Therapeutic Comparative Advertising: Directive and Guidance Document
Cover Letter
Therapeutic Products
Directorate
Holland Cross, Tower "B"
6th Floor, 1600 Scott Street
Address Locator # 3106B
OTTAWA, Ontario
K1A 1B6
April 6, 2001
01-103658-698
9608-6-3/1
To: Stakeholders
Re: Therapeutic Comparative Advertising: Directive and Guidance Document
The Therapeutic Products Directorate (TPD) has completed the review of
the Guidance Document: Data Requirements to Support Comparative Claims
Related to Therapeutic Aspects of Nonprescription Drugs Used in Consumer-Directed
Advertising and Labelling.
This Guidance Document is a complement to the initial Directive on the
Principles for Comparative Claims Related to the Therapeutic Aspects of
Drugs, issued on May 23, 1997. The TPD has now combined the Directive
and the Guidance Document to become one new document: Therapeutic Comparative
Advertising: Directive and Guidance Document. This will facilitate
access to all TPD information in this area.
PART I includes the 1997 Directive which incorporates revisions to the
Sections on Roles and Responsibilities and effective date. By merging
the Directive and Guidance document into one document, it became redundant
to repeat the Roles and Responsibilities in the two documents. Furthermore,
this section is applicable to advertising and labelling for all drugs
for human use regardless of the intended audience.
PART II consists of the Guidance Document detailing the data requirements
to support comparative claims related to the therapeutic aspects of nonprescription
drugs used in consumer-directed advertising and labelling. It was subject
to extensive internal and external consultation in 1999 and 2000. These
data requirements outline the standards adopted by the TPD for use by
independent advertising preclearance agencies and sponsors. Clear standards
are set to avoid any potential disagreement concerning the level of evidence
required to support comparative therapeutic claims and to allow for consistency
in advertising review.
The Guidance Document is effective upon the date of publication for the
review of product labelling. With respect to product advertising, implementation
will take effect upon the finalization of operational guidelines by the
independent advertising preclearance agencies endorsed by the TPD.
The TPD greatly appreciates the input received from industry, health
professional and industry associations, independent advertising preclearance
agencies and various individuals on this issue. The TPD believes that
this framework provides the standards of supporting evidence and presentation
of therapeutic comparative claims in drug advertising such that these
claims will not be false, misleading or deceptive to the intended audience.
Any comments that relate to interpretational issues or clarity should
be forwarded to:
Ann Sztuke-Fournier, BPharm.
Head, Advertising and Communications Unit
Bureau of Licensed Product Assessment
Tunney's Pasture, Finance Building,
Address Locator: 0201D1
Ottawa, Ontario
K1A 1B9
Yours sincerely,
Original signed by:
Robert G. Peterson, MD, PhD, MPH
Director General
THERAPEUTIC COMPARATIVE ADVERTISING DIRECTIVE AND GUIDANCE DOCUMENT
MARCH 2001
Administrative Update : October 2005
Advertising Issues Working Group Health Products and Food Branch
PREFACE
For ease of reference, this document combines Health Canada's Comparative Advertising Directive and Guidance Document
relating to therapeutic attributes of drugs.
The broad principles are outlined in Part I of the Directive - Principles
for Comparative Claims Related to the Therapeutic Aspects of Drugs.
This directive is applicable to all drugs for human use regardless of
the intended audience (health professionals, consumers). The Directive
is basically the same as when it was initially issued on May 23, 1997.
However, this revised version now includes the roles and responsibilities
of the different players, that is the independent advertising preclearance
agencies, Health Canada and the advertising sponsors.
Part II consists of the Guidance Document - Data Requirements to Support
Comparative Claims Related to the Therapeutic Aspects of Nonprescription
Drugs Used in Consumer-Directed Advertising and Labelling. This guidance
outlines the data requirements to support consumerdirected nonprescription
drug comparative advertising and labelling.
Advertising preclearance agencies such as the Pharmaceutical Advertising
Advisory Board and Advertising Standards Canada provide additional guidance
through their respective codes of advertising acceptance.
TABLE OF CONTENTS
PART I - DIRECTIVE
Principles for Comparative Claims Related to the Therapeutic Aspects of
Drugs
A. Purpose
B. Background
C. Scope
D. Definitions
E. Policy
F. Roles and Responsibilities
1. Responsibilities of Independent
Advertising Preclearance Agencies
2. Responsibilities of Health Canada
3. Responsibilities of Advertising Sponsor
G. Effective Date
PART II - GUIDANCE DOCUMENT
Data Requirements to Support Comparative Claims Related to Therapeutic
Aspects of Nonprescription Drugs Used in Consumer-Directed Advertising
and Labelling
A. Purpose
B. Background
C. Definitions
D. Data Requirements
1. Comparative efficacy
1-1 Standard of evidence
1-2 Test and reference products
1-3 Clinical study design/methodology/analysis
1-4 Interpretation
2. Onset or duration of action
2-1 Standard of evidence
2-2 Test and Reference products
2-3 Interpretation
3. Comparison of side effect profiles
and other safety parameters
3-1 A comparison of side effects
and other safety parameters
3-2 Standard of evidence
3-3 Test and reference products
3-4 Interpretation
E. Effective Date
Appendix I
Appendix II
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Health Products and Food Branch |
Issued: May 23, 1997 |
|
Administrative Update: October 2005 |
PART I - DIRECTIVE
Principles for Comparative Claims Related to the Therapeutic Aspects of
Drugs
A. Purpose
To provide a framework for the standards of supporting evidence and presentation
of comparative claims in drug advertising such that these claims will
not be false, misleading or deceptive to the intended audience.
B. Background
Section 9(1) of the Food and Drugs Act prohibits advertising and
labelling for any drug that is "false, misleading or deceptive or is
likely to create an erroneous impression regarding its character, value,
quantity, composition, merit or safety". This legislative provision
is intended to help minimize the risk associated with selection and use
of drug products. To meet this condition, comparative claims must be based
on conclusive evidence that is based on sound scientific principles.
