Guidelines for preparing submissions to the Pharmaceutical Benefits Advisory Committee
(Version 4.3)
December 2008
Pharmaceutical Benefits Advisory Committee
© Commonwealth of Australia 2008
Print (paper-based) publication:
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ISBN: 1-74186-780-0 (print version)
ISBN: 1-74186-781-9 (online)
Publications Approval Number: P3-4706
Address for correspondence
The Secretary
Pharmaceutical Benefits Advisory Committee
GPO Box 9848
CANBERRA ACT 2601
Submissions should be delivered to:
Level 9
Sirius Building
23 Furzer Street
PHILLIP ACT 2606
Technical writing assistance, editing and page layout by Janet Salisbury, Meg Heaslop and team Biotext, Canberra
Filename: PBAC4.3-2(01Dec08).doc
Weblinks: Unless otherwise stated, URLs in this document were accessed on 1 December 2008
Foreword
This revision of the Guidelines for Preparing Submissions to the Pharmaceutical Benefits Advisory Committee is the first full revision of the guidelines since 1995 and has involved substantial changes in many areas of the document. These changes have built on experience gained since the first revision of the guidelines was published in 1995 based on the experience of making decisions relying on cost-effectiveness. The revision process has included extensive discussions among members of the Pharmaceutical Benefits Advisory Committee and its subcommittees, as well as a wide range of contributors from industry, government, academia and the community.
The release of this revision coincides with an increasing international trend towards reliance on information about the costs and effectiveness of medicines by large third-party payers, including governments managing drug subsidy programs. It is anticipated that, as interest and expectations increase, this reliance may start to guide the drug development process internationally. Awareness of this trend has influenced the development of this revision.
These guidelines are structured and comprehensive. They cover a wide range of requests for information. Not all requests will be relevant to all submissions. However, by responding to the requests where appropriate, the key matters for the specific circumstances of each submission will be presented transparently so that they can be understood clearly.
These guidelines reflect best practice as far as possible. The requests for information are designed to promote comparability across submissions and to minimise uncertainty where possible. However, while they represent the currently preferred approach, reflecting the experience of more than one thousand decisions, they are not prescriptive and there is flexibility in their interpretation.
These guidelines will remain subject to regular review. They explicitly provide for the introduction of new methods. As these new methods become established and accepted, they will influence future updates.
I commend this revision to you. It distils the influence of many methodological disciplines, many contributions in a wide consultation process and, perhaps most importantly, many difficult decisions relating to many important submissions.
Lloyd Sansom
Chair
Pharmaceutical Benefits Advisory Committee
Contacts
Pharmaceutical Benefits Advisory Committee Secretariat
The Pharmaceutical Benefits Advisory Committee (PBAC) and its subcommittees have secretariats within the Australian Government Department of Health and Ageing:
PBAC Secretariat Section
Tel: (02) 6289 7099
Fax: (02) 6289 4175
Economics Sub-Committee (ESC) and Drug Utilisation Sub-Committee (DUSC)
Pharmaceutical Evaluation Section
Tel: (02) 6289 7501 (ESC Secretary)
(02) 6289 7293 (DUSC Secretary)
Fax: (02) 6289 8633
Vaccines are considered by the Australian Technical Advisory Group on Immunisation (ATAGI), which also has a secretariat within the Australian Government Department of Health and Ageing:
ATAGI: Immunisation Section
Tel: (02) 6289 8572
Fax: (02) 6289 3677
The secretariats are available for discussion about proposed submissions or related matters. They are also the first point of contact concerning the relevant committee’s discussions and decisions.
