Common Drug Review
New Combination Product
Submission Template
Template for a New Combination Product (Funded Components or CADTHDesignated Tailored CDR Review) 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
email requests@cadth.ca 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 (August 2014)
 Submission Guidelines for the CADTH Common Drug Review (August 2014)
 Category 1 Requirements for a Tailored CDR Review: New Combination Product (Funded
Components or CADTH-Designated Tailored CDR Review) Submission (March 2015)
 CDR Updates (webpage) for any applicable information
Completing the Template:
 Complete all sections of the template with the exception of the following: executive summary, 2.2,
3.3, 4, and appendix 2 which will be completed by the CDR reviewers.
 Do not exceed the page limitations when noted.
 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.
 Provide clear references to source documentation for all bioequivalence, efficacy, and safety data
provided 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 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 new combination product 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 Submission Guidelines for the CADTH Common Drug Review (August 2014) for
details on how to file the submission package.
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CDR SUBMISSION FOR (BRAND NAME)
TABLE OF CONTENTS
ABBREVIATIONS ............................................................................................................................................ 3
EXECUTIVE SUMMARY .................................................................................................................................. 4
1
PRODUCT INFORMATION ..................................................................................................................... 5
1.1 Health Canada-Approved Indications .............................................................................................. 5
1.2 Requested Listing Criteria ................................................................................................................ 5
1.3 Manufacturer’s Rationale and Place in Therapy for the Combination ............................................ 5
2
1.3.1
Rationale..............................................................................................................................................5
1.3.2
Place in therapy ...................................................................................................................................5
1.3.3
Dosing Considerations .........................................................................................................................6
CLINICAL EVIDENCE .............................................................................................................................. 6
2.1 Pivotal Clinical Studies ..................................................................................................................... 6
2.1.1
Name of Clinical Study 1 ......................................................................................................................6
2.1.2
Name of Clinical Study 2 ......................................................................................................................9
2.2 Critical Appraisal of Pivotal Clinical Studies ................................................................................... 11
2.2.1
Internal Validity .................................................................................................................................11
2.2.2
External Validity.................................................................................................................................11
2.3 Summary of Safety ......................................................................................................................... 12
2.3.1
Safety Evaluation Plan .......................................................................................................................12
2.3.2
Safety Populations Evaluated ............................................................................................................12
2.3.3
Overview of Safety ............................................................................................................................12
2.4 Bioequivalence ............................................................................................................................... 13
3
PHARMACOECONOMIC EVALUATION ................................................................................................ 14
3.1 Manufacturer-Submitted Cost Information................................................................................... 14
3.2 Manufacturer-Submitted Information Regarding Current Patent Status ..................................... 15
3.3 Critical Appraisal of Cost Information ............................................................................................ 15
4
DISCUSSION ........................................................................................................................................ 16
APPENDIX 1: DRUG PLAN LISTING STATUS FOR INDIVIDUAL COMPONENTS ............................................. 17
APPENDIX 2: SUMMARY OF PATIENT INPUT .............................................................................................. 19
REFERENCES ................................................................................................................................................ 20
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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
AUC
CDEC
CDR
CI
CSR
DB
FDC
RCT
SAE
WDAE
adverse event
area under the curve
Canadian Drug Expert Committee
CADTH Common Drug Review
confidence interval
Clinical Study Report
double-blind
fixed-dose combination
randomized controlled trial
serious adverse event
withdrawal due to adverse event
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EXECUTIVE SUMMARY
To be completed by CDR reviewers.
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1 PRODUCT INFORMATION
1.1
Health Canada-Approved Indications
Please complete the table (add rows as necessary) with the following information:
 Indications ‒ State the exact wording of each indication to be reviewed by CDR in a separate
row.
