Australian Public Assessment Report (AusPAR) for ...€¦ · Web viewIt will not be updated to reflect subsequent changes to a product that is listed on the ARTG. A new AusPAR will

Therapeutic Goods Administration

About the Therapeutic Goods Administration (TGA) The TGA is a division of the Australian Government Department of Health and Ageing, and is responsible for regulating medicines and medical devices. TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. The work of the TGA is based on applying scientific and clinical expertise to decision-making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. To report a problem with a medicine or medical device, please see the information on the TGA website.About AusPARs An Australian Public Assessment Record (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. AusPARs are prepared and published by the TGA. An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations, and extensions of indications. An AusPAR is a static document, in that it will provide information that relates to a submission at a particular point in time.Copyright© Commonwealth of Australia 2010This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part may be reproduced by any process without prior written permission from the Commonwealth. Requests and inquiries concerning reproduction and rights should be addressed to the Commonwealth Copyright Administration, Attorney General’s Department, National Circuit, Barton ACT 2600 or posted at http://www.ag.gov.au/ccaAustralian Public Assessment Report (AusPAR) Guidance Document Version 1.2 (October 2010) Page 2 of 15

October 2010

Therapeutic Goods Administration A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA.

Copyright© Commonwealth of Australia 2010This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part may be reproduced by any process without prior written permission from the Commonwealth. Requests and inquiries concerning reproduction and rights should be addressed to the Commonwealth Copyright Administration, Attorney General’s Department, National Circuit, Barton ACT 2600 or posted at http://www.ag.gov.au/ccaAustralian Public Assessment Report (AusPAR) Guidance Document Version 1.2 (October 2010) Page 3 of 15

Therapeutic Goods Administration

Contents1. Introduction_______________________________________________________________42. Context_____________________________________________________________________43. Legislative framework___________________________________________________44. Description________________________________________________________________55. AusPAR by submission type____________________________________________66. Process for development of an AusPAR_______________________________76.1 Sources of AusPAR content____________________________________________________________76.2 Review of Draft AusPAR_______________________________________________________________76.3 Commercially Confidential Information______________________________________________86.4 Outcome of review of draft AusPAR__________________________________________________86.5 Failure to Review a Draft AusPAR____________________________________________________87. Publishing an AusPAR___________________________________________________87.1 Approved Submissions________________________________________________________________87.2 Rejected Submissions__________________________________________________________________97.3 Withdrawn Submissions_____________________________________________________________108. Links to Product Information_________________________________________10Appendix 1 - Principles to be applied for the deletion of commercially confidential information in an AusPAR_________________11Introduction_______________________________________________________________________________11General principles________________________________________________________________________11Non-clinical and Clinical Information___________________________________________________13AusPAR Conclusions______________________________________________________________________13

Australian Public Assessment Report (AusPAR) Guidance Document Version 1.2 (October 2010) Page 4 of 15

Therapeutic Goods Administration1. IntroductionCommencing in December 2009, the Therapeutic Goods Administration (TGA) has begun publishing information about its decisions relating to the evaluation of prescription medicines. The information outlines the outcomes of the TGA’s evaluation process, and provides the rationale on which a decision was made to approve or not approve a prescription medicine submission. The information is provided in an Australian Public Assessment Report (AusPAR), which is published on the TGA website. The AusPAR represents a key addition to the regulatory framework for the evaluation of prescription medicines within Australia.An AusPAR will be developed for each major submission for prescription medicines that is considered for entry, or variation of that entry, onto the Australian Register of Therapeutic Goods (ARTG). This will include submissions that relate to new chemical and biological entities, generic medicines, extension of indication/s, and significant variations. More details on the submission types that will have AusPARs prepared are available on the next page.The AusPAR will be a static document, in that it will provide information that relates to a submission at a particular point in time. It will not be updated to reflect subsequent changes to a product that is listed on the ARTG. A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA.2. ContextThe introduction of the AusPAR follows reviews and industry consultation over a number of years. The AusPAR is consistent with similar transparency measures introduced within the European Union and United States.The European Medicines Agency (EMA) has introduced the European Public Assessment Report (EPAR) providing comprehensive information about its evaluation of prescription medicines. Similarly, the US Food and Drug Administration (FDA) publish extensive information about its evaluation of prescription medicines. 3. Legislative frameworkThe legislative basis by which the TGA can publicly release information is contained within Section 61 of the Therapeutic Goods Act 1989 (the Act). The following sections apply: Section 61(5A) provides that the Secretary may release to the public therapeutic good information relating to any decision or action taken under the Act or the Regulations; Section 61(5C) provides that the Secretary may release to the public therapeutic goods information of a kind specified under subsection (5D); Section 61(5D) provides that the Minister may, by legislative instrument, specify kinds of therapeutic good information for the purpose of subsection (5C).The Therapeutic Goods Information Specification 2009 came into effect on 7 November 2009 and provides details of the kinds of information that the TGA can publish.Notwithstanding the basis on which the information can be released, TGA carries additional obligations under Commonwealth legislation, international statute, and common law relating to types of information that can and cannot be released. Examples include the following: Privacy Act 1988;

