Cdr Submission For(BRAND NAME)

Cdr submission for(BRAND NAME)

Template for Subsequent Entry Biologic Submission

Instructions for Manufacturers

Please read the instructions below and consult the recommended documentation before completing the template. If you have any questions regarding the CDR submission filing process or requirements, please with the complete details of your question(s).

Before Completing the Template:

Please review the following documents to ensure an understanding of the CDR procedures and submission guidelines:

Procedure for the CADTH Common Drug Review (August 2014)
Submission Guidelines for the CADTH Common Drug Review(August 2014)
CDR Updates (webpage) for any applicable information.

Completing the Template:

Complete all sections of the Subsequent Entry Biologic Submission Template with the exception of sections 5, 6.4,8 and Appendix 3, which will be completed by the CDR reviewers.

Do not exceed the page limitations in sections 4.1, 4.2.3, 4.3, 4.4, and 6.

Do not write in sections labelled “To be completed by CDR reviewers.”

Use 11-point Calibri font for text outside tablesand 10-point Calibri font for text inside tables.

References must be provided in the following format:

In-text citations must be numbered in order of appearance.
A numbered reference list must be provided in the Citing Medicine format at the end of the document in the References section.

Savethe completed template asa Word document using the following file name structure:

BrandName_Template

Submitting the Template to CDR:

Incorporate the completed subsequent entry biologic (SEB) submission template saved as a Word documentinto a complete package of category 1 requirements in electronic format on a CD, DVD, or USB flash drive.

Please consult the Submission Guidelines for the CADTH Common Drug Reviewfor details on how to file the submission package.

TABLE OF CONTENTS

ABBREVIATIONS

1. PRODUCT INFORMATION

1.1 Overview of the SEB Product

1.2 Overview of the Reference Product

2. INDICATIONS

2.1 Health Canada-Approved Indications

2.2 Indications Under Review by Health Canada

3. MANUFACTURER’S REQUESTED LISTING CRITERIA

3.1 Requested Listing Criteria

3.2 Rationale for Requested Listing Criteria

4. BIOSIMILARITY

4.1 Quality Information

4.2 Pivotal Clinical Studies

4.2.1 Name of Clinical Study 1

4.2.2 Name of Clinical Study 2

4.2.3 Summary of Safety

4.3 Pharmacokinetics

4.4 Immunogenicity

5. CRITICAL APPRAISAL OF CLINICAL STUDIES

5.1 Internal Validity

5.2 External Validity

6. EXTRAPOLATION OF INDICATIONS

6.1 Manufacturer’s Rationale for Extrapolation

6.2 Health Canada’s Conclusion on Extrapolation

6.3 International Regulatory Conclusions on Extrapolation

6.4 CDR Comments on Extrapolation

7. COST COMPARISON

8. DISCUSSION

APPENDIX 1: ADDITIONAL DATA

APPENDIX 2: DRUG PLAN LISTING STATUS FOR REFERENCE PRODUCT

APPENDIX 3: SUMMARY OF PATIENT INPUT

REFERENCES

ABBREVIATIONS

Please provide a list of abbreviations used in your completed template. The list should be in alphabetical order and should use the two-column table format shown in the example below.

AE / adverse event
AUC / area under the curve
CDEC / Canadian Drug Expert Committee
CDR / Common Drug Review
CI / confidence interval
Cmax / maximum concentration
CSR / Clinical Study Report
CTD / Common Technical Document
DB / double-blind
EMA / European Medicines Agency
FDA / Food and Drug Administration
RCT / randomized controlled trial
SAE / serious adverse event
SEB / subsequent entry biologic
WDAE / withdrawal due to adverse event

1. PRODUCT INFORMATION

1.1 Overview of the SEB Product

Please complete all sections of the following table

Characteristics / Manufacturer-Provided Details
Subsequent Entry Biologica / Reference Producta
Brand name:
Non-proprietary name:
Manufacturer:
Strength(s):
Dosage form:
Route of administration:
Drug Identification Number(s):
Therapeutic classification:
Excipients
Impuritiesb

aPlease rename these column headings with brand names of the SEB and the reference product.

bInclude both product and process-related impurities.