Indication(s) to be Reviewed by CDR
State the exact wording of the indication
State the exact wording of the indication
State the exact wording of the indication
1.2 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
State the requested listing criteria for indication 1
State the requested listing criteria for indication 2
State the requested listing criteria for indication 3
1.3
Manufacturer’s Rationale and Place in Therapy for the Combination
Not to exceed two pages of Calibri 11-point font. The required information or evidence must be
succinct and entered directly into the template. References must be provided and are to be included in a
list of references at the end of the template.
The required information or evidence in this section includes:
1.3.1 Rationale
 Provide the therapeutic and pharmacological rationale for the combination.
 Does the use of the combination overcome any issues or problems related to the administration of
the components individually?
1.3.2 Place in therapy
 Provide your perspective on the place in therapy for the new combination product.
 Would the components be the drugs of choice as separate medicines?
 Does the combination contain the most commonly prescribed doses of the individual components?
 Should this combination be used for initiating therapy?
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1.3.3 Dosing Considerations
 Is therapy initiated with the combination or is a switch to the combination necessary after titration?
 Is there a lack of ability to titrate doses due to the combination product not being available in the
necessary dosage strengths?
 Will increasing the dose of one component result in an unnecessary dose increase of the other
component?
2 CLINICAL EVIDENCE
In section 2 of the template, the manufacturer will summarize the key data submitted for the Health
Canada review.
2.1
Pivotal Clinical Studies
The information in section 2.1 must be summarized as succinctly as possible (typically this should not
exceed a total of 10 pages of information in 11-point Calibri font). The required information must be
entered directly into the template. Please summarize comparative pharmacokinetic data in section 2.4,
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). Spaces for two clinical studies are provided in the template, but please
add or remove sections, as required.
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.
Please provide a brief introduction to the pivotal clinical studies and complete the table below. Please
clearly identify all pivotal trials.
Study Name
State the study
name
State the study
name
State the study
name
Design
Provide a brief
description of the
study design
Provide a brief
description of the
study design
Provide a brief
description of the
study design
Objectives
State the study objectives
Population
Therapeutic area and key
characteristics
State the study objectives
Therapeutic area and key
characteristics
State the study objectives
Therapeutic area and key
characteristics
2.1.1 Name of Clinical Study 1
Using the format provided below, please provide details of each clinical trial conducted to establish the
efficacy of the new combination product. Add additional tables and sections as needed.
A. Study Characteristics
 Provide a brief description of the study (one paragraph).
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 Complete the table below with all of the requested information.
NOTES
OUTCOMES
DURATION
DRUGS
STUDY
POPULATION
STUDY
DESIGN
Characteristics
Details for (provide study name)
Objective
Blinding
Study period
Study centres
Design
Randomized (N)
Inclusion criteria
Exclusion criteria
e.g., Pivotal efficacy and safety study
Blinding of investigators and/or patients (e.g., double-blind, open-label)
State the beginning and end dates of the study (YYYY-MM to YYYY-MM)
List the number of centres and the countries involved
e.g., equivalence or non-inferiority
#
Major criteria only
List only major/select criteria
Intervention
Drug, dose, route of administration, frequency of administration
Comparator(s)
Run-in
Treatment
Follow-up
Primary End Point(s)
Drug, dose, route of administration, and frequency of administration, for
each comparator
Specify the duration
Specify the duration
Specify the duration
Define the end point
Other End Points
Define the end points
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.
 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 superiority, 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).
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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 using a table similar to the example provided below.
Summary of Patient Disposition for (insert study name)
Disposition
Screened, N
Randomized, N
Discontinued, N (%)
WDAEs, N (%)
Withdrawal due to SAEs, N (%)
Lost to follow-up, N (%)
Intention to treat, N
Per-protocol, N
Safety, N
New Combination
N
N
N (%)
N (%)
N (%)
N (%)
N
N
N
a
Provide Study Name
Comparator 1a
Comparator 2a
N
N
N
N
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
N
N
N
N
N
N
Comparator 3a
N
N
N (%)
N (%)
N (%)
N (%)
N
N
N
a Please
rename these column headings with the non-proprietary names of the new combination product and the comparators.
