Guide for elaboration of clinical study reports for biological product registration andor post registration change

Guide for Elaboration of Clinical Study Reports for Biological Product Registration and/or Post-Registration

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National Health Surveillance Agency | Anvisa

Guide for Elaboration of Clinical Study Reports for Biological Product

Registration and/or Post-Registration Change

Brasilia 2011

Copyright © 2011. National Health Surveillance Agency. Partial or full reproduction of this works is allowed provided the source is mentioned. Legal deposit in the National Library, according to Decree No. 1.825, dated December 20, 1907. 1st edition.

CEO CEO’s Assistant

Dirceu Aparecido Brás Barbano Luiz Roberto da Silva Klassmann

Directors Directors’ Assistants

Jaime César de Moura Oliveira Luciana Shimizu Takara

José Agenor Álvares da Silva Neilton Araujo de Oliveira

Maria Cecília Martins Brito Luiz Armando Erthal

Head of Cabinet

Vera Maria Borralho Bacelar

General Drug Management

Norberto Rech

Safety & Efficacy Assessment Management

Laura Gomes Castanheira

Elaboration and editing

AGÊNCIA NACIONAL DE VIGILÂNCIA SANITÁRIA

SIA Trecho 5, Área Especial 57, Lote 200

71205-050, Brasilia –

Federal District

Phone: (61) 3462-6000

Home page: www.anvisa.gov.br

Table of contents

1 Introduction ...................................................................................................................................................5

2 Clinical Report Content ......................................................................................................................5

2.1 Index ...................................................................................................................................................5

2.2 List of Abbreviations and Definition of Terms ........................................................................................5

2.3 General Introduction................................................................................................................................5

2.4 Ethics ......................................................................................................................................................6

2.5 Study Objectives ..............................................................................................................................6

2.6 Investigation Plan ...........................................................................................................................6

2.6.1 Study Design General Description ...........................................................................................6

2.6.2 Study Discussion .......................................................................................................................7

2.6.3 Population Screening.....................................................................................................................7

2.6.3.1 Inclusion Criteria...................................................................................................................7

2.6.3.2 Exclusion Criteria..................................................................................................................7

2.6.3.3 Removal of research subjects from therapy or evaluation...................................................7

2.6.3.4 Temporary Postponement of the Start of Test Product Administration……….. ...........................7

2.7 Protocol Amendments ...........................................................................................................................7

2.8 Treatments .........................................................................................................................................7

2.8.1 Treatments administered .............................................................................................................7

2.8.2 Identification of Test Product(s)……………… ..............................................................................7

2.8.3 Dose selection in the study ...........................................................................................................8

2.8.4 Concomitant and previous therapy.....................................................................................................8

2.9 Randomization and Masking ...........................................................................................................8

2.9.1 Allocation Method .......................................................................................................................8

2.9.2 Masking… ................................................................................................................................8

2.10 Efficacy and Safety Endpoints…......................................................................................................8

2.11 Quality Assurance Data................................................................................................................9

2.12 Statistical Methods..........................................................................................................................9

2.12.1 Sample Size Determination…………............................................................................................9

2.12.2 Populations analyzed ...................................................................................................................9

2.12.3 Statistical and Analytical Plans Foreseen............................................................................................9

2.12.4 Statistical and Analytical Plans Used ...........................................................................................9

2.12.5 Interim Analysis ................................................................................................................................9

2.12.6 Imputation of Data .......................................................................................................................9

2.13 Study Research Subjects..........................................................................................................9

2.13.1 Research Subject Layout .............................................................................................9

2.13.2 Protocol Deviations .....................................................................................................................10

2.14 – Efficacy Assessment ........................................................................................................................10

Guide for conduction of nonclinical and clinical studies for registration of alpha-interferons as biological product in development by comparability 3

2.14.1 Set of Data Analyzed……........................................................................................................10

2.14.2 Demographical and Base Characteristics ........................................................................................10

2.14.3 Measures to Verify Treatment Adherence………….. .....................................................................10

2.14.4 Efficacy Results.. ...................................................................................................................10

2.14.4.1 Efficacy Analysis…..................................................................................................................10

2.14.4.2 –Aspects of Statistical Analysis .............................................................................................11

2.14.4.3 –Adjustments for Covariates...................................................................................................11

