Amgen Australia Pty Ltd A B N 31 051 057 428

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Submission in Response to the Proposal for the regulation of IVD companion

diagnostics Consultation Paper           

04 Dec 2018         

Amgen Australia Pty Limited    

Level 7, 123 Epping Road NORTH RYDE NSW 2113

         

COMMERCIAL-IN-CONFIDENCE

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About Amgen:

Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to be one of the world's largest independent biotechnology companies and is developing a pipeline of medicines with breakaway potential.

Amgen maintains an extensive clinical trial program and invests significantly in research and development annually. Amgen's history of clinical trial activity in Australia dates back almost 30 years and our reputation for quality and safety continues to make us one of the most trusted destinations in the world for Amgen research.

Amgen Australia contributes disproportionately to the global cl inical trial effort by being in the top ten countries for active cl inical studies and in the top five for interventional studies. In 2017, this included 694 Australian patients, participating in 49 clinical trials, including 16 investigator-sponsored studies, at over 75 leading Australian hospitals.

Importantly, Australia is a particularly sought-after location for Amgen's early development studies. In 2017, 22% of our work was in Phase I trials and first-in-human studies represented over half of this.

Amgen is committed to taking an active role in contributing to future public policy that is relevant to biologic medicines and industry development in Australia.

Response to the specjfjc jssyes rajseg io the consultatjon Paper

For ease of reference, our comments on the questions for consideration arising from Proposals 1 to 10 of the consultation paper are provided below in tabulated form.

Responses to individual questions are provided in the order in which they were asked in the consultation paper, under each proposal.

Comments on the Proposal for the regulation of IVD companion diagnostics Consultation paper

j; - b - I mm] r • E;t • -. .... • . ,,II~ Questions for consideration - Proposal 1

01 Is the proposed definition of IVD cox clear It is Amgen's opinion that the proposed definition of an IVD Companion Diagnostic is enough? clear enough.

Q2 Is the proposed definition appropriately aligned The proposed definition would seem to be appropriately aligned with the EU and US

with the EU and US FDA definitions? FDA definitions, considering the requirement to account for the definitions of a medicine and a biological therapeutic as currently specified in the Therapeutic Goods Act.

Q3 Do you have any other comments or suggestions No comments. about the proposed definition?

Q4 Do you have any other comments or suggestions No comments. for alternative or additional strategies?

Questions for consideration - Proposal 2

Q5 Is the meaning of 'essential for the safe and It is our opinion that the proposed meaning of 'essential for the safe and effective use' effective use' as used in the definition of IVD cox is clear enough. However, Amgen encourages TGA to develop more precise clear enough? guidance concerning how product labelling will describe the concept of essential for

the safe and effective use.

Q6 Do you have any other comments or suggestions Amgen is of the opinion that references to approved IVD CDx in the Product

about the proposal to include references to Information (PI) of corresponding medicines and biologicals should not be so specific

approved IVD CDx in the PI and CMI of as to result in limitations to usage where there are multiple IVDs available, the use of

corresponding medicines and biologicals? which is supported by appropriate evidence.

For this reason, Amgen supports the TGA proposal that expectations in relation to wording in the PI documents could be negotiated on a case-by-case basis and could refer to either commercially supplied IVD CDx or to in-house IVD CDx as appropriate.

Amgen encourages TGA to ensure that naming of therapeutic goods in product labelling is sufficiently broad so as not to introduce additional regulatory burden in the event of revisions to product names. At the very least, Amgen suggests that reference to trade names of medicines and/or devices should not be included in

lftu ~,111111 - ,_, .... ~ •• ..._-,mm:J1~ .... IHI] 1r.• •~ Q6 contd. product literature. Amgen notes reference to Consumer Medicine Information (CMI) as well as PI in this proposal and encourages TGA to ensure that any requirements for content of CMI concerning IVD CDx appropriately reflects consumer understanding, and expectations for information, relating to their medicines.

Q7 Do you have any other comments or suggestions Amgen encourages TGA to ensure that naming of therapeutic goods in product about the proposal for the IFU of approved IVD labelling is sufficiently broad, so as not to introduce additional regulatory burden into cox to include references to the corresponding the proposed regulatory framework. medicine or biological?

The consultation acknowledges that many IVD CDx are developed overseas, and therefore device instructions for use (IFUs) are not necessarily specific for Australia. Amgen considers that the requirement set forth in the EU IVD regulations, that the IFU for the device must contain the International Non-proprietary Name (INN) of the corresponding medicinal product, should be considered by TGA as in the event of revisions to product names, the corresponding device IFU is unlikely to require major revision.

