Content of the Integrated Summaries of Efficacy and Safety

Required Elements for ISE

To support the evaluation of the study drug’s effectiveness for the claimed indication and recommended usage, the following elements are required within the ISE:

• A list of all studies relevant for the evaluation of the effectiveness with a summary description of critical study design features and study results
• An evaluation of key design features of all studies included in the assessment of effectiveness including similarities and differences and justification of inclusion
• Overall evaluation of effectiveness with all relevant data from controlled studies as well as other supportive studies. This evaluation is usually made in two parts:
  • Part 1: analysis of individual studies including comparisons of results
  • Part 2: analysis of combined studies (pooled analyses)
• Comparison of effectiveness in sub-populations to identify potential differences. Sub-populations should be defined based on the following elements:
  • Demographic factors (age, sex, and race)
  • Predefined or relevant intrinsic or extrinsic factors (e.g., region, disease severity, medical history, concomitant treatments or diseases…)
• Evaluation of information supporting the dosage recommendations and dose interval including differences in dosage in subgroups
• Dose-response information
• Comparison with alternative drugs
• Evaluation of the time course of effect, persistence of effect and tolerance
• Exploratory investigations

Required Elements for ISS

To support the evaluation of the study drug’s safety, the following elements are required within the ISS:

• A list of all studies relevant for the evaluation of safety with a summary description of critical study design features and study safety results
• Evaluation of Treatment Exposure
• Description of the population exposed to the study drug via demographics and baseline characteristics. In particular, it should include information about:
  • Age, gender, race
  • Severity of disease
  • Hospitalization
  • Impaired renal function
  • Concomitant illnesses
  • Concomitant use of particular medications
  • Geographical location
• Comprehensive analysis of Adverse Events (AEs), including all AEs, common AEs including evaluation of relationship to study drug, AEs leading to discontinuation, deaths, other serious AEs, other significant AEs, and Adverse Events of Special Interest (AESI). These analyses should be done overall and by organ system or syndrome
• Evaluation of patterns in laboratory parameters, including central tendencies, ranges of values and number of patients with abnormal values, clinically significant abnormalities and abnormalities leading to discontinuation, all including information about relationship to treatment
• Analysis of any other safety parameters of interest (vital signs, electrocardiogram (ECG, physical examination, etc.)
• Evaluation of special groups and situations:
  • Subgroups analyses of both intrinsic and extrinsic factors
  • Additional analyses should be provided on specific sub-populations related to drug-demographic interactions, drug-disease interactions, or drug-drug interactions
  • Evaluation of potential impact on specific situations like pregnancy and lactation, overdose or drug abuse, rebound effect, and effects on ability to drive or operate machinery or impairment of mental ability also need to be provided if applicable
• Long-term safety evaluation in terms of adverse effects and withdrawal effects
• Both the ISE and ISS are composed of text describing analyses of study results and pooled analyses results, together with key tables and figures supporting the analyses. Other supportive tables and figures, all listings and details of statistical approaches are included in an appendix.

For biological therapeutic proteins and other therapeutic products with a potential to produce immunogenic responses, an Integrated Summary of Immunogenicity (ISI) should also be submitted as part of the BLA package. The ISI presents the evaluation and mitigation for the investigational product regarding immunogenicity-related risks by assessing the link between pharmacokinetics (PK), pharmacodynamics (PD), efficacy and safety endpoints and bioanalytical signals (anti-drug antibodies, ADA) within each clinical study.

Learn More about Integrated Summaries

For more details on what the Integrated Summaries must include and the requirements for the electronic submission of clinical data, download the Comprehensive Guide to the Content of Integrated Summaries of Efficacy and Safety (ISE/ISS).

Series: Content of Integrated Summaries of Efficacy and Safety (ISE/ISS)

• Introduction to Integrated Summaries of Efficacy and Safety (ISE/ISS) 
• Content of the Integrated Summaries of Efficacy and Safety (ISE/ISS) – YOU ARE HERE
• Specific Requirements for Integrated Summaries of Efficacy and Safety(ISE/ISS) in FDA Submissions