2.14.4.4 Management of Exclusions and Missing Data..........................................................................11

2.14.4.5 Subgroup Analysis….. ...........................................................................................................11

2.14.4.6 Dose, Concentration and Response........................................................................................11

2.14.4.7 Drug Interactions and Drug-Disease Relation…………............................................................11

2.14.4.8 – Efficacy Conclusions... ........................................................................................................11

2.15 – Safety Assessment ...................................................................................................................11

2.15.1 – Level of exposure to the test product…...............................................................................12

2.15.2 – Adverse Events (AEs) ..............................................................................................................12

2.15.2.1 – Summary of Adverse Events ...............................................................................................12

2.15.2.2 – Analysis of Adverse Events ..............................................................................................12

2.15.2.3 – Listing of Adverse Events… .............................................................................................12

2.16 – Deaths and Other Serious Adverse Events.......................................................................................12

2.16.1 – Listing and Narrative of deaths and other adverse events. ........................................................12

2.16.2 – Analysis and Discussion of Deaths and Other Adverse Events.......................................................12

2.17 – Lab Assessment..........................................................................................................................12

2.17.1 – Patient Individual Alterations ..............................................................................................13

2.17.2 – Clinically Significant Individual Abnormalities..................................................................13

2.18 – Safety Conclusions ................................................................................................................13

2.19 – Discussion and General Conclusions.................................................................................................13

2.20 – Reference List ............................................................................................................................13

3 References ..................................................................................................................................................13

4 Guide for conduction of nonclinical and clinical studies for registration of alpha-interferons as biological product in development by comparability

1 Introduction

This Guide provides direction on the minimum information required and the adequate format for organization and presentation of a clinical report in a biological product and new biological product registration or post-registration application.

This Guide addresses only the format and content requirements for the presentation of clinical data in a registration or post-registration application.

With regard to the clinical studies required for biological product and new biological product registration and post-registration, the scientific bases and regulatory requirements with regard to the types of studies are established by the standards in effect and which must be complied with.

All other items not related to the clinical studies, as well as specific standards, must be complied with to obtain the health registration or an occasional post-registration change.

To evidence the efficacy and safety of a biological product, clinical studies conducted with the product must be submitted, according to requirements of Resolution RDC No. 55/2010 and its updates, it being recommended that the clinical report contain the minimum content and format as specified in this Guide.

2 Clinical Report Content

The report on the clinical studies conducted with the biological product must contain the minimum information described below.

2.1 Index

The report must contain an index made up of:

- The page number or other information to locate each section, including tables, figures and graphs;

- A list and locations of appendices, tabulations and any form of report, if provided.

2.2 List of Abbreviations and Definition of Terms

The list of abbreviations and definition of specific or uncommon terms or units of measurement used in the report must be provided.

2.3 General Introduction

The report must contain a general introduction informing the name and indication of the tested product and must contextualize the test drug and related diseases.

The scientific rationale used for clinical development of the product must also be explained.

This introduction must also briefly inform which studies were conducted, their development phases and objectives.


For each study, a summary of the study must be presented, with numerical information of the results, accompanied by the table below:

Name of finished test product (active ingredient)

Name of requesting company

Study title and code

Country(ies) where the study

was conducted

Manufacturers of the test product

Main coordinating investigator

Study start and end date

Study development phase

Objectives

Methodology (study design, including randomization and masking)

Number of research subjects (planned and analyzed)

Inclusion criteria

Exclusion criteria

Test product dosage and administration route

Numbers & manufacturing date of finished product used in the study

Treatment duration

Study control

Comparer product

Comparer product manufacturer

Main criteria for efficacy assessment (or main endpoints)

Main criteria for safety assessment (or main endpoints)

Statistical treatment

Summary of conclusions:

Efficacy

Safety

Report elaboration date

2.4 Ethics

It must be demonstrated that the study and all changes were analyzed and approved from the ethical point of view.

2.5 Study Objectives

The primary, secondary and exploratory objectives of the study must be described.

2.6 Investigation Plan

2.6.1 Study Design General Description

The general plan and study design must be described briefly.