Questions for consideration - Proposal 3

Q8 Do you have any comments or suggestions about Amgen has no objection to the proposal to classify all companion diagnostics as the proposal to c lassify all companion Class 3 IVDs. diagnostics as Class 3 IVDs to ensure appropriate and consistent regulation of IVD cox in future?

Q9 Is the proposed amendment to Rule 1.3 clear Amgen is of the opinion that the proposed amendment to Rule 1.3 of Schedule 2A in enough? the Medical Device Regulations is suitably clear and unambiguous.

Questions for consideration - Proposal 4

Q1 0 Do you have any comments or suggestions about With respect to the proposal to require a compulsory audit of all IVD CDx prior to the proposal to require a compulsory audit of all inclusion in the ARTG, the consultation notes that where suitable evidence of IVD cox prior to inclusion on the ARTG? assessment by a comparable overseas regulator is provided then TGA assessment

could be abridged, and the audit assessment fee reduced accordingly.

lftu ~,111111 - ,_, .... ~ •• ..._-,mm:J1~ .... IHI] 1r.• •~ Q10 contd. The potential impact of a compulsory audit of the IVD CDx on the timelines for review and approval of both a medicine/biological and an accompanying IVD CDx, where applications are made in parallel for approval of both, is of concern to Amgen .

As sponsors make use of accelerated approval pathways (such as the provisional approval pathway) to make medicines available to patients sooner, the clinical evidence and level of assessment (supporting safe and effective use of the IVD CDx) available to TGA from comparable overseas regulators is expected to vary. Amgen encourages TGA to consider further how any abridged audit assessment procedure could work in practice, and to define in regulatory guidelines the extent of such assessments based upon the level of information available.

Q11 Is the proposed amendment to Regulation 5.3 The proposed amendment to Regulation 5.3 (1 )U) is, in our opinion, suitably clear and clear enough? unambiguous.

Questions for consideration - Proposal 5

Q12 Do you have any comments or suggestions about Amgen supports the concept of unique identification of individual IVD CDx included in the proposal to amend Regulation 1.6 to require a the ARTG and encourages alignment with overseas regulators to avoid imposition of unique product identifier as a characteristic for additional regulatory burden upon industry. identification of all lVD companion diagnostics in applications for inclusion on the ARTG?

Q13 Do you have any other suggestions for the No comments. effective identification of IVD companion diagnostics that are included on the ARTG?

Q14 Do you have any comments or suggestions Amgen encourages TGA to ensure that identification of IVD companion diagnostics is regarding the publishing of a list of approved IVD straightforward and does not require manual ongoing maintenance. This could companion diagnostics on the TGA website readily be achieved with a searchable flag in the ARTG entries for IVD CDx. (similar to the US FDA approach)?

Questions for consideration - Proposal 6

Q15 As discussed under proposal 4, a compulsory Amgen acknowledges the intent of the proposal to ensure that clinical evidence

audit to ensure the safety and performance of all adequately supports IVD CDx safety and performance and encourages TGA to IVD cox could become a requirement. It is ensure that the proposed compulsory audit does not introduce unnecessary therefore proposed that an application audit fee regulatory burden, particularly for devices with a history of safe and effective use in should apply to all IVD cox to ensure full cost Australia. recovery by the TGA for the assessments

Q15 contd. required. Do you have any comments or suggestions about the proposal that an application audit fee should apply to all IVD cox applications for inclusion (subject to any fee reductions that may be applicable for abridged assessments)?

Q16

Q17

Do you have any other comments or suggestions about the proposal that an assessment fee should apply to applications to vary an ARTG inclusion of an IVD cox where an assessment is required for a new intended purpose for the device?

Questions for consideration - Proposal 7

Do you have any comments on the proposal for transitioning of IVD cox under existing ARTG entries to meet the proposed new requirements as outlined in this paper?

•-11••· ~ •• ..._-,mm:J1~ .... 11(1] 1r.• •~

Amgen acknowledges the intent of the proposal, to ensure that TGA applies appropriate cost recovery principles to what is essentially a retrospective approval step for existing medical devices. In consideration of this, we encourage TGA to consider any unanticipated consequences to industry that may arise from the imposition of assessment fees resulting from such an undertaking.

As a company whose mission is to serve patients, Amgen encourages TGA to consider the potential impacts of transition timeframes on the ongoing ability of healthcare professionals to maintain access to existing IVD CDx, where there is a demonstrated clinical need associated with treatment of patients under their care.