Please provide a brief summary of the similarities and differences between the SEB and the reference product, particularly with respect to the following:

pharmaceutical form and composition
the dosage form, strength, and route of administration
purity and impurities.

1.2 Overview of the Reference Product

Please provide a brief description of the reference product that was used to apply for market authorization in Canada. Clearly state if the reference biologic drug is authorized for sale and marketed in Canada. Ifanon-Canadian reference biologic drug was used, briefly explain the rationale for this choice.

2.INDICATIONS

2.1 Health Canada-Approved Indications

Please complete the table (add rows as necessary) with the following information:

Indications ‒ State the exact wording of each indication in a separate row.
Extrapolation ‒ Indicate if the indication was approved by Health Canada based on extrapolation of clinical data.

Indication(s) / Extrapolation
State exact wording of indication / Yes / No
State exact wording of indication / Yes / No
State exact wording of indication / Yes / No

2.2 Proposed Indications under Review by Health Canada

Please complete the table (add rows as necessary) with the following information:

Proposed Indications ‒ State the exact wording of each proposed indication in a separate row.
Anticipated date of NOC – Provide the month and year for the anticipated date NOC.

Proposed Indication(s) / Anticipated Date of NOC
State proposed indication / Month, Year
State proposed indication / Month, Year
State proposed indication / Month, Year

3. MANUFACTURER’S REQUESTED LISTING CRITERIA

3.1 Requested Listing Criteria

Please state the requested listing criteria in the table below, using a separate row for each indication (add additional rows as necessary).

Requested Listing Criteria for Indications to be Reviewed by the CADTH Common Drug Review
State the requested listing criteria for indication 1
State the requested listing criteria for indication 2
State the requested listing criteria for indication 3
State the requested listing criteria for indication 4

3.2 Rationale for Requested Listing Criteria

Provide a clear rationale for all of the requested listed criteria noted in section 3.1 withreferences where appropriate.

4. BIOSIMILARITY

In section 4 of the template, the manufacturer will summarize the key data submitted for the Health Canada review. The required information or evidence must be succinct and entered directly into the template. Please summarize comparative pharmacokinetic and immunogenicity data in sections 4.3 and 4.4 respectively, even if these were pre-specified endpoints of the pivotal trials (i.e., please do not report these data multiple times in the template).

References must be provided in the following format:

•In-text citations must be numbered in order of appearance.

•A numbered reference list must be provided using the Citing Medicine format in the References section located at the end of the template.

4.1QualityInformation

Section 4.1 must not exceed three pages.

Provide a brief overview of the quality ofinformation that was used as the basis for demonstrating similarity between the SEB and the reference product. Focus on the key results that were used to justify the reduced non-clinical and clinical data packages for the SEB. Keep the description of the tests and the results succinct and provide references for where the complete details can be located. Whenever possible, use a table to present findings.

Table Example

Test Method(s) / Summary of Results / Reference(s)
Primary structure

Provide the name of test(s) using bullet(s)

/ Provide a brief summary of the results / Provide referencesa
Higher-order structure

Provide the name of test(s) using bullet(s)

/ Provide a brief summary of the results / Provide referencesa
Purity

Provide the name of test(s) using bullet(s)

/ Provide a brief summary of the results / Provide referencesa

aReferences should allow the reader to quickly locate the detailed results and discussions of these analyses in the submission (e.g., Section XX, Module X.X.X).

4.2Pivotal Clinical Studies

Please provide a brief introduction to the pivotal clinical studies and complete the table below. Please clearly identify all pivotal trials.

Study Name / Design / Objectives / Population
State the study name / Provide a brief description of the study design / State the study objectives / Therapeutic area and key characteristics

4.2.1 Name of Clinical Study 1

Using the format provided below, please provide details of each clinical trial conducted to establish the efficacy of the SEB relative to the reference product.Add additional tables and sections as needed.

a) Study Characteristics

Provide a brief descriptionof the study(one paragraph).
Complete the table below with all of the requested information.

