, Sam Salek2 and Stuart Walker3
(1)
Centre of Regulatory Excellence, Duke-NUS Graduate Medical School, Singapore, Singapore
(2)
Department of Pharmacy, University of Hertfordshire, Hatfield, UK
(3)
Centre for Innovation in Regulatory Sciences, London, UK
Introduction
The evolution in the requirements for assessing the benefits and risks of medicinal products has resulted in changes in the evaluation processes. Beyond the separate assessment of benefits and risks, the emphasis is now on the balance between the two, having to justify the potential harms in view of the efficacy claims. In a changing society where the demand is for transparency of such decision-making processes, there is now a major challenge to adequately communicate relevant information to stakeholders. The articulation of benefit–risk decisions remains both a responsibility and an opportunity.
The European Medicines Agency (EMA) and the US FDA have provided guidances on the assessment of medicines. EMA provided a reflection paper on the assessment of benefits and risks of medicines (EMA 2008), while US FDA (as part of the PDUFA V) has implemented a benefit–risk framework to allow the appropriate discussion on the considerations taken into account for a regulatory decision (FDA 2012a, b). While these may enhance the benefit–risk evaluation of a product, there is currently no standard template for the documentation and communication of the evaluation outcomes and benefit–risk decisions. Individual agencies have their own internal evaluation report templates and also those for publicly available assessment reports. Consequently, stakeholders seeking information on the assessment of a product may be presented with similar information in different formats.
The results from a study on BR frameworks (Chap. 3) showed that both regulatory agencies and pharmaceutical companies believe that a benefit–risk framework would enhance the quality (transparency and consistency) of communication and should provide documentation for a structured discussion, acting as a tool for communication among peers within the organization and between the organization and stakeholders. The 8-step universal benefit–risk framework, UMBRA (Chap. 4), was therefore proposed, and this framework encompasses the principles of existing frameworks by other major regulatory agencies such as the US FDA (FDA 2013a, b, c, d, e) and EMA (EMA 2010) (Table 7.1). A documentation tool was also developed to support this framework and formed part of the Benefit–Risk Assessment Support System (BRASS; Chap. 4).
Table 7.1
Comparisons of US FDA and EMA benefit–risk assessment frameworks with the universal benefit–risk framework
Frameworks reviewed | Core elements | |||||||
|---|---|---|---|---|---|---|---|---|
Framing the decision | Identifying benefits and risks | Assessing benefits and risks | Interpretation and outcome | |||||
US FDA | Analysis of conditions and unmet medical needs | Clinical benefits, risks | Evidence and uncertainties | Conclusions and reasons, risk management plans | ||||
EMA PrOACT-URL | Nature and framing of the problem | Objectives, favorable and unfavorable effects | Alternatives regarding options to be evaluated and the consequences | Trade-offs and benefit–risk balance | Evaluating uncertainty | Effects table and risk tolerance | Consistency of decisions (linked decisions) | |
Universal benefit–risk framework | Step 1 | Step 2 | Step 3 | Step 4 | Step 5 | Step 6 | Step 7 | Step 8 |
Decision context | Building the value tree | Customizing the value tree | Weighting (relative importance) of benefits and risks | Scoring the options | Evaluating uncertainties | Concise presentation of results (visualization) | Expert judgment and communications | |
This BR Template was designed to enhance effective documentation and communication of decisions and was used as the basis of comparison in this study. The outcomes from three agencies showed that the BR. Template is useful for documenting and communicating a benefit–risk decision (Chap. 5), while the BR Summary Template was investigated and similarly found to be adequate for the above purposes (Chap. 6). It is noted that there are currently publicly available assessment reports from the major regulatory agencies. This study aims to review these publicly available assessment reports to see if they adequately fulfill the functions found in the BR Template and BR Summary Template.
