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 Common Drug Review (CDR) submission process, please email [email protected] 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 Common Drug Review (January 2013); . Common Drug Review Submission Guidelines for Manufacturers (January 2013); . 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 review team.  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 tables and 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.  Save the completed template as a 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 document into a complete package of Category 1 requirements in electronic format on a CD, DVD, or USB flash drive.  Please consult the Common Drug Review Submission Guidelines for Manufacturers for details on how to file the submission package.

TABLE OF CONTENTS

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 Manufacturer-Provided Details Characteristics 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. If a non-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 separate rows for each indication (add additional rows as necessary).

Requested Listing Criteria 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 with references 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 end points 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.

4.1 Quality Information

Section 4.1 must not exceed three pages.

Provide a brief overview of the quality of information 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 Provide a brief summary of the results Provide a test(s) using bullet(s) references Higher-order structure Provide the name of Provide a brief summary of the results Provide a test(s) using bullet(s) references Purity Provide the name of Provide a brief summary of the results Provide a test(s) using bullet(s) references 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).

4.2 Pivotal 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 Provide a brief State the study objectives Therapeutic area and key name description of the characteristics study design

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

Characteristics Details for (provide study name) STUDY Objective e.g., Pivotal pharmacokinetic study, pivotal efficacy and safety study DESIGN 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 Randomized (N) # POPUL Inclusion criteria Major criteria only ATION 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 DURATI Run-in Specify the duration ON Treatment Specify the duration Follow-up Specify the duration OU Primary End Point(s) Define the end point TCO Other End Points MES

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.  Summarize the patient disposition for the study in the table below.

Summary of Patient Disposition for (insert study name) Provide Study Name Disposition 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 a Please 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 end points of the study.

Safety Results Summarize the key safety end points of the study.

4.2.2 Name of Clinical Study 2 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 description of the study (one paragraph).  Complete the table below with all of the requested information.

Characteristics Details for [Provide study name] STUDY Objective e.g., Pivotal pharmacokinetic study, pivotal efficacy and safety study DESIGN 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 Randomized (N) # POPUL Inclusion criteria Major criteria only ATION 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 DURATI Run-in Specify the duration ON Treatment Specify the duration Follow-up Specify the duration OU Primary End Point(s) Define the end point TCO Other End Points MES

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) Provide Study Name Disposition 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 a Please 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 end points of the study.

Safety Results Summarize the key safety end points of the study

4.2.3 Summary of Safety

Section 4.2.3 must not exceed three pages.

In this section of the template, the manufacturer will summarize the key safety data for 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) Comparison of SEB versus Pharmacokinetics SEBa Reference Producta Reference Product AUC Difference (CI); P value Cmax Tmax (h) T1/2 (h) Bioavailability Degradation a Please 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

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.

6.1 Manufacturer’s Rationale for Extrapolation Please provide the rationale for any extrapolation of data to other indications with references to the sections in the Common Technical Document where complete details are located.

6.2 Health Canada’s Conclusion on Extrapolation Please provide Health Canada’s conclusions regarding the extrapolation of data to other indications using the exact wording that is stated in the official documentation (e.g., Health Canada’s Biologics Safety and Efficacy Assessment Report [BSEAR] and/or Clarifaxes). Please ensure that the statements are appropriately referenced to allow the reader to locate the source of the statements.

6.3 International Regulatory Conclusions on Extrapolation Please limit the information in this section to issues related to indications that were approved by Health Canada for the SEB under review (or those that are likely to be approved, in the case of a submission filed on a pre-NOC basis). CADTH considers foreign regulator discussions regarding indications that are not approved in Canada to be beyond the scope of the CDR review.

Please provide a brief overview of the following (if applicable):  European Medicines Agency’s conclusions regarding the extrapolation of indications.  US Food and Drug Administration’s conclusions regarding the extrapolation of indications.  Australian Therapeutic Goods Administration’s conclusions regarding the extrapolation of indications.

Please ensure that all statements are appropriately referenced.

6.4 CDR Comments on Extrapolation

7. COST COMPARISON

 Summarize the cost differential between the SEB compared with the reference product in a brief paragraph.  Provide the following information in a table (an example is provided below):  price of the SEB for all strengths per smallest unit to four decimal places;  price of the reference product per smallest unit to four decimal places;  sources of price information must be provided as footnotes below the table.  Clearly identify the name of the SEB, name of the reference product, and the indication(s) in the title of the table.  If the recommended dosage for the SEB and/or reference product varies across different indications, please provide a separate cost for each indication.

TABLE: COST COMPARISON OF SEB AND THE REFERENCE PRODUCT FOR INDICATION Recommended Average Drug Drug / Comparator Strength Dosage Form Price ($)b Dosec Cost ($) SEBa $X.XXXX Reference producta $X.XXXX

a Please rename these row headings with brand names of the SEB and the reference product. b Provide sources for price information. c Provide sources for the dosage information.

CDR Reviewer Comments Regarding Cost Information

To be completed by CDR Reviewers.

8. DISCUSSION

APPENDIX 1: ADDITIONAL DATA

Please include any large tables or figures in this section of the template. Please ensure the following is included:  All items in this section must be well-labelled (e.g., Table 6: Adverse Events from Study X).  All items in this section must be clearly referenced in the main body of the template. For example, “please see Table 6 in Appendix 1 for complete details regarding the adverse events reported in the Study X.”

APPENDIX 2: DRUG PLAN LISTING STATUS FOR REFERENCE PRODUCT

For each indication that is approved by Health Canada for the SEB (or likely to be approved, in the case of a submission filed on a pre-NOC basis), please provide the publicly available listing status and criteria for the reference product.

Step 1: Use the following abbreviations to complete the table. Use a separate row for each indication and add more rows if necessary.

Abbreviation Description EX Exception item for which coverage is determined on a case-by-case basis FB Full benefit NB Not a benefit RES Restricted benefit with specified criteria (e.g., special authorization, exception drug status, limited use benefit) UR Under review ‒ Information not available

Listing Status for (name of reference product) CDR-Participating Drug Plans Indicat N ion(s) BC AB SK MN ON NB PE NL YK NT NIHB DND VAC S Indicat ion 1 Indicat ion 2 Indicat ion 3 Indicat ion 4 AB = Alberta, BC = British Columbia, DND = Department of National Defence; MN = Manitoba; NIHB = Non-Insured Health Benefits Program; NL = Newfoundland and Labrador; NS = Nova Scotia; NT = Northwest Territories; ON = Ontario; PE = Prince Edward Island; SK = Saskatchewan; VAC =Veterans Affairs Canada; YK = Yukon.

Step 2: For all restricted benefit entries (RES), please state the criteria used by each drug plan. Use a separate table for each indication and add or delete rows as necessary. Restricted Benefit Criteria for (name of reference product) for the treatment of (state the indication) Drug Plan Criteria for Restricted Benefit Add name State the exact criteria

Add name State the exact criteria Add name State the exact criteria

APPENDIX 3: SUMMARY OF PATIENT INPUT

To be completed by CDR based on input received from patient groups.

REFERENCES

Please provide a numbered list of references using the Citing Medicine format. Each number in the reference list must correspond to the in-text citation for that reference.