In accordance with the requirements of the Food and Drugs Act
and Regulations, pharmaceutical manufacturers are required to file a submission
containing information and material to establish the safety and efficacy
of a drug product prior to marketing, and to be in receipt of marketing
authorization in the form of a Notice of Compliance(NOC) and/or a Drug
Identification Number (DIN).
A drug submission in support of a request for issuance of a NOC or a
DIN is required to establish the safety and efficacy of the product on
its own merits. Apart from bioequivalence studies for second entry new
drugs, a premarket drug submission is not generally required to
include comparative data that would support a comparative claim. Although,
some drug submissions do, in fact, include comparative data in support
of clinical efficacy (e.g., where use of a placebo control would be inappropriate
/unethical) comparative advertising claims are generally supported by
evidence that was not submitted for premarket review.
It is Health Canada's responsibility to
provide interpretation of regulatory provisions, and to set minimum standards
for data requirements that would support market authorization and
advertising claims. Consistent standards that are published for the reference
of all stakeholders are essential to consistent regulatory, and preclearance
review decisions and to a transparent, equitable regulatory system. In
the absence of adequate standards, there can be no assurance that comparative
advertising claims will not be misleading, and that they will support
the appropriate selection and use of drug products.
In a preliminary round of consultation on this issue in June 1996, stakeholders
indicated that standards for comparative claims should ensure that the
claim:
- is evidence-based and balanced,
- does not compromise health and safety,
- promotes informed choice,
- supports the selection of appropriate therapies that will lead to
improved health outcomes
- is subject to independent review prior to dissemination,
- is not unfairly disparaging of competing products or drugs, and that
- the standards consider the differing needs of the various target audiences.
The Competition Act which applies to all marketing practices in
Canada, also prohibits misleading or deceptive representations in advertising
and requires that performance or efficacy claims be based on "adequate
and proper" tests. Related interpretative guidelines state, inter alia,
that these tests must be "concluded before the representation is made";
that "the results must not only be significant but must be meaningful";
and that" the reliability of the data resulting from a test is conditional
upon achievement of similar results from a repetition of the test".
It is also pertinent to note that the U.S. Food and Drug Administration,
in a 1994 letter to the pharmaceutical industry, indicated that comparability
or superiority claims made on behalf of drug products are "subject to
the same standards for review as for efficacy and safety claims in a product's
approved labelling", and that comparative efficacy claims "generally must
be based on at least two adequate and well controlled studies".
The principles expressed by stakeholders in the June 1996 consultation
and the requirements of other regulatory authorities mentioned above were
used as a guide in the development of this Directive. In turn, the principles
expressed in this Directive are intended to guide the development by the
independent advertising review agencies of more detailed standards for
evidence and presentation of comparative claims related to therapeutic
aspects of drugs.
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C. Scope
This Directive applies to comparative claims, relating to therapeutic
attributes, that are made in advertising for all drugs for human use,
regardless of the intended audience or the medium of dissemination1.
The policy provisions also apply to such claims made in product labelling.
This Directive does not apply to comparison of nontherapeutic
aspects of drug advertising, e.g., taste, flavour, colour, packaging,
market position, or to claims of cost effectiveness or quality of life;
neither does the policy refer to comparison with non-drug therapies.
The comparison relates to drug products/ingredients that have been authorized
for sale in Canada.
D. Definitions
For the purposes of this Directive, the following terms are defined:
Comparative claim is a statement that compares
an identified attribute of one drug product/ingredient to that of another/other
drug product(s)/ingredient(s) in terms of comparability or superiority2.
Terms of market authorization are comprised of
information in the Product Monograph and the document that assigns a Drug
Identification Number (DIN) (including related product labelling material
and prescribing information) authorized by Health Canada
upon issuance of the DIN.
Indication(s) for use is(are) the therapeutic/diagnostic/prophylactic
use(s) defined in the authorized product information, and may include
limitations to the drug product's use, such as the applicability to a
specific population, (e.g.,pediatric), or other special conditions (e.g.,
in combination with other therapies).
Conditions of use include the circumstances under
which the product is used for the authorized indication(s), e.g., with
adjunctive therapies, in-patient vs outpatient, daytime vs nighttime use.
Clinical relevance refers to the practical value
of the claim itself in assisting prescribers and consumers to select an
appropriate therapy, and to the practical value of a statistically significant
effect when one treatment is compared to another.
Ingredient refers to the active ingredient(s)
unless otherwise qualified.
E. Policy
Consistent with the provisions of Section 9(1) of the Food and Drugs
Act, pharmaceutical manufacturers are required to observe the following
principles in making claims that compare the therapeutic aspects of drugs:
- the compared drugs/products have an authorized indication for use
in common, and the comparison is related to that use; or, in addition
to the common indication for use, a second authorized indication is
claimed as an added benefit of the advertised drug; and
- the comparison is drawn between drugs under the same conditions of
use, e.g., at equivalent part(s) of their authorized dose ranges (e.g.,
maximum vs. maximum dosage), in a similar population; and
- the claim does not conflict with the terms of market authorization
of the compared products3,
and
- the claim is of clinical relevance in humans, i.e., relevant to treatment
selection, and, where this is not readily apparent, its clinical relevance
can be justified by the sponsor, and
- the evidence generated to substantiate the claim is conclusive and
based on:
- consideration of all relevant data, and
- scientifically accurate, unbiased, reproducible data obtained
from studies conducted and analyzed to current scientific standards
using established research methodologies and validated end points,
and
- appropriate interpretation of the data4.
- the claim and its presentation should:
- identify the compared entities5,
and
- the medicinal use related to the claim where this is not readily
apparent6, and
- not obscure the therapeutic use of the advertised product/ingredient7,
and
- not attack the compared drug product(s)/ingredient(s) in an unreasonable
manner, and
- be expressed in terms, language and graphics that can be understood
by the intended audience.
