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CDR SUBMISSION FOR (BRAND NAME)

Template for Subsequent Entry Biologic Submission

Instructions for ManufacturersPlease 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.

Common Drug Review Subsequent Entry Biologic Submission Template

http://www.cadth.ca/en/products/cdr/cdr-update

http://www.cadth.ca/media/cdr/process/CDR_Submission_Guidelines_e.pdf

http://www.cadth.ca/media/cdr/process/CDR_Procedure_e.pdf

mailto:[email protected]


TABLE OF CONTENTS

ABBREVIATIONS...........................................................................................................................................3

1. PRODUCT INFORMATION........................................................................................................................4

1.1 Overview of the SEB Product.............................................................................................................4

1.2 Overview of the Reference Product...................................................................................................4

2. INDICATIONS...........................................................................................................................................5

2.1 Health Canada-Approved Indications................................................................................................5

2.2 Indications Under Review by Health Canada.....................................................................................5

3. MANUFACTURER’S REQUESTED LISTING CRITERIA..................................................................................6

3.1 Requested Listing Criteria..................................................................................................................6

3.2 Rationale for Requested Listing Criteria............................................................................................6

4. BIOSIMILARITY.........................................................................................................................................7

4.1 Quality Information...........................................................................................................................7

4.2 Pivotal Clinical Studies.......................................................................................................................8

4.2.1 Name of Clinical Study 1............................................................................................................................8

4.2.2 Name of Clinical Study 2..........................................................................................................................11

4.2.3 Summary of Safety...................................................................................................................................14

4.3 Pharmacokinetics.............................................................................................................................15

4.4 Immunogenicity...............................................................................................................................16

5. CRITICAL APPRAISAL OF CLINICAL STUDIES...........................................................................................17

5.1 Internal Validity...............................................................................................................................17

5.2 External Validity...............................................................................................................................17

6. EXTRAPOLATION OF INDICATIONS........................................................................................................18

6.1 Manufacturer’s Rationale for Extrapolation....................................................................................18

6.2 Health Canada’s Conclusion on Extrapolation.................................................................................18

6.3 International Regulatory Conclusions on Extrapolation...................................................................18

6.4 CDR Comments on Extrapolation.....................................................................................................19

7. COST COMPARISON...............................................................................................................................20

8. DISCUSSION...........................................................................................................................................21

APPENDIX 1: ADDITIONAL DATA................................................................................................................22

APPENDIX 2: DRUG PLAN LISTING STATUS FOR REFERENCE PRODUCT.....................................................23

APPENDIX 3: SUMMARY OF PATIENT INPUT.............................................................................................24

REFERENCES..............................................................................................................................................25


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 eventAUC area under the curveCDEC Canadian Drug Expert CommitteeCDR Common Drug ReviewCI confidence intervalCmax maximum concentrationCSR Clinical Study ReportCTD Common Technical DocumentDB double-blindEMA European Medicines AgencyFDA Food and Drug AdministrationRCT randomized controlled trialSAE serious adverse eventSEB subsequent entry biologicWDAE 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 DetailsSubsequent Entry Biologica Reference Producta

Brand name:Non-proprietary name:Manufacturer:Strength(s):Dosage form:Route of administration:Drug Identification Number(s):Therapeutic classification:ExcipientsImpuritiesb

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 IndicationsPlease 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) ExtrapolationState exact wording of indication Yes / NoState exact wording of indication Yes / NoState exact wording of indication Yes / No

2.2 Proposed Indications under Review by Health CanadaPlease 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 NOCState proposed indication Month, YearState proposed indication Month, YearState proposed indication Month, Year


3. MANUFACTURER’S REQUESTED LISTING CRITERIA

3.1 Requested Listing CriteriaPlease state the requested listing criteria in the table below; using separate rows for each indication (add additional rows as necessary).

Requested Listing CriteriaState the requested listing criteria for indication 1

State the requested listing criteria for indication 2



3.2 Rationale for Requested Listing CriteriaProvide 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 ExampleTest 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


referencesa

Purity Provide the name of


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).


4.2 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 PopulationState 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 1Using 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)

STU

DYDE

SIGN

Objective e.g., Pivotal pharmacokinetic study, pivotal efficacy and safety studyBlinding 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 involvedDesign e.g., equivalence or non-inferiority

STU

DY

POPU

LATI

ON Randomized (N) #

Inclusion criteria Major criteria onlyExclusion criteria List only major/select criteria

DRU

GS

Intervention Drug, dose, route of administration, frequency of administration

Comparator(s) Drug, dose, route of administration, and frequency of administration, for each comparator

DURA

TIO

N Run-in Specify the durationTreatment Specify the durationFollow-up Specify the duration

OU

TCO

ME

S

Primary End Point(s) Define the end point

Other End Points

NO

TES 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)

DispositionProvide Study Name

SEBa Reference Producta

Screened, N N NRandomized, N N NDiscontinued, 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 NPer-protocol, N N NSafety, 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 ResultsSummarize the key efficacy end points of the study.

Safety ResultsSummarize the key safety end points of the study.


4.2.2 Name of Clinical Study 2Using 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]

STU

DYDE

SIGN

Objective e.g., Pivotal pharmacokinetic study, pivotal efficacy and safety studyBlinding 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 involvedDesign e.g., equivalence or non-inferiority

STU

DY

POPU

LATI

ON Randomized (N) #

Inclusion criteria Major criteria onlyExclusion criteria List only major/select criteria

DRU

GS

Intervention Drug, dose, route of administration, frequency of administration

Comparator(s) Drug, dose, route of administration, and frequency of administration, for each comparator

DURA

TIO

N Run-in Specify the durationTreatment Specify the durationFollow-up Specify the duration

OU

TCO

ME

S

Primary End Point(s) Define the end point

Other End Points

NO

TES 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)

Disposition Provide Study NameSEBa Reference Producta

Screened, N N NRandomized, N N NDiscontinued, 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 NPer-protocol, N N NSafety, 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 ResultsSummarize the key efficacy end points of the study.

Safety ResultsSummarize 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 PlanProvide 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 EvaluatedSummarize 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 SafetySummarize 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 valueCmaxTmax (h)T1/2 (h)BioavailabilityDegradation

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 ExtrapolationPlease 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 ExtrapolationPlease 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 ExtrapolationPlease 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

Drug / Comparator Strength Dosage Form Price ($)b RecommendedDosec

Average Drug Cost ($)

SEBa $X.XXXXReference 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 DescriptionEX Exception item for which coverage is determined on a case-by-case basisFB Full benefitNB Not a benefitRES 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)

Indication(s)CDR-Participating Drug Plans

BC AB SK MN ON NB NS PE NL YK NT NIHB DND VACIndication 1Indication 2Indication 3Indication 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 BenefitAdd name State the exact criteriaAdd name State the exact criteriaAdd 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.

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