SAE = serious adverse event; WDAE = withdrawal due to adverse event.
Efficacy
Summarize the results for the primary endpoint and key secondary endpoints
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CDR SUBMISSION FOR (BRAND NAME)
2.1.2 Name of Clinical Study 2
Using the format provided below, please provide details of each clinical trial conducted to establish the
efficacy of the new combination 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.
NOTES
OUTCOMES
DURATION
DRUGS
STUDY
POPULATION
STUDY
DESIGN
Characteristics
Details for (provide study name)
Objective
Blinding
Study period
Study centres
Design
Randomized (N)
Inclusion criteria
Exclusion criteria
e.g., Pivotal efficacy and safety study
Blinding of investigators and/or patients (e.g., double-blind, open-label)
State the beginning and end dates of the study (YYYY-MM to YYYY-MM)
List the number of centres and the countries involved
e.g., equivalence or non-inferiority
#
Major criteria only
List only major/select criteria
Intervention
Drug, dose, route of administration, frequency of administration
Comparator(s)
Run-in
Treatment
Follow-up
Primary End Point(s)
Drug, dose, route of administration, and frequency of administration, for
each comparator
Specify the duration
Specify the duration
Specify the duration
Define the end point
Other End Points
Define the end points
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.
 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 superiority, equivalence, and/or non-inferiority testing.
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 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 using a table similar to the example provided below.
Summary of Patient Disposition for (insert study name)
Disposition
Screened, N
Randomized, N
Discontinued, N (%)
WDAEs, N (%)
Withdrawal due to SAEs, N (%)
Lost to follow-up, N (%)
Intention to treat, N
Per-protocol, N
Safety, N
New Combinationa
N
N
N (%)
N (%)
N (%)
N (%)
N
N
N
Provide Study Name
Comparator 1a
Comparator 2a
N
N
N
N
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
N
N
N
N
N
N
Comparator 3a
N
N
N (%)
N (%)
N (%)
N (%)
N
N
N
a Please
rename these column headings with the non-proprietary names of the new combination product and the comparators.
SAE = serious adverse event; WDAE = withdrawal due to adverse event.
Efficacy
Summarize the results for the primary endpoint and key secondary endpoints
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2.2
2.2.1
Critical Appraisal of Pivotal Clinical Studies
Internal Validity
To be completed by CDR reviewers
2.2.2
External Validity
To be completed by CDR reviewers
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2.3
Summary of Safety
2.3 must not exceed three pages of 11-point Calibri font. In this section of the template, the
manufacturer will summarize the key safety data for the new combination product. 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.
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.
2.3.1 Safety Evaluation Plan
Provide a brief overview of the overall safety evaluation plan for the new combination product, 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.
2.3.2 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.
2.3.3 Overview of Safety
Summarize the key findings of the safety evaluation for the new combination product. Whenever
possible, focus on the comparative safety of the new combination product as compared with the
individual components. 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.
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2.4
Bioequivalence
Section 2.4 must not exceed three pages of information in 11-point Calibri font. The required
information or evidence must be succinct and entered directly into the template. References must be
provided and are to be included in a list of references at the end of the template.
The required information or evidence in this section includes:
 Evidence of bioequivalence of the combination with the individual components.
 A statement indicating whether the individual components have uncomplicated or complicated and
variable pharmacokinetic characteristics.
 Evidence that the pharmacokinetic properties (e.g., absorption) of the combination are similar to
those of the individual components.
Table 1: Bioequivalence Profile for Combination Product*†
Parameter
Component A
as Combination AB
Component A as
A + B‡
Component B
as Combination
AB
Component B as
A + B‡
AUC (0-T)
 Mean
 Standard deviation
 Coefficient of variance
 Ratio of relative means
 90% confidence interval
Cmax
 Mean
 Standard deviation
 Coefficient of variance
 Ratio of relative means
 90% confidence interval
Tmax
 Mean
 Standard deviation
 Coefficient of variance
*Add
columns to the table, as needed, to accommodate the number of components.