Characteristics / Details for (provide study name)
Study
Design / Objective / e.g., Pivotal pharmacokinetic study, pivotal efficacy and safety study
Blinding / Blinding of investigators and/or patients (e.g., double-blind, open-label)
Study period / State the beginning and end dates of the study (YYYY-MM to YYYY-MM)
Study centres / List the number of centres and the countries involved
Design / e.g., equivalence or non-inferiority
Study Population / Randomized (N) / #
Inclusion criteria / Major criteria only
Exclusion criteria / List only major/select criteria
Drugs / Intervention / Drug, dose, route of administration, frequency of administration
Comparator(s) / Drug, dose, route of administration, and frequency of administration, for each comparator
Duration / Run-in / Specify the duration
Treatment / Specify the duration
Follow-up / Specify the duration
Outcomes / Primary End Point(s) / Define the endpoint
Other End Points
Notes / Publications /

Provide references for all publications related to this study.
Provide the clinicaltrials.gov identification code (e.g., NCTXXXXXXXX).

Intervention and Comparators

Briefly describe the interventions employed in the trial, including dose, route and frequency of administration, duration, etc.
Please clearly state if a non-Canadian reference product was used in the trial.
If the trial is blinded, indicate the use of matched placebos, double-dummy controls, etc.
Describe any concomitant medications required or permitted during the study.

Outcomes

Describe the key efficacy and safety outcomes for the study (definitions and measurement).

Statistical Analyses

Briefly describe the statistics protocol for equivalence and/or non-inferiority testing.
Briefly describe the rationale for the equivalence and/or non-inferiority margins used.
Briefly define analysis sets (e.g., intention to treat or per-protocol).
Please provide references for where the complete details can be located (e.g., sections of the Common Technical Document and/or Clinical Study Report).

b) Results

Baseline Characteristics

Summarize major/relevant demographic and baseline characteristics using a table.
Comment on similarity/differences among groups and across studies.
Comment on concomitant conditions, medications, and other relevant issues.

Patient Disposition

Provide a brief paragraph summarizing the patient disposition for the study.
Summarizethe patient disposition for the study in the table below.

Summary of Patient Disposition for (insert study name)

Disposition / Provide Study Name
SEBa / Reference Producta
Screened, N / N / N
Randomized, N / N / N
Discontinued, N (%) / N (%) / N (%)
WDAEs, N (%) / N (%) / N (%)
Withdrawal due to SAEs, N (%) / N (%) / N (%)
Lost to follow-up, N (%) / N (%) / N (%)
Intention to treat, N / N / N
Per-protocol, N / N / N
Safety, N / N / N

aPlease rename these column headings with brand names of the SEB and the reference product.

SAE = serious adverse event; WDAE = withdrawal due to adverse event.

Efficacy Results

Summarize the key efficacy endpoints of the study.

Safety Results

Summarize the key safety endpoints of the study.

4.2.2 Name of Clinical Study 2

a) Study Characteristics

Provide a brief description of the study (one paragraph).
Complete the table below with all of the requested information.

Characteristics / Details for [Provide study name]
Study
Design / Objective / e.g., Pivotal pharmacokinetic study, pivotal efficacy and safety study
Blinding / Blinding of investigators and/or subjects (e.g., double-blind, open-label)
Study period / State the beginning and end dates of the study (YYYY-MM to YYYY-MM)
Study centres / List the number of centres and the countries involved
Design / e.g., equivalence or non-inferiority
Study Population / Randomized (N) / #
Inclusion criteria / Major criteria only
Exclusion criteria / List only major/select criteria
Drugs / Intervention / Drug, dose, route of administration, frequency of administration
Comparator(s) / Drug, dose, route of administration, and frequency of administration, for each comparator
Duration / Run-in / Specify the duration
Treatment / Specify the duration
Follow-up / Specify the duration
Outcomes / Primary End Point(s) / Define the endpoint
Other End Points
Notes / Publications /

Provide references for all publications related to this study.
Provide the clinicaltrials.gov identification code (e.g., NCTXXXXXXXX).

Intervention and Comparators

Briefly describe the interventions employed in the trial, including dose, route and frequency of administration, duration, etc.
Please clearly state if a non-Canadian reference product was used in the trial.
If the trial is blinded, indicate the use of matched placebos, double-dummy controls, etc.
Describe any concomitant medications required or permitted during the study.