The information supplied must include the treatments studied; the population of research subjects studied, and the number of research subjects to be included if the study is not concluded; the level and method of masking; the type(s) of control(s) used, such as active controls, placebos or historical controls; the method of allocation for each treatment arm of the study, such as randomization, stratification; the sequence and duration of all the study periods, including pre-randomization and post-treatment periods, the periods of abstinence and single therapy and the periods of double-blind treatment and flowchart with the assessment calendar.

2.6.2 Study Discussion

The control chosen and the study design used must be discussed and justified.

Known or potential problems associated with the study design or control group chosen must be discussed in function of the disease and specific therapies of the study.

2.6.3 Population Screening

2.6.3.1 Inclusion Criteria

The population and screening criteria used to insert the research subjects in the study must be described. Diagnostic

criteria used, as well as the specific requirements of pathologies must be presented.

Suitability of the population for the study purposes must be discussed.

2.6.3.2 Exclusion Criteria

The criteria and reasons for exclusion must be specified.

The possible impact of exclusions must be discussed in the report’s conclusion, or in an overview of safety and efficacy.

2.6.3.3 Removal of research subjects from therapy or evaluation

The predetermined reasons for removal of research subjects from the evaluation, if any, must be described, as well as the nature and duration foreseen for any follow-up in these research subjects.

2.6.3.4 Temporary Postponement of the Start of Test Product Administration

The criteria adopted to postpone the start of test product administration must be informed.

2.7 Protocol Amendments

The amendments made to the approved clinical protocol must be described briefly.

2.8 Treatments

2.8.1 Treatments administered

The treatments that were administered in each study arm, and for each study period, must be described, including the route, mode of administration and posology.

2.8.2 Identification of Test Product(s)

The text of the report must provide a brief description of the test product(s) and of the product used as comparer.


The formula, dosage and action mechanism of the products, in addition to other product characteristics, must be described.

The manufacturing codes and dates of the test product batches that were used in the study must be informed. Any modification

in the comparer product made during the study must be described.

2.8.3 Dose selection in the study

The doses and dose intervals used in the study must be informed, discussed and justified for all treatments.

2.8.4 Concomitant and previous therapy

The drugs or procedures that were authorized before and during the study must be described.

The effects of these concomitant therapies, like the occurrence of drug interactions or direct effects on the endpoints of the study and independent effects must be discussed.

2.9 Randomization and Masking

2.9.1 Allocation method

The methods used to allocate research subjects to the treatment groups must be described. Any uncommon

characteristics must be justified.

2.9.2 Masking

A brief description of the procedures used to perform the masking must be supplied, including the circumstances in which there would be removal of masking for an individual or all research subjects, such as, for example, in case of serious adverse events.

If the masking is deemed unnecessary to reduce the bias of some or all observations, this must be justified.

If the masking is deemed desirable but not viable, the reasons and implications must be discussed

2.10 Efficacy and Safety Endpoints

The efficacy and safety endpoints evaluated, including lab tests conducted, must be described. A flowchart with the

frequency and date of efficacy and safety measurements must be presented.

The means for gathering data of serious adverse events must be described.

The method for assessment of adverse events by the investigator, sponsor or by the audit team must be described and the criteria for this classification of adverse events must be provided.

The primary measures and parameters used to determine efficacy must be clearly specified and their choice justified.

The justification and discussion of the methods to evaluate efficacy and safety used must be presented.


2.11 Quality Assurance Data

Description of the measures adopted by the sponsor to assure quality and reliability of the data gathered must be provided. If no control system is used, this must be indicated and justified.

2.12 Statistical Methods

Must describe the statistical methods foreseen and used in analysis of the results, as well as description of the method used to calculate the sample size and description of the hypothesis test.

2.12.1 Sample Size Determination

Must present description of the method used to calculate the sample size, accompanied by scientific reference. The parameters used in its calculation must be described, accompanied by scientific justification for its choice.

In studies that intend to verify a difference between groups, the difference determined as acceptable between groups, to determine superiority or non-inferiority, must be clinically justified. Such justification must be accompanied by a scientific rationale with presentation of references, which must be annexed to the clinical report.

2.12.2 Populations analyzed

All the populations analyzed must be described and a categorization must be presented according to the type of analysis used, such as treatment intention, per protocol and/or safety population.

2.12.3 Statistical and Analytical Plans Foreseen

The statistical methods that were foreseen for analysis of the results of each efficiency and safety endpoint must be described in detail for analysis of subgroups and adjustments for covariates.