Address for correspondence
The Secretary
Pharmaceutical Benefits Advisory Committee
GPO Box 9848
CANBERRA ACT 2601
Submissions should be delivered to:
Level 9
Sirius Building
23 Furzer Street
PHILLIP ACT 2606
Record of updates
Date / Version / Summary of changesAugust 1990 / 1.0 / Draft guidelines issued for comment
August 1992 / 2.0 / Minor rearrangement, extension and clarification
November 1995 / 3.0 / Clarification of technical aspects of measuring changes in costs and outcomes
November 2002 / 3.1 / Update to include minor changes endorsed since November 1995
November 2006 / 4.0 / Major revision and reorganisation of text
December 2006 / 4.1 / Version for co-publishing in HTML format, with excerpts in RTF format, plus minor editorial corrections
December 2007 / 4.2 / Version to provide clarification in Subsections A.1, A.5, B.7, C, D.5, F.3, PT1 based on initial feedback on the major revision and to update URLs.
December 2008 / 4.3 / Version to enable primary publication in pbs.gov.au website, update URLs and correct a small number of typographical errors
1
Contents
Foreword......
Contacts......
Record of updates......
Abbreviations......
PART I GENERAL INFORMATION......
1Role of the Pharmaceutical Benefits Advisory Committee......
1.1Overview of PBAC roles......
1.2Membership of PBAC and its subcommittees......
1.3Assessing suitability for listing......
1.4Processing submissions......
2Introduction to the guidelines......
2.1Development of the guidelines......
2.2Structure of the guidelines......
2.3Writing and style conventions used in these guidelines......
2.4The future......
3Types of submissions......
3.1Submissions to list generic equivalents......
3.2Minor submissions......
3.3Major submissions......
3.4Resubmissions......
4Rationale and basis for the economicevaluation......
4.1Analysis of cost-effectiveness......
4.2Interpretation of clinical and economic evidence......
4.3Australian context......
4.4Uncertainty......
4.5Relevant factors influencing PBAC decision making......
4.6Flexibility in interpretation of the guidelines......
5Organisation of a major submission......
5.1Choice of information......
5.2Overview of a major submission......
5.3Presentation of the submission......
5.4Provision of alternative information......
5.5Submissions relying on new methods or techniques......
6Lodging a major submission......
6.1Submission checklist......
6.2Provision of information to allow independent verification of computer analyses
6.3Provision of information after lodgment of the submission......
PART II GUIDELINES FOR PREPARING THE MAIN BODY OF A MAJOR SUBMISSION
Submission executive summary......
Section A Details of the proposed drug and its intended use on the PBS......
Introduction......
A.1Requested PBS listing and pharmacological class and action......
A.2Indications and requested restrictions......
A.3Treatment details......
A.4Main comparator......
A.5Clinical management algorithms......
A.6Differences between the proposed drug and the main comparator......
Section B Clinical evaluation for the mainindication......
Introduction......
B.1Description of search strategies......
B.2Listing of all direct randomised trials......
B.3Assessment of the measures taken by investigators to minimise bias in the direct randomised trials
B.4Characteristics of the direct randomised trials......
B.5Outcome measures and analysis of the direct randomised trials......
B.6Systematic overview of the results of the direct randomised trials......
B.7Extended assessment of comparative harms......
B.8Interpretation of the clinical evidence......
Section C Translating the clinical evaluation to the listing requested for inclusion in the economic evaluation
Introduction......
C.1Identification of issues to be addressed......
C.2Focused analytical plan......
C.3Results of premodelling studies......
C.4Relationship of each premodelling study to the economic evaluation....
Section D Economic evaluation for the main indication......
Introduction......
D.1Overview of the economic evaluation......
D.2Population and circumstances of use reflected in the economic evaluation
D.3Structure and rationale of the economic evaluation......
D.4Variables in the economic evaluation......
D.5Results of the economicevaluation......
D.6Sensitivity analyses......
Section E Estimated extent of use and financial implications......
Introduction......
E.1Justification of the selection of sources of data......
E.2Estimation of use and costs of the proposed drug......
E.3Estimation of changes in use and cost of other drugs......
E.4Estimated financial implications for the PBS/RPBS or the NIP......
E.5Estimated financial implications for government health budgets......
E.6Identification, estimation and reduction of uncertainty......
Section F Options to present additional relevant information......
Introduction......
F.1Quality use of medicines......
F.2Risk-sharing arrangements......
F.3Other relevant factors......