Freedom of Information Act 1989;

Common law (legal duty of confidence);


ConclusionPharmacovigilance

ClinicalNon-clinical

QualityIntroductionAusPAR

This section comprises basic information about the product, provided in tabulated form extracted from the submission

This section provides a summary of the non-clinical safety aspects of a productThis section provides a summary of the clinical efficacy and safety aspects of a productThis section provides a summary of the pharmacovigilance systems and risk management activities of a product

This section provides a summary of salient issues identified during evaluation and sets out the rationale for the decision by the delegate

This section provides a summary of the quality aspects of a product

Therapeutic Goods Administration Agreement between the World Intellectual Property Organisation and the World Trade Organisation Agreement on Trade-Related Aspects of Intellectual property Rights (1994) (the TRIPS Agreement); and The Australia-United States Free Trade Agreement. 4. Description An AusPAR for a prescription medicine is a document prepared by the TGA which records crucial aspects of the evaluation of a submission leading to a decision by the TGA. Its component sections are provided in Figure 1. AusPAR structure and content may vary according to a range of factors such as: Submission / Product Type. What the submission relates to (as per Figure 2) Procedural. If the submission was referred to an expert advisory committee, for example the Australian Committee on Prescription Medicines (ACPM), formerly known as Australian Drug Evaluation Committee (ADEC) Substance type. If the submission relates to a radiological agent, radiopharmaceutical, certain vaccines, or a range of other substances Process. If the decision or other information relating to the evaluation changes as a result of a review or appeal.

Figure 1 - AusPAR components


Therapeutic Goods Administration5. AusPAR by submission typeThe following diagram summarises how the TGA will exercise its discretion in relation to the preparation and publication of an AusPAR for submissions known as category 1 and 2 within the regulatory framework for prescription medicines.

SubmissionAusPAR

Yes NoTGA

DiscretionNew Chemical or Biological Entity New salt/ester, or existing active ingredient Biosimilar medicine New combination Extension of Indication New Generic Medicine New medicinal product strength New dosage form New route of administration Change/increase in patient group Change in dosage Additional Trade Name Change of formulation (excipient) or change of container PI Change, requiring the evaluation of clinical, non-clinical or bioequivalence data Editorial change to PI Figure 2 – Summary of AusPARs for category 1 and 2 submissions


Sources of AusPAR contentSubmission

Chemistry and quality control evaluation report

Pharmacovigilance summary

Module 4 assessment reportModule 5 clinical evaluation report

Evaluation report for biopharmaceutic data

Source of content Section

Delegate decisionExpert advisory groups

Delegate overview

1. Introduction to product submission2. Quality3. Non-clinical4. Clinical5. Pharmacovigilance

6. Conclusion

Therapeutic Goods Administration6. Process for development of an AusPAR6.1 Sources of AusPAR content An AusPAR is compiled by the TGA using key components and stages of the evaluation and assessment process for most prescription medicine submissions as shown below in Figure 3.

Figure 3 - AusPAR sources of content

6.1.1 AusPAR content for new generic medicinesFor new generic medicines the format of the AusPAR will include: an extract of the decision letter the statement of bioequivalence the approved Product Information.6.2 Review of Draft AusPAROnce an AusPAR is drafted, the sponsor is provided with the opportunity to review the document prior to it being published. This review is provided for the purposes of allowing a sponsor to identify any significant commercially confidential information which, although permitted to be released under sections 61 (5C) and 61 (5D) of the Therapeutic Goods Act 1989 (the Act), the TGA may decide not to publish in an AusPAR. If a sponsor requests the removal of content considered significantly commercially confidential, the sponsor may provide alternative text for consideration by the TGA as replacement content.