2.12.4 Statistical and Analytical Plans Used

A detailed description of the statistical methods used must be provided and, if different from those foreseen, justification must be presented for its alteration and a brief discussion on eventual implications of the change(s) for the study interpretation.

2.12.5 Interim Analysis

In cases where here is interim analysis to be conducted during the study, description and justification for such must be presented.

2.12.6 Imputation of Data

In cases where there is imputation of data, a justification must be presented explaining how the statistical analysis would be conducted in such cases.

2.13 Study Research Subjects

The information related to the study research subjects must be presented in descriptive form, accompanied by flowchart.

2.13.1 Research Subject Layout

To demonstrate the flow of research subjects during the study, the number of research subjects that were screened, excluded, the reason for exclusion, how many were randomized and how many completed each stage of the study must be informed, in addition to explaining the reasons for the exit of research subjects during the study.


A list of withdrawn research subjects must be annexed to the report, containing information on the treatment, patient number, gender, age, date of last visit, treatment duration, concomitant drugs and reason for exiting the study.

2.13.2 Protocol Deviations

All protocol deviations related to the inclusion and exclusion criteria and study conduction must be informed and justified.

2.14 – Efficacy Assessment

The results for all endpoints and exploratory analyses described in protocol must be presented.

2.14.1 Set of Data Analyzed

The exact number of research subjects that constitutes each set of data or each analysis population must be informed, as well as description of these research subjects, in terms of characteristics that made them to be analyzed in a certain population.

A table must be annexed to the report containing information on the research subjects and the data that was excluded from the efficacy analysis.

The reason for the exclusions must be informed.

2.14.2 Demographical and Base Characteristics

All data related to the demographic and base characteristics of the research subjects must be presented, as well as other factors that arise during the study that can affect the response.

Comparability of the treatment groups for all relevant characteristics must be indicated through tables or graphs.

For each analysis population, a table with the demographical characteristics must be presented. On describing the characteristics of the populations, the text/table must contain information on the demographical characteristics (gender, age, etc.), factors related to the disease, other factors that may influence the response to treatment and other relevant factors whenever pertinent.

Relevant individual data, like certain lab data and concomitant drugs, must be presented in the form of table annexed to the report.

2.14.3 Measures to Verify Treatment Adherence

The procedure adopted to verify adherence of research subjects to the treatment must be described and analysis of the adherence to treatment must be presented in the form of a table annexed to the report.

2.14.4 Efficacy Results

2.14.4.1 Efficacy Analysis

All data gathered on the efficacy parameters must be presented. It must contain comparisons of the primary and secondary endpoints

and pharmacodynamics in the different groups analyzed.

The analysis described must show the size of the difference found, accompanied by the variation measurements, confidence intervals and results of the hypothesis tests.

If the study data has been analyzed by an independent committee, these results must be presented, as well a comparison


of the results obtained by the committee and by the study team.

2.14.4.2 –Aspects of Statistical Analysis

The statistical analyses conducted must be described, with detailing of the statistical methods used, including discussion on the adjustments made for measurements of baseline demographical characteristics and concomitant therapies, management of exclusions and missing data, adjustments for multiple comparisons, special analyses of multicenter studies and adjustments in interim analyses.

In case there are changes in the analyses after removing the masking, these must be discussed and justified.

2.14.4.3 –Adjustments for Covariates

The selection and adjustment of demographic covariates or baseline measurements or any other prognostic covariate or factor must be described in this part, including the methods used to make the adjustments.

Any change in the method foreseen in the protocol must be described and justified.

2.14.4.4 Management of Exclusions and Missing Data

The number of research subjects that were excluded from each group and the quantity of missing data must be presented, preferably in the form of a table. The implications of this missing data in the study results, mainly in relation to the power, of the study must be discussed.

The reasons for the exclusions or absence of data must also be described.

2.14.4.5 Subgroup Analysis

Analysis of the pre-specified subgroups and analysis of pertinent subgroups must be described, even if not specified in protocol, provided the sample size allows obtainment of conclusions.

2.14.4.6 Dose, Concentration and Response

When the dose in each research subject varies, the actual doses received by the research subjects must be demonstrated and the individual doses of the patient must be tabulated.