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F. Roles and Responsibilities
Health Canada has currently endorsed two independent advertising preclearance
agencies, the Pharmaceutical Advertising Advisory Board and Advertising
Standards Canada. Additional information on the roles and responsibilities
of these agencies and Health Canada may be located in these distinct policies:
PAAB and Health Canada Roles and Consultation
Related to Advertising Review.
Advertising Standards Canada
and Health Canada Roles
and Consultation Related to Advertising Review and Complaint Adjudication.
The independent advertising preclearance agencies are responsible for
the evaluation of comparative claims in accordance with the principles
and standards outlined in this Directive and Guidance Document. Additional
clarification of their roles with respect to comparative advertising is
provided below.
1. Responsibilities of Independent Advertising
Preclearance Agencies
- Develop and publish explicit, detailed Standard Operating Procedures
for review of comparative therapeutic claims to ensure that the same
standards and criteria contained in the "Directive" and "Guidance Document"
are applied to all such evaluations (internal agency consistency and
inter-agency consistency to ensure expected outcomes) and that they
are in accordance with those exercised by Health Canada when granting market
authorization.
- Function as the first level for lodging drug advertising complaints
from any source (trade competitors, health professionals, associations,
consumers).
- Ensure that the comparative claim does not compromise consumer safety
or consumer protection against false or misleading advertising by:
- declining misleading advertising (e.g., those that contain an
incomplete message);
- obtaining from the advertiser all the information required by
the Guidance Document necessary to draw valid conclusions and a
balanced view;
- reviewing comparative claims in the context of the available
body of scientific evidence with respect to the comparator drugs;
- requesting labelling that is current and consistent with the
terms of market authorization and any promotional materials relevant
to the proposed claim and campaign; and
- consulting with Health Canada on any perceived new indications, unclear
safety issues, etc..
2. Responsibilities of Health Canada
- Retain ultimate responsibility for decisions regarding product safety.(e.g.,
Health Canada takes direct action if advertising claims lead to potential
health safety hazards).
- Evaluate comparative therapeutic claims submitted to Health Canada in the
context of a submission (DINA, NDS, SNDS).
- Establish effective liaison with independent advertising preclearance
agencies by making publicly available distinct Policies and Standard
Operating Procedures outlining the roles and consultation processes
for complaints adjudication between Health Canada and advertising preclearance
agencies. Provide relevant information within the constraints of maintaining
confidentiality.
- Inform and seek input from independent advertising preclearance agencies
and advertising sponsors of new processes, procedures, policies and
guidelines in development related to the review of therapeutic comparative
claims in labelling and advertising.
- Review and determine the acceptability of new therapeutic claims
and/or conditions of use should the comparison fall outside the scope
of the parameters under which market authorization was granted. This
will be undertaken pursuant to the filing of the appropriate submission
to Health Canada.
- Ensure transparency in its decision making and documentation of the
data upon which market authorization was based, subject to existing
parameters of confidentiality.
- Upon request, advise the independent advertising preclearance agencies
on unclear safety issues, new indications, etc., within the constraints
of maintaining confidentiality.
- Review and approve all comparative therapeutic claims to be included
in the labelling (as opposed to advertising) of drugs.
- If required, audit the independent advertising preclearance agencies
to ensure compliance with the terms of the agreement between Health Canada
and the independent advertising preclearance agency.
- Function as the next level of appeal, when all appeal mechanisms
of the advertising preclearance agencies have been utilized without
a resolution of the appeal for advertising complaints.
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3. Responsibilities of Advertising Sponsor
- Submit to Health Canada comparative claims which represent conditions of
use that exceed the parameters under which marketing authorization was
granted (e.g., new dose, indications, population), in the context of
a drug submission.
- Observe the advertising regulatory provisions outlined in the Food
and Drugs Act and its Regulations and all applicable codes, guidelines,
guidances and policies.
- Demonstrate to independent advertising preclearance agencies that
the comparative therapeutic claim has not been extrapolated beyond the
actual conditions and study populations of the supporting comparative
clinical trials unless a sound, scientific justification has been provided
for doing so.
- Provide to independent advertising preclearance agencies sound scientific
evidence in support of the comparative therapeutic claims that is in
accordance with the requirements outlined in the "Directive" and "Guidance
Document".
- Provide to independent advertising preclearance agencies copies of
labelling that is current and consistent with the terms of market authorization
(most recent Health Canada-approved Product Monograph, Labelling Standard, Prescribing
Information, Patient/Consumer Package Insert, or label, as the case
may be) and any promotional materials relevant to the proposed claim
and campaign.
- Provide authorization for independent advertising preclearance agencies
to access the data upon which Health Canada market approval was based.
- Ensure the continuing validity of the comparative claims by reassessing
the supportive evidence and amending the claim(s) to remain consistent
with emerging new data or information.
G. Effective Date
With respect to the review of product labelling, this Directive became
effective upon the date of first publication, May 23, 1997.
With respect to product advertising, this Directive is effective upon
the date of publication and will be put into operation upon finalization
of implementation guidelines by independent advertising preclearance agencies
such as the Pharmaceutical Advertising Advisory Board (PAAB) and Advertising
Standards Canada (ASC).
The PAAB, has incorporated the Health Canada Directive: Principles for Comparative
Claims Related to the Therapeutic Aspects of Drugs in Section 5 and
11 of their Code of Advertising Acceptance on January 1, 1999. These Sections
provide guidance for the preclearance of comparative therapeutic claims
for use in advertising of prescription and nonprescription drugs directed
to health professionals.
Implementation guidelines for the preclearance of comparative therapeutic
claims for use in advertising of nonprescription drugs directed to consumers,
pursuant to Part II of this document, remain to be finalized.