†In accordance with current Health Canada bioequivalence standards and data requirements.
‡Component A plus Component B, given concurrently.
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3 PHARMACOECONOMIC EVALUATION
3.1
Manufacturer-Submitted Cost Information
The required information or evidence must be succinct and entered directly into the template. Sources
of price information must be provided and are to be included as footnotes below the tables.

Provide price of the new combination product (price for all strengths per smallest unit to four
decimal places) and its daily cost compared with the price of individual components.
Table 2: Cost Comparison of New Combination Product and Individual Components
Drug / Comparator
Combination product
generic name
(Brand name)
Individual component A
(brand and generics)
Individual component B
(brand and generics)
Individual component up to
Z, if applicable
(brand and generics)
Total (A+B+…+Z)



Strength
Dosage
Form
Price ($)
Recommended
Daily Use
Daily Drug
Cost ($)
A mg/B mg/...Z
mg
$A/B/…/Z
$
A mg
$A
$ daily A
B mg
$B
$ daily B
Z mg
$Z
$ daily Z
$ Total of
Individual
Components
Include any relevant information on patent expiration for the individual components as a footnote
to the table.
Provide source and where applicable, indicate if the price is a confidential price submitted by the
manufacturer.
Summarize cost differences and potential cost savings of the new combination product compared
with individual components.
 Summary of potential cost savings based on Table 1.
 Quantify the potential daily savings or price difference of the new combination product
compared with the price of individual components together; provide a range on the cost
difference or daily savings.
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Cost Comparison Table
A list of prices for all appropriate comparators. Comparators are not restricted to drugs, but may be
devices or procedures. Costs are manufacturer list prices, unless otherwise specified.
 List comparators alphabetically by generic name.
Table 3: Cost Comparison Table
Drug / Comparator
Strength
Dosage
Form
Price ($)
Recommended
Daily Use
Average Daily
Drug Cost ($)
A/B/…/Z
(Combination
Product brand)
Comparators
Note: Where applicable, indicate if price is a confidential price submitted by the manufacturer.
Provide sources for cost information and dosage information.
3.2
Manufacturer-Submitted Information Regarding Current Patent Status
The required information in this section includes:
 expiry date(s) of all Canadian market exclusivity patent(s) for the components
3.3
Critical Appraisal of Cost Information
To be completed by CDR reviewers.
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4 DISCUSSION
To be completed by CDR reviewers.
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APPENDIX 1: DRUG PLAN LISTING STATUS FOR INDIVIDUAL COMPONENTS
For each indication that is approved by Health Canada for the new combination products (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 individual components of the combination
product as well as other relevant comparators. CADTH may update the information provided by the manufacturer with new information
provided by the CDR-participating drug plans, as required.
Step 1: Use a separate table for each indication being reviewed by CDR.
Step 2: Add the non-proprietary names for each individual component to the “Components” column, use a separate row for each component
of the new combination product.
Step 3: Use the following abbreviations to complete the table.
Abbreviation
EX
FB
NB
RES
UR
‒
Description
Exception item for which coverage is determined on a case-by-case basis
Full benefit
Not a benefit
Restricted benefit with specified criteria (e.g., special authorization, exception drug status, limited use benefit)
Under review
Information not available
Listing Status for Individual Components of the New Combination Product
Components
CDR-Participating Drug Plans
BC
AB
SK
MB
ON
NB
NS
PE
NL
YK
NT
NIHB
DND
VAC
Drug 1*
Drug 2*
Drug 3*
Drug 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.
* Add non-proprietary name for each component
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Step 4: 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 component) for the treatment of (state the indication)
Drug Plan
Add name
Criteria for Restricted Benefit
State the exact criteria
Add name
State the exact criteria
Add name
State the exact criteria
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APPENDIX 2: SUMMARY OF PATIENT INPUT
To be completed by the CADTH Common Drug Review staff based on input received from patient
groups.
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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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