PART III FURTHER INFORMATION FOR PREPARING THE MAIN BODY OF A MAJOR SUBMISSION
Section B(i) Clinical evaluation for the main indication: Presenting an indirect comparison of randomised trials
B(i).1Description of search strategies......
B(i).2Listing of all randomised trials considered for inclusion in an indirect comparison
B(i).3Assessment of the measures taken by investigators to minimise bias in the randomised trials included in the indirect comparison
B(i).4Characteristics of the randomised trials included in the indirect comparison
B(i).5Outcome measures of the randomised trials included in the indirect comparison
B(i).6Results of the indirect comparison......
B(i).7Extended assessment of comparative harms......
B(i).8Interpretation of the clinical evidence......
Section B(ii) Clinical evaluation for the main indication: Presenting nonrandomised studies
Introduction......
B(ii).1 Description of search strategies......
B(ii).2 Listing of all nonrandomised studies......
B(ii).3Assessment of the measures taken by investigators to minimise bias in the nonrandomised studies
B(ii).4 Characteristics of the nonrandomised studies......
B(ii).5 Outcome measures of the nonrandomised studies......
B(ii).6 Results of the comparison involving nonrandomised studies......
B(ii).7 Extended assessment of comparative harms......
B(ii).8 Interpretation of the clinical evidence......
Section C(i) Translating the clinical evaluation: Guidance in relation to indirect comparisons based on randomised trials or nonrandomised studies
C(i).1–C(i).4Relevant premodelling studies
Section D(i) Economic evaluation for the main indication: Presenting a cost- minimisation approach
D(i).1Estimation of the equi-effective doses......
D(i).2Presentation of a cost-minimisation analysis or a cost analysis......
Section E(i) Estimated extent of use and financial implications: Market-share approach
Introduction......
E(i).1Justification of the selection of sources of data......
E(i).2Estimation of use and costs of the proposed drug......
E(i).3Estimation of changes in use and cost of other drugs......
E(i).4Estimated financial implications for the PBS/RPBS or the NIP......
E(i).5Estimated financial implications for government health budgets......
E(i).6Identification, estimation and reduction of uncertainty......
PART IV INFORMATION REQUESTS FOR SPECIFIC PRODUCT TYPES....
Product type 1Fixed combination products......
Introduction......
PT1.1Matters to consider for the listing of fixed combination products......
PT1.2Providing advice under subsection 101(4AC)......
Product type 2Nutritional products......
Introduction......
PT2.1General requests for additional information......
PT2.2Additional information requested for specific medical conditions......
PT2.3Additional guidance for identifying the main comparator......
Product type 3Vaccine products......
Introduction......
PT3.1Details of the proposed vaccine and its intended use on the PBS or NIP (submission section A)
PT3.2Clinical evaluation for the main indication (submission section B)......
PT3.3Translating the clinical evaluation to the listing requested for inclusion in the economic evaluation (submission section C)
PT3.4Economic evaluation for the main indication (submission sectionD)
PT3.5Estimated extent of use and financial implications (submission sectionE)
APPENDIXES......
Appendix 1Relevant factors influencing decision making by PBAC......
Appendix 2Improving the alignment between TGA registrations and PBS restrictions
Appendix 3Grandfathering......
Appendix 4Expert opinion......
Appendix 5Assessment of noninferiority......
Appendix 6Utility valuation of health outcomes......
Appendix 7Monetary valuation of healthoutcomes......
Appendix 8Including nonhealth care resources and nonhealth outcomes in a supplementary analysis
Appendix 9Developing utilisation and financial estimates......