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PART II - GUIDANCE DOCUMENT
Data Requirements to Support Comparative Claims Related to Therapeutic
Aspects of Nonprescription Drugs Used in Consumer-Directed Advertising
and Labelling
A. Purpose
To provide data requirements to support the inclusion of comparative
therapeutic claims for use in consumer-directed nonprescription drug advertising
and labelling. This Guidance Document complements the Directive, Principles
for Comparative Claims Related to the Therapeutic Aspects of Drugs
issued by Health Canada on May 23, 1997, revised in March 2001 and updated in October 2005.
B. Background
These data requirements have been developed after extensive consultation
with industry, associations, independent advertising preclearance agencies
and Health Canada. They set the minimum standards for data requirements that
would support the inclusion of comparative therapeutic claims for use
in consumer-directed nonprescription drug advertising and labelling.
This Guidance Document outlines the standards adopted by Health Canada for use
by independent advertising preclearance agencies and sponsors. Clear standards
are set to avoid any potential disagreement concerning the level of evidence
required to support comparative claims.
C. Definitions
For the purpose of this guidance document, the following terms are defined:
Comparative Therapeutic Claim:
A statement that compares an identified therapeutic attribute of one drug
product/ingredient to that of another /other drug product(s)/ingredient(s)
in terms of equivalence, parity or superiority.
Types of Comparative Claims:
Superiority - Product claims performance better than another product (Brand
A works better than Brand B at relieving heartburn).
Equivalence - Product claims equal or identical performance to another
product. (Brand A works as well as Brand B at relieving heartburn).
Parity - Product claims show no proven superiority in any given parameter,
i.e., that the available products have equal efficacy. (Nothing has been
shown to relieve heartburn better than Brand A)
Product:
Refers to the Brand Name of a particular drug which may be composed of
one or more active ingredients.
Ingredient:
Refers to the active ingredient(s) unless otherwise qualified.
Brand Name:
Means, with reference to a drug, the name, whether or not including the
name of any manufacturer, corporation, partnership or individual, in English
or French, that is assigned to the drug by its manufacturer, under which
the drug is sold or advertised, and that is used to distinguish the drug.
Clinical Relevance to the consumer:
Refers to the practical value of the claim itself in assisting consumers
to select an appropriate therapy. Practical value means offering a clinically
significant benefit or advantage which can easily be understood and seen
by the consumer when one treatment is compared to another, e.g., lack
of side effect, ease of administration, faster onset of action, longer
lasting relief etc...
Systematic Review1:
A summary of the medical literature that uses explicit methods to perform
a thorough literature search and critical appraisal of individual studies
and that uses appropriate statistical techniques to combine these valid
studies.
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D. Data Requirements
Evidence to support comparative therapeutic claims of nonprescription
drugs must be conclusive, definite, validated and must possess the highest
level of evidence.
Reproducibility of efficacy or product superiority can normally be obtained
through the internationally accepted standard of two independent, randomized
clinical trials. At least two studies provide the confirmatory evidence
required for a reasonable expectation that the results are accurate.
However, the review Bureau may determine that one large well-conducted
clinical trial adequately powered, may suffice. In such circumstances,
a rationale to use only one clinical trial must be provided and this must
be discussed with Health Canada on a case by case
basis. Also, the study must be designed in the very beginning to show
superiority. This type of study design is quite different from that normally
used for ordinary clinical trials to show safety and efficacy. Ordinary
clinical trials which may have accidentally shown some potential superiority
after the trial was completed, normally are not of an adequate design
and power to conclusively demonstrate product superiority.
However the review Bureau may determine that one large well-conducted
clinical trial, adequately powered showing an unintended consequence of
superiority, could be used as one of the two clinical studies to support
the newly found superiority claim. The second clinical trial must be appropriately
designed to demonstrate superiority. In such circumstances, a rationale
must be provided to this exception and discussed with Health Canada on a case by case basis.
1. Comparative efficacy
Statements may be made regarding the comparative efficacy of drug products
/ ingredients in meeting the claimed indication for use provided the general
provisions of the directive, this guidance document and this section are
met. This document does not include provisions for the use of comparative
effectiveness data. The science in this area is constantly evolving
and it is deemed premature to include this data for comparative advertising
purposes at this time.
1-1 Standard of evidence
- For drugs that are subject to the requirements of Division 8 of the
Food and Drug Regulations, the efficacy parameters measured in
comparative studies should be the same as those that were evaluated
in the context of premarket submission review and upon which market
authorization was based. As medical knowledge progresses, newer criteria
may also be appropriate for therapeutic comparison. However their usage
is to be in addition to and not in place of the traditional measures,
and sufficient justification of their usage must be presented. In addition,
the use of the new outcome measures for comparison must not result in
new therapeutic claims. In the case of drugs bearing a DIN but not subject
to Division 8, the parameters measured should be consistent with those
generally used to establish the efficacy of the relevant ingredient(s)
that support the claimed indication for use.
- Product to product (brand name A to brand name B) comparison
- Statements that make an equivalence, parity, or a superior
efficacy claim must be supported by at least two independent2,
well-designed, adequately controlled, blinded, randomized clinical
studies that have been conducted to current scientific standards
(see Section 1-3(a)). The two studies must be specifically designed,
a priori, and of sufficient sample size, measurable endpoint(s)
and power, to clearly demonstrate product superiority for a specific
claim(s). and
- Sponsors should provide an attestation that the results of supporting
studies reflect the "body of available evidence3"
and have not been superseded by contradictory findings4;
or, a justification for any difference should be provided for consideration.
or
- If conditions i) and ii) are not presented then data reported
in the public domain (e.g., articles in peer reviewed, reputable
scientific journals that are used to support a product-to-product
comparison) or data in product monographs should pertain to the
products cited in the claim (such data are also subject to the standards
cited in Section 1-1 b) (i) and (ii)5.