Therapeutic Goods AdministrationCompletion of an AusPAR is independent from other regulatory processes. That is, the delegate decision, marketing approval, and related regulatory processes are not dependent on finalisation of an AusPAR. 6.2.1 Review PeriodThe TGA provides a sponsor with 14 calendar days to undertake a review of the proposed AusPAR and identify any information that they feel is commercially confidential that they do not want published in an AusPAR. 6.3 Commercially Confidential Information The TGA recognises the potential impact that disclosure of significant commercially confidential information may have. The purpose of section 61 of the Act is to allow information, including confidential information, to be made publicly available or to be made available to certain parties for a particular purpose. However, the TGA may elect to not publish confidential information even though this power exists under the Act. Guidance on the classification of commercially confidential information is provided at Appendix 1 - Principles to be Applied for the Deletion of Commercially Confidential Information. It provides guiding principles and procedural direction to assist the TGA and a sponsor to identify what information could be identified for consideration for removal by the TGA from a draft AusPAR. Information that is already in the public domain is not considered as commercially confidential. For example, the prior publication of an evaluation outcome from an overseas regulator would be considered information already in the public domain. 6.4 Outcome of review of draft AusPARFollowing a sponsor’s review of a draft AusPAR, the TGA will review any proposed changes relating to the removal of commercially confidential information by a sponsor. Should there be disagreement about the proposed inclusion/removal of content, an internal review process will be applied by the TGA. This will involve a sponsor providing a request / justification for the removal of the content in writing to the TGA, which will be referred for advice (as needed) prior to making a decision about its inclusion/exclusion. The internal review process will be undertaken with the aim of publishing the completed AusPAR within 4 weeks from the date the product is included on the Australian Register of Therapeutic Goods (ARTG). More details about publishing timeframes for an AusPAR, based on whether the Aus PAR is approved, not approved or the submission is withdrawn are in the next Section - Publishing an AusPAR. 6.5 Failure to Review a Draft AusPARIf a sponsor does not respond to a TGA request to review an AusPAR, the TGA will proceed to publish the AusPAR in accordance with Section 61 of the Act. 7. Publishing an AusPAR The timeframe for when an AusPAR for a prescription medicine will be published by the TGA is dependent on whether the submission is approved or not approved by the delegate under Section 25 of the Act. Also, where the submission is withdrawn prior to a decision by a delegate under Section 25 of the Act, an AusPAR may be published; this will depend on when the withdrawal letter is received from the sponsor. The circumstances for publishing an AusPAR and applicable timeframes are provided in the relevant sections below.7.1 Approved SubmissionsWhere approval is given for a prescription medicine to be supplied in Australia, the TGA will aim to publish the AusPAR within 4 weeks from the date the product is included on the ARTG. This period is inclusive of the 14 day sponsor review period of the draft AusPAR.


Therapeutic Goods AdministrationThe provisions available to a sponsor for a review of a decision made under section 25 of the Act are described in the document Australian Regulatory Guidelines for Prescription Medicines. A sponsor has up to 90 days from notification of a decision in which to request a review of the decision. This applies to all decisions (approved or not approved decisions) made by a delegate. An AusPAR will be published for a submission for which approval was provided in any aspect and there are a number of examples where such “partial” approvals have been published. Where a review/appeal is received in relation to a submission for which “partial” approval was provided, the AusPAR will not be withheld from publishing. As indicated above, the TGA will aim to publish the AusPAR within the 4 week period from the time the product was included on the ARTG. In this situation, full details of the approved aspect(s) will be published but for the aspect(s) for which a review/appeal has been lodged, only the nature of the decision will be mentioned. In addition, appropriate notation will be made on the AusPAR and on the TGA website indicating that the decision is under review/appeal. Then at the conclusion of the internal review/appeal process, the published AusPAR will be updated to include the full details of the submission and to reflect any changes arising from the review/appeal process, following a sponsor review of the document in accordance with the previously described review process. If the sponsor is not satisfied with the outcome of a Section 60 appeal, and applies to the Administrative Appeals Tribunal (AAT) for review the AusPAR is not withheld from publishing pending any possible AAT appeal. As for the circumstance of an internal review/appeal, an appropriate notation will be made on the AusPAR and on the TGA website indicating that the decision is under AAT review.7.2 Rejected SubmissionsAn AusPAR will be published for a submission that has been rejected by the TGA. An AusPAR for a submission that is rejected will follow a similar format as for the same submission type that is accepted. If the decision of the delegate is to reject a submission the publication of the AusPAR will be withheld pending the expiration of the 90 day appeal period and finalisation of any associated Section 60 appeal process.The AusPAR will then be updated, if necessary, to reflect any changes arising from the review/appeal, before being forwarded to the sponsor for review in accordance with the review process previously described in this document. At this point, publication of the AusPAR will follow the same process as for an approved submission. If the sponsor is not satisfied with the outcome of a Section 60 appeal, and applies to the Administrative Appeals Tribunal (AAT) for review the AusPAR is not withheld from publishing pending any possible AAT appeal. An appropriate notation will be made on the AusPAR and on the TGA website indicating that the decision is under AAT review.At the conclusion of any AAT review, or other external court decision/outcome, the published AusPAR will be updated to reflect any changes arising from the review process. At this stage the sponsor will be provided the opportunity to review the document in accordance with the previously described review process.