2.14.4.7 Drug Interactions and Drug-Disease Relation

Any apparent relation between the response observed and the concomitant therapy and between the response and concomitant or previous disease must be informed.

2.14.4.8 – Efficacy Conclusions

The important conclusions on efficacy must be presented in a concise manner, considering the primary and secondary endpoints, pre-specified statistical approaches, as well as alternative analyses and exploratory analysis results.

2.15 – Safety Assessment

The analyses of data gathered on safety must be presented, considering the level of exposure to the test product, such as dose and treatment duration.

The identification and frequency of all adverse events must be presented, with an in-depth analysis of the adverse events that resulted in early withdrawal of research subjects and in death, whether these events are related to the test product or not.

The summary of data must be presented in the form of tables and graphs.


Listings of the individual data of the research subjects must be sent, as well as narratives of serious adverse events or events of interest to the test product.

In all tabulations and analyses, the events associated with the test product and/or comparer product must be described.

2.15.1 – Level of exposure to the test product

It must describe the extent to which the research subjects were exposed to the test drug, according to the number of research subjects exposed, exposure duration and dose to which they were exposed.

2.15.2 – Adverse Events (AEs)

2.15.2.1 – Summary of Adverse Events

The adverse events reported during the study must be described concisely, with presentation of tables and graphs, encompassing the adverse events of all the study arms.

The tables must include changes in the vital signs and lab alterations and listing of all adverse events, organized by corporal systems, by number of research subjects in each treatment group in which the event occurred, and by rate of occurrence.

2.15.2.2 – Adverse Event Analysis

A comparative analysis of the adverse events between the treatment and control groups must be provided.

2.15.2.3 – Listing of Adverse Events

All adverse events for each research subject, including the same event on various occasions, must be listed and annexed to this report.

The listing must include the duration, seriousness, gravity of the event and causality evaluation.

2.16 – Deaths and Other Serious Adverse Events

2.16.1 – Listing and Narration of deaths and other adverse events

A narrative of each death must be presented, as well as for other serious adverse events and other clinically important adverse events.

The description of these events must contain at least the identification and characteristics of the patient, the treatments to which he was subjected, the nature and intensity of the event, clinical course, relevant lab measures, measures adopted as a result of the event, if and when the drug was suspended, post-death findings and conclusion of the investigator and sponsor on the causality.

2.16.2 – Analysis and Discussion of Deaths and Other Adverse Events

A discussion on the meaning of the death, other serious adverse and other significant adverse events leading to withdrawal, dose reduction or establishment of concomitant therapy must be presented.

2.17 – Lab Assessment

A discussion of abnormal lab results identified must be presented, with comparison between the study groups.

A table containing all abnormal results per research subject must be annexed to the report.


2.17.1 – Patient Individual Alterations

An analysis of the individual lab changes of the research subject per treatment group must be presented.

2.17.2 – Clinically Significant Individual Abnormalities

Clinically relevant observations like vital signs, physical data and other observations related to safety must be provided with the comparative analysis between eh groups evaluated.

2.18 – Safety Conclusions

A discussion must be presented on the overall safety assessment of the test product, with highlight on events resulting from dose change or the need for concomitant drug and serious adverse events and deaths, which resulted in exclusion from the study.

The research subject groups of higher risk must be identified and special attention must be paid to potentially vulnerable subjects, who may be present in small number in the study.

2.19 – Discussion and General Conclusions

The efficacy and safety results and the risk-benefit ratio must be discussed.

The discussion and conclusions must clearly indicate any new or unexpected finding, with comments on its significance.

The clinical relevance and importance of the results must also be discussed in light of other existing scientific data. Any specific

benefit or special precaution required for individuals or groups of risk and the implications for the conduction of future studies must

be identified.

2.20 – Reference List

A list of articles from pertinent literature for evaluation of the study must be provided.

3 References

1. Guideline for Industry - Structure and Content of Clinical Study Reports (ICH Guidance Documents E3/1995)

2. Piaggio G, Elbourne DR, Altman DG, J. Pocock SJ, Evans SJW - for the CONSORT Group. Reporting of Noninferiority and Equivalence Randomized Trials -An Extension of the CONSORT Statement. JAMA 2006; 295

3. Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Ann Int Med 2010;152


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