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- Ingredient to ingredient or product to ingredient comparisons
The ability to make comparative efficacy claims for ingredient to ingredient
or product to ingredient comparisons, may be limited since most randomized
clinical studies are actually conducted on specific products or brand
names. The ability to extrapolate results for specific products to ingredients
in comparative advertising claims is acknowledged. A meta-analytic approach
may be the only option available, but must be subject to rigorous methods.
The meta-analysis must include individual trials that were subject to
the standards cited in Section 1-1 b) (i) and (ii).
- Statements that make an equivalence, parity, or superior efficacy
claim of one drug ingredient to another drug ingredient,
or of one drug product to another drug ingredient
may be supported by a systematic review and meta-analysis of published
and sponsor-generated data from studies in which the conditions
of use of the compared drugs are consistent with those authorized
in Canada and meet the standards cited in Section 1-1 (b)(i) and
(ii).
- The systematic review should adhere as closely as possible to
the following methodological guidelines6:
- the research plan should be documented a priori, and should
include:
- the question(s) to be addressed by the review;
- a reproducible and robust method for finding all relevant
studies for review7,
with search parameters stated;
- a reproducible method for selecting studies, from those
retrieved, for detailed review (inclusion and exclusion
criteria, with a list of excluded studies);
- a reproducible method for evaluating the scientific quality
of studies;
- a reproducible method for extracting evidence from studies;
- identification of proposed subgroup analyses;
- a documented justification to support any changes in the
predetermined plans for data retrieval and subgroup analyses;
- labelling of all subgroup analyses according to whether they
are a priori or a posteriori;
- use of sensitivity analyses to test the robustness of results
relative to features of the primary studies and to key assumptions
and decisions made in the selection, analysis and presentation
of studies and their findings;
- the results of the systematic review and meta-analysis should
be provided.
- Data quoted from two or more Product Monographs, derived from
studies that were head-to-head, are acceptable support for comparative
claims of clinical efficacy. Factors such as study methodologies,
patient populations, dosing and measurement criteria used in the
separate trials must be similar. The side-by-side presentation of
efficacy data must be comparable, otherwise it could leave a misleading
impression.
- Product/ingredient to all other Canadian products/ingredients
for the same indication
- Evidence and data generated to support equivalence, parity,
or superiority claims of one product/ingredient over all others
for the same indication should be consistent with the requirements
for individual comparisons and subject to the standards cited in
Section 1-1(b) and (c).
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1-2 Test and reference products
- For product vs. product comparisons, the actual products cited in
the comparison should be used in the supporting comparative clinical
trials.
- Data generated to support a product to product comparison
from clinical trials conducted in other countries with non-Canadian
versions of the products cited in the comparison, may be
used to support comparison of the equivalent Canadian products
provided it can be demonstrated that:
- the sponsor's Canadian product is identical8
to, or has no major change(s)9
from the corresponding non-Canadian product used in the original
studies and this has been verified by the manufacturer; and
- the compared product complies with Health Canada Policy: Canadian Reference Product;
or
- the compared product is a product which would not be subject
to a bioequivalence study for premarket approval in accordance with
Health Canada Guideline Preparation of Drug Identification Number Submissions
and meets the criteria in Appendix II;
- the Canadian and non-Canadian comparator products are shown to
be bioequivalent10.
Where these criteria are not met, clinical studies using the Canadian
versions of the compared products are required.
1-3 Clinical study design/methodology/analysis
- The clinical studies in support of a product to product comparison
should be conducted and analysed according to the principles embodied
in the guideline of the International Conference on Harmonisation; Structure
and Contents of Clinical Trial Reports and Statistical Principles for
Clinical Trials.
For example:
- the clinical studies should be designed to investigate the comparison
of interest;
- the clinical studies should be double blinded (investigator and
subjects) or justification provided as to why this could not be
accomplished, and what alternative measures have been employed to
ensure lack of bias;
- the study population should be representative of the target population;
all subjects assigned to the treatments should be accounted for;
the sample size must be based on statistical power analysis.
1-4 Interpretation
- The minimum acceptable level of statistical significance of the measured
difference between treatments is p
< 0.05; the 95% confidence
intervals should also be stated;
- Evidence of clinical relevance should be presented in order to assist
the consumer in selecting an appropriate therapy.
- Failure of the clinical studies to demonstrate a statistically
significant difference in the measured effect is not sufficient to enable
a claim of equivalence between the compared treatments.
Equivalence can only be established using hypotheses structured for
assessing equivalence11.
- The comparative efficacy claim should not be extrapolated beyond
the actual conditions and study populations of the supporting comparative
clinical trials unless a sound, scientific justification can be provided
for doing so.
For example:
- justification is required for making a comparative claim about
benefits to the elderly when the supporting evidence was obtained,
for example, from studies in young, healthy adults, or for
benefits to smokers when smokers formed a minor proportion of the
study population;
- an extrapolation from data supporting an ingredient-to-ingredient
comparison of efficacy [ Section 1-1(c) meta-analysis] to a product-to-product
comparison of efficacy may be appropriate, e.g., if it can be demonstrated
that the measurement of efficacy (endpoint) used in the comparison
is independent of formulation or route of administration; the
standards of evidence for this type of extrapolation must be comparable
to those needed to obtain product approval in Canada.
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2. Onset or duration of action
Comparison may be made between drug products/ingredients regarding the
onset or duration of action where this measurement is of clinical relevance12-1
in humans, provided the general provisions of the directive, the guidance
document and this section are met. This comparison should be based on
existing Health Canada approved product information, since new information on onset
of action is subject to Health Canada review.
2-1 Standard of evidence
- The onset or duration of action should be determined through measurement
of the same parameters used to establish efficacy in the context of
premarket submission review and market authorization, or justification
provided where this is not the case.
- Product to product (brand name A vs. brand name B) comparison
- Two clinical trials, as outlined in Section 1-1(b), 1-2, 1-3(a)
and 1-4(c) are required to support a comparison of the onset or
duration of action of two products.