Therapeutic Goods Administration7.3 Withdrawn SubmissionsA Sponsor may withdraw a submission/product at any time. The TGA may publish the advice that an application has been withdrawn and/or publish an AusPAR for the withdrawn submission. Whether or not publication of an AusPAR will occur will vary according to when the withdrawal letter is received from the sponsor, as outlined below in Figure 4.

Time of WithdrawalWithdrawal

Letter AusPAR

Yes No Yes NoBefore acceptance of the submission by the TGA After acceptance of a submission, but: for submissions for review by the Advisory Committee on Prescription Medicines (ACPM) (formerly known as ADEC), before the delegate’s overview is sent to the sponsor for submissions not for review by ACPM, before the end of the 14 day period for evaluation report review by the sponsor

After: for submissions for review by ACPM, the delegate’s overview is sent to the sponsor for submissions not for review by ACPM, the end of the 14 day period for evaluation report review by the sponsor

Figure 4 - AusPAR publication indicators where a submission is withdrawn

8. Links to Product InformationTo ensure the AusPAR can be read in conjunction with the relevant approved Product Information (PI), a copy of the PI will be included in the AusPAR document when it is published by the TGA. This version of the PI will remain static (similar to the AusPAR) and will be ‘watermarked’ to ensure that this is clear to the reader that a later version of the PI may be approved and available via the TGA PI/CMI publishing facility.Publishing the approved PI to the AusPAR does not replace the requirement for the sponsor to load their PI, and Consumer Medicine Information (CMI) documents onto the TGA eBusiness Services system.


Therapeutic Goods AdministrationAppendix 1 - Principles to be applied for the deletion of commercially confidential information in an AusPARIntroductionContent for an AusPAR will be derived from various outputs (reports, minutes, and related documents) of the evaluation and decision-making processes. Prior to the commencement of AusPAR, these outputs were developed solely for internal audiences, advisory groups recognised by statute, and sponsors of the submissions. Although these documents contained information that was confidential, the risk of inadvertent and/or unauthorised disclosure of the confidential information to unauthorised parties was low. These regulatory outputs now provide the basis for the content of an AusPAR. Given that the AusPAR will be publicly available, it is essential that any commercially sensitive information be identified and removed prior to publishing an AusPAR. This document does not purport to provide a legal basis for the removal and/or inclusion of information in an AusPAR. Rather, it provides general principles to assist the TGA and a sponsor come to a point of resolution where a disagreement occurs. This guide closely aligns to similar guidance provided by the European Medicines Agency (EMA). General principlesOpenness and transparency of the regulatory process is important in the promotion of public health. However, unless there is an overriding public interest in disclosure, the TGA will refrain from disclosing commercially confidential information when it might hurt the interest or prejudice to an unreasonable degree the commercial interests, of individuals or companies concerned.For the purposes of AusPARs, the TGA has adopted the EMA approach which broadly defines the following two categories of commercially confidential information: Confidential intellectual property, “know-how” and trade secrets (including e.g. formulas, programs, process or information contained or embodied in a product, unpublished aspects of trade marks, patents etc.); and Commercial confidences (e.g. details of commercial arrangements, development plans of a company). These principles will be applied so that commercially confidential information is deleted prior to publication or disclosure of an AusPAR. Information that is already in the public domain is not considered commercially confidential. If information has been in the public domain through a breach of the law, it could still be considered confidential in accordance with the principles of this document. However, the onus is on an owner of the information to inform the TGA (in writing) of the breach.In general, detailed information about the composition and product development may be commercially confidential but more general information should be disclosed. However, it is acknowledged that in certain circumstances, even a general description of a specific aspect could be regarded as commercially confidential, if justified.Composition and product developmentIn general, pharmaceutical development information for new products is commercially confidential. This includes detailed data concerning active substances, formulation and manufacturing and test procedures and validation. The final qualitative formulation (composition) of the authorised product is not commercially confidential.In general, the names of manufacturers or suppliers of the active substance or the excipients are accepted as commercially confidential, unless disclosure is necessary for public health reasons (e.g. for some biological products).Australian Public Assessment Report (AusPAR) Guidance Document Version 1.2 (October 2010) Page 12 of 15