Objectives
The objectives of this study were to:
Compare the format of the US FDA’s, EMA’s, HC’s, and TGA’s publicly available assessment reports with the BR Template and BR Summary Template
Evaluate whether these four regulatory agencies have an effective approach for communicating benefit–risk decisions to all stakeholders
Examine the utility of the BR Summary Template for communicating benefit–risk decisions by the US FDA and EMA using a case study
Methods
In order to establish the utility of the BR Template, four major reference agencies were selected, namely, US FDA, EMA, Health Canada, and TGA. The criteria for choosing these reference agencies was based on a positive history of established regulatory processes, global recognition of regulatory standards, and the public availability of assessment reports. Therefore, for the purpose of comparison in this study, the following report formats of the four reference agencies were used:
US FDA – Medical Review and the Risk–Benefit Assessment
EMA – European Public Assessment Report (EPAR) and the Executive Summary
Health Canada – Summary Basis of Decision (SBD)
TGA – Australian Public Assessment Report (AusPAR)
The abovementioned report formats were expected to be common in their function to the BR Template, which is to document and communicate the information supporting benefit–risk decisions and regulatory outcomes. Report format templates were retrieved online for each agency. In the absence of an official document that explained the structure of the format, a recent publicly available assessment report would be used to review the contents of the report or support the understanding of the format. Comparison of the report formats from the four reference agencies was conducted by reviewing the section headings of the report against those of the BR Template and BR Summary Template. Where there was a summary in the reference agency’s format, this would be directly compared with the BR Summary Template and the findings were tabulated and presented.
Furthermore, to illustrate the use of the BR Summary Template, a case study was conducted using a recent US FDA Medical Review (FDA 2012b), EPAR (EMA 2013c), and AusPAR (TGA 2014) for the same product. Zaltrap® (aflibercept) was chosen as it was approved around the same time by both agencies (03 August 2012 for US FDA, 01 February 2013 for EMA, and 02 April 2014 for TGA). Importantly, the US FDA Medical Review was written according to the new five-step benefit–risk framework that features the Risk–Benefit Assessment. These two respective summaries were transferred into the BR Summary Template and the omissions reviewed.
Results
The outcomes will be presented in four parts:
Part I – Formats of the four reference agencies’ publicly available report templates
Part II – Comparison of the four reference agencies’ report templates with the BR Template
Part III – Comparison of the four reference agencies’ report templates with the BR Summary Template
Part IV – Case study of US FDA’s, EMA’s, and TGA’s summary reports on Zaltrap®
Part I: Formats of Reference Agencies’ Publicly Available Report Templates
US FDA Medical Review
The US FDA Medical Review consists of nine sections (Table 7.2), with the opening section presenting the recommendations and Risk–Benefit Assessment (based on the five-step benefit–risk framework). The remaining sections present the details of the assessment supporting the recommendations. It is known that the publicly available reports from the US FDA are a redacted subset of the complete evaluation data. The original dataset will include discussions of queries and responses by the sponsor with the US FDA.
Table 7.2
Format of US FDA Medical Review
US FDA Medical Review | |
|---|---|
Section | Content |
1 | Recommendations/risk–benefit assessment |
2 | Introduction and regulatory background |
Product information | |
Tables of currently available treatment for proposed indications | |
Availability of proposed active ingredient in the USA | |
Important safety issues with consideration to related drugs | |
Summary of pre-submission regulatory activity related to submission | |
Other relevant background information | |
3 | Ethics and good clinical practices |
Submission quality and integrity | |
Compliance with GCP | |
Financial disclosures | |
4 | Significant efficacy/safety issues related to other review disciplines |
Chemistry manufacturing and controls | |
Clinical microbiology | |
Preclinical pharmacology/toxicology | |
Clinical pharmacology (mechanism of action, pharmacodynamics, pharmacokinetics) | |
5 | Sources of clinical data |
Tables of studies/clinical trials | |
Review strategy | |
Discussion of individual studies/clinical trials | |
6 | Review of efficacy |
Efficacy summary | |
Indication (methods, demographics, subject disposition) | |
Protocol violations | |
Analysis of primary endpoints | |
Analysis of secondary endpoints | |
Other endpoints | |
Subpopulations | |
Analysis of clinical information relevant to dosing recommendations | |
Additional efficacy issues/analyses | |
7 | Review of safety |
Safety summary | |
Methods (studies, categorization, pooling of data) | |
Adequacy of safety assessment (overall exposure, dose response, special animal and/or in vitro testing, metabolic/clearance/interaction workup, potential AE for similar drugs) | |
Major safety results (deaths, nonfatal SAE, dropouts/discontinuation, significant AE, specific primary safety concern) | |
Supportive safety results (common AE, lab findings, vital signs, ECGs, special safety studies, immunogenicity) | |
Other safety explorations (dose dependency, time dependency, drug–demographic/drug–disease/drug–drug interactions) | |
Additional safety evaluations (human carcinogenicity, human reproduction/pregnancy data, pediatric and effects on growth, overdose/abuse potential/withdrawal/rebound) | |
Additional submissions/safety issues | |
8 | Post-marketing experience |
9 | Appendices |
EMA’s EPAR
The EPAR consists of an Executive Summary and four sections (Table 7.3). The publicly available EPAR is extracted from the complete assessment report which would have included responses and justifications to EMA for queries raised. Agency-specific requirements are those relating to submission information and regulatory processes.