Outcomes

Describe the key efficacy and safety outcomes for the study (definitions and measurement).

Statistical Analyses

Briefly describe the statistics protocol for equivalence and/or non-inferiority testing.
Briefly describe the rationale for the equivalence and/or non-inferiority margins used.
Briefly define analysis sets (e.g., intention to treat or per-protocol).
Please provide references for where the complete details can be located (e.g., sections of the Common Technical Document and/or Clinical Study Report).

b) Results

Baseline Characteristics

Summarize major/relevant demographic and baseline characteristics using a table.
Comment on similarity/differences among groups and across studies.
Comment on concomitant conditions, medications, and other relevant issues.

Patient Disposition

Provide a brief paragraph summarizing the patient disposition for study.
Summarize the patient disposition for the study in the table below.

Summary of Patient Disposition for (insert study name)

aPlease rename these column headings with brand names of the SEB and the reference product.

SAE = serious adverse event; WDAE = withdrawal due to adverse event.

Efficacy Results

Summarize the key efficacy endpoints of the study.

Safety Results

Summarize the key safety endpoints of the study

4.2.3Summary of Safety

Section 4.2.3 must not exceed three pages.

In this section of the template, the manufacturer will summarize the key safety datafor the SEB. The required information or evidence must be succinct and entered directly into the template. Whenever possible, please focus on integrated safety data in this section.Avoid restating the results of the individual clinical studies as these should be summarized in sections 4.2.1 and 4.2.2.

References must be provided in the following format:

•In-text citations must be numbered in order of appearance.

•A numbered reference list must be provided in the Citing Medicine format at the end of the document in the References section.

a) Safety Evaluation Plan

Provide a brief overview of the overall safety evaluation plan for the SEB, with references to documents where the complete details can be located (e.g., module 2.7.4 of the Common Technical Document). Please keep this description to a maximum of a half page.

b) Safety Populations Evaluated

Summarize the largest controlled safety population that is addressed in the Summary of Clinical Safety module of the Common Technical Document.Please keep this description to a maximum of a half page.

c) Overview of Safety

Summarize the key findings of the safety evaluation for the SEB. Whenever possible, focus on the comparative safety of the SEB as compared with the reference product. For important statements, provide references for where complete details can be located in the submission (e.g., module 2.7.4, module 2.5, Clinical Study Reports).If you wish to include large tables (i.e., in excess of a half page) as part of this summary, please include them in a well-labelled appendix.

4.3 Pharmacokinetics

Section 4.3 must not exceed one page.

Please summarize the evidence that demonstrates that the pharmacokinetic properties of the SEB are similar to those of the reference product, including any statistical comparisons between the SEB and the reference product. Include a summary table displaying key data.

Table Example (please adjust as necessary)

Pharmacokinetics / SEBa / Reference Producta / Comparison of SEB versus Reference Product
AUC / Difference (CI); P value
Cmax
Tmax (h)
T1/2 (h)
Bioavailability
Degradation

aPlease rename these column headings with brand names of the SEB and the reference product.

AUC = area under the curve; CI = confidence interval; Cmax = maximum concentration; SEB = subsequent entry biologic.

4.4 Immunogenicity

Section 4.4 must not exceed one page.

Summarize the methods and results of immunogenicity assays performed in the study. Provide the proportion of patients in each treatment group that developed antidrug antibodies and provide a description of the type of antibodies that were detected (e.g., neutralizing antibodies, cross-reactivity antibodies). Include a summary table displaying key data if appropriate.

5.CRITICAL APPRAISAL OF CLINICAL STUDIES

5.1 Internal Validity

To be completed by CDR reviewers

5.2 External Validity

To be completed by CDR reviewers

6.EXTRAPOLATION OF INDICATIONS

Section 6 must not exceed five pages.

If the SEB has been granted approval for indications based on extrapolation of data to other indications, please complete both sections 6.1 and 6.2. If the SEB has not been granted approval for any indications based on extrapolation, please indicate “Not applicable” for each of the extrapolation sections below.