Commercial in Confidence Not Commercial in Confidence

Details on the validation of the active substance manufacturing processOperating parameters and specific material requirements

Detailed information on the test methods used and the specification and quantitative acceptance criteria established for the active substance - unless the tests meet specific monographs in the European Pharmacopoeia

Qualitative and quantitative information – unless disclosure is necessary for public health reasons Detailed information concerning the particulars of studies

Naming specific impuritiesDetailed description of the synthetic process

General information on the characterisation of the active substance and statements confirming that the molecule is appropriately characterisedStatements confirming that the manufacturing and control processes have been validated

A general description of the types of test methods used and the appropriateness of the specification

A general statement on the results of studies regarding polymorphism and particle size

Information on the structure of the active substance Structure

Synthesis

Polymorphism and particle size

Characterisation

Biotechnology products

Cell banks

Manufacturing

Fermentation and purification

Test methods, specifications,

acceptance criteria

General information

Impurities and degradation

Details of characterisation methodsA general description of the active ingredient for biotechnology products, including type of molecule and its general structural features (e.g. number of amino acids, general glycosylation details) or of the type of producer cell (e.g. E.Coli, S. Cerevisiae, Chinese Hamster Ovary cells, Madin Darby Kidney cells) A general statement on the establishment of the Master Cell Bank (MCB) or Working Cell Bank (WCB) and on the stability of the cell banks

Therapeutic Goods AdministrationActive substances The principles contained in the diagram below apply to pharmaceutical and biological products, and will also apply to novel excipients.

Figure 5 – Classification of commercially confidential information for active substances


Commercial in Confidence Not Commercial in Confidence

Detailed descriptions of the manufacturing and control processes for the productDetails on the validation of the manufacturing process

Detailed information on the test methods included in the specification of the finished product and the quantitative acceptance criteria is commercially confidential, unless the tests are of Pharmacopoeial standard

Qualitative and quantitative information relating to degradation products is regarded as confidential unless disclosure is necessary for public health reasonsGeneral statements that the types of methods and specification used were appropriate.

Information on the outcome of stability studies (e.g. carried out in real time conditions or accelerated conditions).

Degradation products

Stability studies

Manufacturing

Test methods, specifications,

acceptance criteria

Therapeutic Goods AdministrationFinished productThe principles contained in the diagram below apply to pharmaceutical and biological products. Any confidentiality issue regarding novel packaging or medical device aspects should be justified by the sponsor and will be assessed according to the below principles.

Figure 6 - Classification of commercially confidential information for finished product

Non-clinical and Clinical Information As a general rule information encompassing non-clinical and clinical development and its subsequent assessment by TGA is not regarded as commercially confidential. An exception to this rule would be, for example, specific details on a method used in a study, which, upon justification from the sponsor, could be regarded as trade secret.Another example of commercially confidential information could be a development plan from the company, e.g. for a different indication, when it is neither requested by TGA nor related to the safety of the product. However, when such studies, their results and their timelines are part of the conditions for ARTG approval, they are not regarded as commercially confidential information.Data generated by the sponsor using another sponsor’s product, e.g. comparative studies against the reference medicinal product are not commercially confidential by virtue of this fact only. However the commercial confidentiality of such data shall be assessed in accordance with the principles set out in this document.AusPAR ConclusionsThe outcome of discussions involving the delegate and/or expert advisory committees is not commercially confidential, but the considerations described throughout this document will be applied in every case. Divergent views with (or within) an expert advisory committee, data related to the concerns raised, and recommendations for rejection are not generally commercially confidential.


Therapeutic Goods AdministrationPO Box 100 Woden ACT 2606 AustraliaEmail: [email protected] Phone: 1800 020 653 Fax: 02 6232 8605www.tga.gov.auReference/Publication #

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Australian Public Assessment Report (AusPAR) for ...€¦ · Web viewIt will not be updated to reflect subsequent changes to a product that is listed on the ARTG. A new AusPAR will