Table 7.3
Format of EMA’s EPAR
EMA’s EPAR | |
|---|---|
Section | Content |
Executive summary | |
1 | Background information on the procedure |
Submission of the dossier | |
Steps taken for the assessment of the product | |
2 | Scientific discussion |
Introduction | |
Quality aspects | |
Introduction | |
Active substance | |
Finished medicinal product | |
Discussion on chemical, pharmaceutical, and biological aspects | |
Conclusions on the chemical, pharmaceutical, and biological aspects | |
Recommendations for future quality development | |
Nonclinical aspects | |
Introduction | |
Pharmacology | |
Pharmacokinetics | |
Toxicology | |
Ecotoxicity/environmental risk assessment | |
Discussion on nonclinical aspects | |
Conclusion on nonclinical aspects | |
2 | Clinical aspects |
Introduction | |
Pharmacokinetics | |
Pharmacodynamics | |
Discussion on clinical pharmacology | |
Conclusion on clinical pharmacology | |
Clinical efficacy | |
Dose–response studies | |
Main studies | |
Supportive studies | |
Discussion on clinical efficacy | |
Conclusion on clinical efficacy | |
Clinical safety | |
Discussion on clinical safety | |
Conclusion on clinical safety | |
Pharmacovigilance | |
User consultation | |
3 | Benefit–risk balance |
4 | Recommendations |
Health Canada’s SBD
The Health Canada’s Summary Basis of Decision (SBD) consists of eight sections (Table 7.4). This is a publicly available document that presents the relevant information to support the decision made by Health Canada for the product (Health Canada 2012a, b). Unlike US FDA Medical Review and EPAR, there is no separate summary portion as the SBD is meant for this purpose. The agency-specific information is related to submission milestones, recent and post-authorization activities. These disparities are not considered to influence the processes on the assessment of benefits and risks.
Table 7.4
Format of Health Canada’s Summary Basis of Decision
Health Canada’s Summary Basis of Decision | ||
|---|---|---|
Section | Content | Purpose |
PAAT | Post-authorization activities table | List of post-authorization activities for the approved product |
1 | What was approved? | Information on approved indication, intended population, contraindications, and product presentations |
2 | Why was < product > approved? | Discussion on basis of benefit–risk balance |
3 | What steps led to the approval of < product > ? | Submission milestones |
4 | What follow-up measures will the company take? | Information on post-approval commitment |
5 | What post-authorization activity has taken place for < product > ? | Information provided as link to earlier section on post-authorization activity table (PAAT) |
6 | What other information is available about drugs? | Links to other webpages within the Health Canada website |
7 | What was the scientific rationale for Health Canada’s decision? | Details on: (a) Clinical basis of decision (i) Clinical pharmacology (ii) Clinical efficacy (iii) Clinical safety (iv) Safety topics of special interest (b) Nonclinical basis of decision (c) Quality basis of decision |
TGA’s AusPAR
The TGA AusPAR consists of six sections (Table 7.5) (TGA 2012), the format being close to the EPAR but without the Executive Summary. As with the previous formats of the other three agencies, agency-specific information are those related to individual regulatory and submission information. It is known that the AusPAR contains information extracted from the complete, original assessment reports.