- Alternatively, sponsors should justify and provide information
on alternative methods used and data generated to support the comparison.
For example, comparative pharmacokinetic/pharmacodynamic studies
may be appropriate in this context, provided that a strong correlation
can be established between the measured endpoint and the onset or
duration of the therapeutic effect of the compared products. In
no circumstances would extrapolation of the claim beyond the actual
conditions of the supporting studies be acceptable.
e.g., where the rate of absorption is a direct measure of the onset
of symptom relief; or where differences in duration of action can
be attributed to modification of the dosage form of the advertised
product, as supported by comparison of the authorized Product Monographs/product
labelling.
- Sponsors should provide an attestation that the results of supporting
studies reflect the "body of available evidence3"
and have not been superseded by contradictory findings; alternatively,
a justification for any difference should be provided for consideration;
- Ingredient to ingredient and product to ingredient comparisons
- Comparisons may be drawn with respect to onset and/or duration
of action provided sponsors adequately justify the method(s) used,
and the data generated, to support the comparative claim relating
to onset or duration of action.
- Product/ ingredient to all other Canadian products/ingredients
for the same indication
- Evidence and data generated to support equivalence, parity, or
superiority claims of one product/ingredient over all others for
the same indication with respect to onset/duration of action should
be consistent with the requirements for individual comparisons and
subject to the standards cited in Section 2-1.
2-2 Test and Reference products
- For product vs. product comparisons, the actual products cited in
the comparison should be used in the supporting comparative clinical
trials.
- Data generated to support a product to product comparison
from clinical trials conducted in other countries with non-Canadian
versions of the products cited in the comparison, may be
used to support comparison of the equivalent Canadian products
provided it can be demonstrated that:
- the sponsor's Canadian product is identical8
to, or has no major change(s)9
from the corresponding non-Canadian product used in the original
studies and this has been verified by the manufacturer;
and
- the compared product complies with Health Canada
Policy: Canadian Reference Product;
or
- the compared product is a product which would not be subject
to a bioequivalence study for premarket approval in accordance with
Health Canada Guideline Preparation of Drug Identification Number Submissions
and meets the criteria in Appendix II;
- the Canadian and non-Canadian comparator products are shown to
be bioequivalent10.
Where these criteria are not met, clinical studies using the Canadian
versions of the compared products are required.
2-3 Interpretation
- The minimum acceptable level of statistical significance of the measured
difference between treatments is p<0.05; the 95% confidence interval
should also be stated.
- Evidence of clinical relevance should be presented in order to assist
the consumer in selecting an appropriate therapy.
- Failure of the clinical studies to demonstrate a statistically
significant difference in the measured effect is not sufficient to
enable a claim of equivalence between the compared treatments.
Equivalence can only be established using hypotheses structured for
assessing equivalence11.
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3. Comparison of side effect profiles and other
safety parameters
Statements that compare the side effect and safety profiles, of drug
products or ingredients, may be made in consumer-directed advertising
provided the general provisions of the Directive, this Guidance document
and this section are met.
3-1 A comparison of side effects and other
safety parameters may be done if the following conditions (where applicable)
are met:
- the approved indications are disclosed in the advertisement;
- the side effect is self-limiting, self-recognizable, understandable
and of clinical relevance to the consumer (e.g., dizziness, drowsiness,
dry mouth);
- given the broad spectrum of nonprescription drugs, all comparisons
for products that have complex side effect/safety profiles must present
the benefits and the risks of each drug to provide an accurate, balanced
and fair representation;
- as the complexity or seriousness of adverse effects and safety concerns
increase, the access to easily understandable patient information for
the sponsor's drug must increase and be readily available for consumers;
- sponsors should always provide easy access to the complete patient
information on proper drug use, (e.g., patient package insert, Product
Monograph) which may include simultaneous dissemination to targeted
audiences in various mediums such as print, 1-800 information lines,
broadcast, Internet etc. (the amount of information made available would
increase especially as complexity of comparisons increase);
- comparisons that require medical/scientific knowledge to accurately
interpret the results are to be avoided in consumer directed advertising;
- the advertisement should not impact negatively on patient compliance,
nor deter or cause delay from seeking appropriate treatment. Provisions
should be included to refer consumers to a qualified health care professional
(pharmacist, nurse, physician etc) if consumers require additional information
or if symptoms persist;
- the advertisement does not attack the compared drug product(s)/ingredients(s)
in an unreasonable, disparaging manner;
Comparison of drug interactions, complex adverse reactions, contraindications,
precautions, risks and other safety factors are difficult to present
to consumers without being potentially misleading or deceptive. This
is especially difficult to achieve in most advertising media which are
limited in time and length. Furthermore, generalizations concerning
comparisons of product effects may not always be applicable to each
individual because other confounding factors such as the individual's
medical conditions, use of multiple drug therapies etc., may directly
impact on the selection of appropriate drug therapy. It is considered
misleading to focus on a comparison of one particular side effect or
safety parameter of a drug product to show a benefit, when in fact the
product may show other side effects or safety concerns that compare
unfavourably with the comparator product.
In most cases, a fair and balanced presentation of comparable effects
can only be carried out when a complete comparison of the benefits and
risks of two drugs is done. The overall safety of a drug depends on
many factors and to highlight only one aspect provides an incomplete
picture of the product merit and may be inherently misleading. Even
in such a complete comparison, caution is required because the message
may still be confusing if an evaluation of that material requires medical/scientific
knowledge to accurately interpret that information.
Claims based on differences that are subtle or require the disclosure
of study parameters in order to accurately interpret the results, obviously
should not be advertised to the public but only to the health professional
who has the expertise to understand the scientific complexities and
nuances. Therefore, if such comparisons are targeted to the public,
they must be considered with caution as the amount of information required
to provide a fair and balanced view of the relative safety may exceed
the amount of information that can reasonably be provided to and/or
understood by the consumer in most consumer advertising messages.