Appendix 10Measures taken by the investigators to minimise bias in nonrandomised studies
Tables
Table3.1...... Checklist of information to be included in a minor submission
Table 6.1Checklist of information to be included in a major submission
Table ES.1Checklist for the executive summary of a major submission
Table B.2.1Summary of identification of direct randomised trials from the search of the published literature
Table B.2.2Summary of identification of sponsor’s direct randomised trials and information from the manual search of retrieved citations
Table B.2.3Trials (and associated reports) presented in the submission
Table B.2.4Reasons to exclude each trial from further detailed assessment
Table B.2.5Comparative summary of characteristics of direct randomised trials
Table B.2.6Comparative summary of results of direct randomised trials
Table B.3.1Summary of the measures undertaken to minimise bias in the direct randomised trials
Table B.3.2Flow of participants through the direct randomised trials
Table B.4.1Eligibility criteria in the direct randomised trials
Table B.4.2Characteristics of participants in the direct randomised trials varying across randomised groups
Table B.4.3Interventions compared by the direct randomised trials
Table B.5.1Primary outcomes and statistical analyses of the direct randomised trials
Table B.5.2Patient-relevant secondary outcomes and analyses in the direct randomised trials
Table B.6.1Results of [patient-relevant outcome] (available as dichotomous data) across the direct randomised trials (relative risk)
Table B.6.2Results of [patient-relevant outcome] (available as dichotomous data) across the direct randomised trials (risk difference)
Table B.6.3Results of [patient-relevant outcome] (available as continuous data) across the direct randomised trials (end point)
Table B.6.4Results of [patient-relevant outcome] (available as continuous data) across the direct randomised trials (change)
Table B.6.5Results of [patient-relevant outcome] across the direct randomised trials (available as time-to-event data)
TableB.8.1 Classification of the therapeutic relativity of the proposed drug over its main comparator and guide to the suitable type of economic evaluation
Table C.2.1Assessment of treatment effect variation across subgroups
Table C.2.2Assessment of relative treatment effect variation across subgroups
Table C.2.3Assessment of absolute treatment effect variation across subgroups
Table C.2.4Summary of assessment of treatment effect variation across subgroups
Table C.2.5Reasons to exclude each direct randomised trial
Table C.4.1Summary of results of premodelling studies and their uses in the economic evaluation
Table D.2.1Comparison of characteristics of trial and requested populations and circumstances of use
Table D.4.1List of health care resource items and unit costs included in the economic evaluation
Table D.5.1List of health care resource items and summary of cost impacts in the economic evaluation
Table D.5.2List of health care resource items and summary of cost impacts for each health state in a state transition model
Table D.5.3List of health states and summary of cost impacts included in the economic evaluation
Table D.5.4List of health states and summary of health outcomes included in the economic evaluation
Table D.5.5Assessment of the implications for the economic evaluation of applying the clinical evaluation (Step1 then Step2)
Table D.5.6Assessment of the implications for the economic evaluation of extrapolating and transforming the clinical evaluation (Step3)
Table D.6.1Analyses of the implications for the economic evaluation of usage beyond the requested populations and circumstances of use
TableE.1.1...... Categories of data sources
Table B(i).2.1Trials (and associated reports) presented in the submission
Table B(i).2.2Reasons to exclude each trial from the indirect comparison
Table B(i).2.3Summary of randomised trials used to conduct the indirect comparison
Table B(i).6.1Summary of results of the indirect comparison
Table B(ii).2.1Studies (and associated reports) presented in the submission
Table B(ii).2.2Reasons to exclude each study
TableA1.1...... Factors that are more readily quantified
TableA1.2...... Examples of factors that are less readily quantified
Table A4.1Methods to collect and collate expert opinion
Figures
Figure 5.1Key decisions and stages in preparing a major submission to PBAC (bold boxes show steps for the majority of submissions and are described in Part II of these guidelines; alternative steps for a minority of submissions are described in Part III)
FigureA.1 Key information requests for submission section A of a major submission to PBAC
FigureB.1 Key information requests for submission section B of a major submission to PBAC
Figure B.2Assessment of statistical significance of superiority and noninferiority
FigureC.1 Key information requests for submission section C of a major submission to PBAC
Figure D.1Key information requests for submission section D of a major submission to PBAC
Figure E.1Key information requests for submission section E of a major submission to PBAC
Figure B(i).1Key information requests for submission section B of a major submission to PBAC with clinical data from an indirect comparison of randomised trials
Figure B(ii).1Key information requests for submission section B of a major submission to PBAC with clinical data from nonrandomised studies
Figure C(i).1Key information requests for submission section C of a major submission to PBAC with clinical data from an indirect comparison of randomised trials (Section B(i)) or from nonrandomised studies (Section B(ii))
Figure D(i).1Key information requests for submission section D of a major submission to PBAC in which the therapeutic conclusion from submission section B is noninferior
Figure E(i).1Key information requests for submission section E of a major submission to PBAC using the market share approach for estimating the extent of use and financial implications
Figure A9.1Development of utilisation and financial estimates (submission sectionE): relationship between the epidemiology and market-share approaches
Boxes
Box 1.1Roles of the Pharmaceutical Benefits Advisory Committee......