Table 7.5
Format of TGA’s AusPAR
TGA’s AusPAR | |
|---|---|
Section | Content |
1 | Introduction to product submission |
Submission details | |
Product background | |
Regulatory status | |
Product information | |
List of abbreviations | |
2 | Quality findings |
Drug substance | |
Drug product | |
Biopharmaceutics | |
Advisory committee considerations | |
Quality summary and conclusions | |
3 | Nonclinical findings |
Introduction | |
Pharmacology | |
Pharmacokinetics | |
Toxicology | |
Nonclinical summary and conclusions | |
4 | Clinical findings |
Introduction | |
Pharmacodynamics | |
Pharmacokinetics | |
Dosage selection for pivotal studies | |
Efficacy | |
Safety | |
Clinical summary and conclusions | |
5 | Pharmacovigilance findings |
Risk management plan | |
6 | Overall conclusion and risk–benefit assessment |
Background | |
Quality | |
Nonclinical | |
Clinical | |
Risk management plan | |
Risk–benefit analysis | |
Outcome | |
Part II: Comparison of the Four Reference Agencies’ Report Templates with the BR Template
The outcomes showed that the format of the reference agencies’ reports are generally similar, and when compared with the BR Template, they were all found to lack the features that list the identified benefits and risks, application of values and weights (relative importance), and visualization of the assessment outcomes (Table 7.6). In addition, while it is acknowledged that relevant discussions and considerations contributing to the final benefit–risk decision maybe reported in the existing reference agencies’ templates, the BR Template allowed for this through a structure of guided questions.
Table 7.6
Comparison of sections of reference agencies’ publicly available assessment reports with the BR Template
BR template | US FDA | EMA | Health Canada | TGA | |
|---|---|---|---|---|---|
Content | Medical Review | Section 1 (Risk–Benefit Assessment) | EPAR | SBD | AusPAR |
1 Background | |||||
1.1 Specify proposed therapeutic indication | Section 2 | Analysis of condition | Section 1: scientific discussion | Not available | Section 1 |
1.2 Treatment modalities evaluated | Section 2 | Analysis of condition | Section 1: scientific discussion | Not available | Section 1 |
1.3 Other current available treatment options not considered or evaluated | Section 2 | Current treatment options | Section 1: scientific discussion | Not available | Section 1 |
1.4 Known risks with compounds of same therapeutic class | Section 2 | Risk | Section 1: scientific discussion | Section 7: clinical | Section 1 |
1.5 Medical need | Section 2 | Analysis of condition, current treatment options | Section 1: scientific discussion | Section 2 | Section 1 |
1.6 Aims of treatment and expected treatment size | Section 2 | Analysis of condition, current treatment options | Section 1: scientific discussion | Not available | Section 1 |
2 Overall summary | |||||
2.1 Quality overall summary | Section 4 | Not available | Section 2: quality aspects | Section 7: quality | Section 6: quality |
2.2 Nonclinical overall summary | Section 4 | Not available | Section 2: nonclinical aspects | Section 7: nonclinical | Section 6: nonclinical |
2.2.1 Comments on relevant findings and potential implications/investigations required | Section 4 | Not available | Section 2: nonclinical aspects | Section 7: nonclinical | Section 3 |
2.2.2 Conclusions implicating benefit–risk assessment for humans | Section 4 | Not available | Section 2: nonclinical aspects | Section 7: nonclinical | Section 3 |
2.3.1 Human pharmacology: overall summary | Section 4 | Not available | Section 2: clinical aspects | Section 7: clinical pharmacology | Section 4 |
2.3.2 Human pharmacology conclusions | Section 6 | Not available | Section 2: clinical aspects | Section 7: clinical pharmacology | Section 6: clinical |
2.4.1 Clinical overall summary | Section 6 | Benefit | Section 2: clinical efficacy | Section 7: clinical | Section 6: clinical |
2.4.2 Clinical conclusions | Section 6 | Benefit | Section 2: clinical efficacy | Section 7: clinical | Section 6: clinical |
3 Identified benefits and risks | |||||
3.1 Listing of all benefits and justification for inclusion and exclusion
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