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3-2 Standard of evidence
- The side effects and safety parameters compared must be limited to
those that are cited in Health Canada approved terms of market authorization
and/or labelling of the products compared (for a product vs. product
comparison), or of those currently required to be referenced in Health Canada approved PM or labelling of products containing only those ingredients
compared (for an ingredient vs. ingredient comparison)
- Product to product (brand name A vs. brand name B) comparison
- To support product to product comparison of side effect and safety
profiles, the evidence based on clinical or other studies must be
supported by at least two independent2,
well designed, adequately controlled, blinded, randomized clinical
studies that have been conducted to current scientific standards,
which meet the conditions outlined in Section 1-1(b), 1-2, 1-3(a)
and 1-4(c).
- Sponsors must provide an attestation that the results of supporting
studies reflect the "body of available evidence"3
in the public domain and have not been superseded by contradictory
findings, or an explanation/ justification for any difference should
be provided for consideration. The "attestation" must contain the
results of either a meta-analysis or a systematic review to show
that the two studies reflect the body of medical evidence, provided
the conditions in Section 1-2 are met for International data.
- Comparison of the authorized product information may be used
to support comparison of the side effect and safety profile of the
advertised product in contrast to the compared product, provided
that:
- effects unique to differences in formulation and route of
administration have been accounted for;
- the study populations, methodologies, dosing and measurement
criteria are comparable;
- the side-by-side presentation of adverse events and safety
data are comparable.
Otherwise, adverse event and safety data quoted from two or
more Product Monographs, derived from studies that were not
head-to-head and were not comparable are unacceptable.
- Ingredient to ingredient and product to ingredient comparisons
In addition to the criteria outlined in Section 3-2 (a) and (b):
- Statements that compare the side effect and safety profiles of
drug ingredients in terms of their presence or absence12-2
should be based on evidence obtained through a systematic review13
of the available evidence relating to the compared ingredients.
- With respect to a comparison of the incidence of side effects
of ingredients, the method of quantifying the incidence must be
identical for all compared entities, and the data and method of
calculation must be provided.
- Product/ingredient to all other Canadian products/ingredients
for the same indication
- Evidence and data generated to support side effect and safety
profiles of one product/ingredient versus all others for the same
indication should be consistent with the requirements outlined for
individual comparisons in Section 3-2.
3-3 Test and reference products
Refer to Sections 1-2 and 2-2.
3-4 Interpretation
- The minimum acceptable level of statistical significance of the measured
difference between treatments is p
< 0.05; the 95% confidence
intervals should also be stated.
- Evidence of clinical relevance should be presented in order to assist
the consumer in selecting an appropriate therapy.14
- Failure of the clinical studies to demonstrate a statistically significant
difference in the measured effect is not sufficient to enable a claim
of equivalence between the compared treatments . Equivalence can only
be established using hypotheses structured for assessing equivalence.11
E. Effective Date
With respect to the review of product labelling, this guidance document
is effective upon the date of publication.
With respect to product advertising, this Guidance Document is effective
upon the date of publication and will be put into operation upon finalization
of implementation guidelines by the independent advertising preclearance
agencies endorsed by Health Canada.
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Appendix I
PREPARATION OF DRUG SUBMISSIONS INVOLVING COMPARATIVE BIOAVAILABILITY STUDIES AND BIOEQUIVALENCE
Health Canada has published numerous guidelines and policies to assist manufacturers in filing drug submissions. The following provides a list of contacts and Web site addresses for those guidelines and policies which may be of particular interest to sponsors of Abbreviated New Drug Submissions (ANDS); New Drug Submissions (NDS) which involve comparative bioavailability studies related to bioequivalence; and supplements to such submissions. This list is NOT INCLUSIVE, and one must appreciate that the Web site is subject to continual update and improvement, but this list should be helpful in accessing the more relevant guidances.
Health Products and Food Branch (HPFB) Web site address:
http://www.hc-sc.gc.ca/ahc-asc/branch-dirgen/hpfb-dgpsa/index_e.html
Guidances related to Bioavailability and Bioequivalence Studies
Draft Guidance for Industry - Preparation of Comparative Bioavailability Information for Drug Submissions in the CTD Format - May 18th, 2004
Notice
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ guide-ld/ctd/ctdbe_notice_avis_e.html
Draft Guidance Document
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ guide-ld/ctd/draft_ebauche_ctdbe_e.html
Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part A: Oral Dosage Formulations used for Systemic Effects 1992
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ guide-ld/bio/bio-a_e.html
Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part B: Oral Modified Release Formulations - July 23, 1997 http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ guide-ld/bio/bio-b_e.html
Canadian Reference Product - December 5, 1995 http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ pol/crp_prc_pol_e.html
Bioequivalence of Proportional Formulations: Solid Oral Dosage - March 7, 1996
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ pol/bioprop_pol_e.html
Guidance for Industry : Pharmaceutical Quality of Aqueous Solutions - February 15th, 2005
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ guide-ld/chem/aqueous_aqueuses_e.html
Bioequivalence Requirements: Drugs Exhibiting Non-linear Pharmacokinetics -DRAFT - July 3rd, 2003
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ pol/nonlin_pol_e.html
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Related Guidances
Guidance to Industry; Management of Drug Submissions Health Canada Policy; Appeals Procedures for Drug Submissions - April 4, 2003
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ pol/appe_pol_e.html
Guideline on Preparation of Drug Identification Number (DIN) Submissions - February 22, 1995
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ guide-ld/din/pre_din_ind_e.html
Stereochemical Issues in Chiral Drug Development - February 14, 2000
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ guide-ld/chem/stereo_e.html
Letter to Associations - Comprehensive Summary - Chemistry and Manufacturing (CS(CM-rDNA)) and Certified Product Information Document (CPID) April 1, 1996
http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/ qualit/prod/lett-cmrdna-cfadnr/cscm-sgcf_let_e.html
Generic Parenteral Drugs, Submissions for - March 1, 1990
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ pol/gen_subm_pres_pol_e.html
Submissions for Topical Non-Steroidal Anti-inflammatory Drugs (Topical NSAIDs) - July 22, 1998
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ pol/topnsaids_ainstop_pol_e.html
Guidance for Clinical Trial Sponsors : Clinical Trial Applications
Notice
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ guide-ld/clini/ctdctanotice_ctddecavis_e.html
Guidance Document
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/ guide-ld/clini/ctdcta_ctddec_e.html
Modification to Good Manufacturing Practices (GMP) Guidelines 2002 Edition, May 23, 2002
http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/ guide-ld-2002/index_e.html
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Appendix II
- It must be documented that the foreign comparator drug product is
authorized for marketing by the health authority of a country with drug
assessment criteria documented to be comparable to those in Canada as
required in the Food and Drugs Act and interpreted in Health Canada Guidelines and Policies.