Box1.2General guidelines followed by PBAC......
Box 1.3Timeline of PBAC procedures......
Key points — writing style used in these guidelines......
Key points — types of submissions......
Key points — approach to economic evaluation......
Key points — organisation of a major submission......
BoxB.3.1 Checklist for assessing the quality (internal validity) of randomised trials 71
Contents1
Abbreviations
the Act / National Health Act 1953ACIR / Australian Childhood Immunisation Register
ACTR / Australian Clinical Trials Registry
ADEC / Australian Drug Evaluation Committee
AQoL / Assessment of Quality of Life
AR-DRG / Australian Refined DiagnosisRelated Group
ARTG / Australian Register of Therapeutic Goods
ATAGI / Australian Technical Advisory Group on Immunisation
ATC / anatomical therapeutic chemical
CBA / cost-benefit analysis
CEA / cost-effectiveness analysis
CI / confidence interval
CUA / cost-utility analysis
CV / contingent valuation
DoHA / Australian Government Department of Health and Ageing
DPMQ / dispensed price for maximum quantity
DUE / drug usage evaluation
DUSC / Drug Utilisation Sub-Committee
ESC / Economics Sub-Committee
HUI / Health Utilities Index
ID / identification
ITT / intention to treat
MAUI / multi-attribute utility instrument
MBS / Medicare Benefits Scheme
NIP / National Immunisation Program
NNT / number needed to treat
NPS / National Prescribing Service
NPWP / Nutritional Products Working Party
PBAC / Pharmaceutical Benefits Advisory Committee
PBPA / Pharmaceutical Benefits Pricing Authority
PBS / Pharmaceutical Benefits Scheme
QALY / quality-adjusted life-year
QUM / quality use of medicines
RADAR / Rational Assessment of Drugs and Research
RDI / recommended dietary intake
RPBS / Repatriation Pharmaceutical Benefits Scheme
RSA / risk-sharing arrangement
SG / standard gamble
TGA / Therapeutic Goods Administration
TGP / Therapeutic Group Premium
TPN / total parenteral nutrition
TTO / time trade-off
WTP / willingness to pay
Abbreviations1
PART I
GENERAL INFORMATION
1Role of the Pharmaceutical Benefits Advisory Committee
1.1Overview of PBAC roles
The Pharmaceutical Benefits Advisory Committee (PBAC) is established under the National Health Act 1953 (the Act). Its primary role is to recommend to the Minister for Health which drugs and medicinal preparations should be subsidised by the Australian Government under the Pharmaceutical Benefits Scheme (PBS). In doing this, PBAC is required by the Act to consider both the effectiveness and cost of the proposed drugs and medicinal preparations.
Since the beginning of 2006, PBAC has also been required under the Act to recommend to the Minister for Health vaccines for funding under the National Immunisation Program (NIP). The principles described here for considering PBS listing of drug products in general also apply to the funding for vaccines by the NIP. Accordingly, in the remainder of these guidelines, unless otherwise indicated, references to the PBS should be taken to include the NIP, and the term ‘drugs’ to include vaccines. Following due process, PBAC regularly reviews the list of PBS items, including restrictions, maximum quantities and number of repeats. It also provides advice about any other matters relating to the PBS that are referred to it by the minister.