic Submissions (NeeS) for human medicinal products in the EU
• Dossier Format: Regulatory and procedural guidance
• Multinational Clinical Trials in Europe and the Voluntary Harmonisation Procedure (VHP)
• Guidance document for sponsors for a Voluntary Har-monisation Procedure (VHP) for the assessment of mul-tinational Clinical Trial Applications