- It must be documented that the foreign comparator drug product is
marketed in the country of origin by the same innovator company or corporate
entity which currently markets the same medicinal ingredient(s) in the
same dosage form in Canada, or that it is marketed in the country of
origin through a licensing arrangement with the same company or corporate
entity which currently markets the product in Canada.
- Labelling for the foreign comparator drug product and the comparator
drug product marketed in Canada must be submitted and shown to be comparable.
- The foreign comparator drug product must be the same as the comparator
drug product marketed in Canada with respect to colour, shape, size,
weight, type of coating, flavour, fragrance, etc. The sponsor must justify
that differences, if any (e.g. flavour, fragrance), between the foreign
comparator drug product and the comparator drug product marketed in
Canada would not affect the results obtained from the foreign comparative
clinical trials.
PART I - Reference
1. Not applicable
to direct-to-consumer advertising of prescription drugs which is restricted
by regulation (Section C.01.044 of the Food and Drugs Regulations) to
name, price and quantity.
2. Claims
such as "non-drowsy", "acts in half an hour" , "low incidence of side
effect ..." that do not refer directly (more effective than product B)
or by implication (e.g., more effective, faster) to other drug products/ingredients
do not fall within the scope of this policy, but nevertheless must be
supported by evidence based on sound scientific principles.
3. For drugs
subject to Division 8, Part C of the Regulations, the Health Canada Policy: Changes to Marketed Drugs provides guidance on product
information changes that require the filing of a Supplemental New Drug
Submission, Notifiable Change etc. For drug products assigned a DIN but
not subject to Division 8, Part C of the Regulations, Section C.01.014.4
of the Regulations identifies the product information changes that require
a new DIN application, provided the new information does not render the
product subject to Division 8, Part C of the Regulations.
4. extrapolation
beyond the actual conditions of the supporting studies is not acceptable.
5. i.e..,
hanging comparisons such as "better", " faster acting" are unacceptable,
as are vague statements such as "compared to the leading brand...."
6. where
the advertised entity has more than one indication for use, it should
be clear to which use the claim refers.
7. i.e.,
the comparative claim should be afforded no more prominence than the therapeutic
use.
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PART II - Reference
1. Definition
from: Sackett DL, Strauss SE, Richardson WS, Rosenberg W, Haynes RB. Evidence-Based
Medicine: How to Practice and Teach EBM; New York; Churchill Livingstone;
Second Ed.:2000. The appraisal of individual studies submitted by the
sponsor includes the review of the data submitted.
2. The term
'independent' is not meant to exclude company-sponsored clinical trials.
3. 'Body
of available evidence' is defined as 'the information reasonably available
as published or unpublished studies, other data in respected medical literature,
generally available in the public domain at that point in time'.
4. Intended
to ensure that the results are viewed in the context of all available
information.
5. Peer
review of published articles is not all conducted to the same standard.
6. Consistent
with the principles expressed in: Cook DJ, Sackett DL and Spitzer WO.
Methodologic Guidelines for Systematic Reviews of Randomized Control Trials
in Health Care from the Potsdam Consultation on Metaanalysis. J. Clin.
Epidemiol.1995;48:167-171.
7. With
respect to a product vs. ingredient comparison, every effort should be
made to locate, include and identify all studies in which the advertised
product was compared.
8. Identical
master formula and manufacturing process
9. Major
change(s) as defined by a Level 1 or Level 2 change in Health Canada Policy on Changes to Marketed New Drugs.
10. If
the comparator product, in accordance with current Health Canada Guidelines and Policies (see Appendix I), would require a
bioequivalence study(ies) for premarket approval, then the Canadian and
foreign comparator products must be shown to meet these bioequivalence
criteria to allow for the use of the foreign comparative clinical trials.
11. e.g.,
Section 3.3.2, ICH E9 document on Statistical Principles for Clinical
Trials; Dunnett CW, Gent M. Biometrics 1977;33:509-602. Blackwelder WC.
Clin Trials 1982;3:345-353.
12-1.
As defined in the Definitions of this Guidance document. Refers to the
practical value of the claim itself in assisting consumers to select an
appropriate therapy.
12-2.
As per the requirements of the Consumer Drug Advertising Guideline (Amendment
October 1991) Absence of Side Effects section, p. 21a-21c.
13. it
is recognized that it may not be possible to include a quantitative analysis.
14. The
independent preclearance agency will ensure that the numerical (e.g. %)
representations of data are not misleading to the consumer. For example,
in the case of adverse events this may be measured by one of the following:
absolute risk reduction or ARR (the difference of the adverse event rates
for the two products) or relative risk reduction or odds ratio* or RRR%
(the adverse event rate for one product divided by the adverse event rate
for the other product multiplied by 100). The number needed to treat (NNT),
must also be considered. *(Sackett DL, Strauss SE, Richardson WS, Rosenberg
W, Haynes RB. Evidence-Based Medicine: How to Practice and Teach EBM;
New York; Churchill Livingstone; Second Ed.:2000.)
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