As is noted elsewhere in this consultation, there are many IVD CDx already included on the ARTG with an intended purpose that meets the proposed definition of an IVD CDx. In consideration of the risks associated with availability of appropriate clinical evidence to support transitioning existing ARTG entries, and the expected volume of work associated with these activities, it appears that a 2-year transition period may not be readily achievable in practice.

Noting that the new European IVD Regulation 2017/746 was introduced by a comparable overseas regulator, Amgen encourages TGA to consider an identical 5-year timeframe for the transition of existing ARTG entries. Should TGA consider the proposed 2-year transition period to be appropriate, Amgen further encourages the exploring of an alternative option whereby sponsors could, on a case by case basis, apply for an extension to the transition period with such requests to be made and evaluated based upon their own merit.

lftu ~,111111 - ,_, .... ~ •• ..._-,mm:J1~ .... IHI] 1r.• •~ Q18 In particular, do you have any comments on No comments. options a,b and c for the auditing of existing IVD cox transitioning to the new framework?

Questions for consideration - Proposal 8

Q19 Do you have any comments on the transition No comments. timeframe proposed for existing IVD cox to meet the requirements of the new framework?

Questions for consideration - Proposal 9

Q20 Do you have any comments or suggestions on Amgen agrees that where an in-house IVD CDx supports the safe and effective use the proposal that in-house IVD cox should of a targeted therapy, that it's use should be supported by appropriate clinical comply with the clinical evidence and analytical evidence and analytical data. performance requirements applicable to all lVD cox? Amgen encourages TGA to ensure that equivalent standards of evidence and

compliance are applied to all IVD CDx, whether they are commercial or in-house devices. The current situation whereby Class 3 in-house IVDs are not required to be included in the ARTG is potentially inconsistent with the goals of this consultation paper concerning identification of IVD CDx and precludes identification of in-house IVD CDx from the ARTG entry details. It is difficult to determine how the coordinated pre-market assessment of a therapeutic good and its corresponding in-house IVD CDx would occur with the current arrangements for in-house IVDs.

We welcome the development of guidelines for cl inical evidence and analytical performance requirements for IVD CDx, including in-house IVD, and look forward to the communication of further information from TGA on the timelines for availability of guideline documents.

Q21 Do you have any comments or suggestions No comments. regarding the compliance of in-house IVD cox with the proposals outlined in this paper?

Q22

Questions for consideration - Proposal 10

To provide assurance of the safety and efficacy of targeted therapies, an IVD cox and its corresponding medicine or biological should ideally be evaluated and approved concurrently. Do you have any comments or suggestions regarding the ways in which concurrent evaluation may be facilitated?

•-11••· ~ •• ..._-,mm:J1~ .... 11(1] 1r.• •~

Amgen agrees with the TGA proposal to review an application for an IVD CDx within the context of, and in conjunction with, its corresponding therapeutic good in a coordinated review and supports the development of guidance for sponsors on the requirements for clinical evaluations and labelling.

The consultation paper is not clear, however, as to how concurrent evaluation may be facilitated and the potential impact this will have upon the timelines for product registration and reimbursement applications. Where an application for reimbursement runs in parallel with an application to register a new therapeutic good, the availability of a Delegates Overview/Summary from the TGA Delegate is required to support a decision by the PBAC on reimbursement. Likewise, a favourable decision from the MSAC is required for reimbursement of an in vitro diagnostic test through a comparable process. Amgen suggests that TGA fully considers how these processes will run in parallel, and the potential impact to timelines and availability of products to patients.

Furthermore, with the introduction of the Provisional Approval Pathway and the opportunity to obtain registration whilst clinical development continues, has TGA considered how coordinated pre-market assessment will take place where there is a potentially limited cl inical data set and accelerated assessment timeframes to consider?

The consultation paper clearly recognises that instances will exist where an Australian sponsor partners with a third party to concurrently bring a new therapeutic good and an accompanying IVD CDx to the market. It is not immediately clear what provisions may be proposed for the sponsor to initiate communication between themselves, the third party IVD CDx manufacturer, and the TGA. Could TGA please clarify how, for example, a '3-way' meeting between concerned parties could be initiated under the proposals outlined in this consultation and how the assessment between TGA assessors is proposed to take place under accelerated approval timeframes?

lftu ~,111111 - ,_, .... ~ •• ..._-,mm:J1~ .... IHI] 1r.• •~ Q23 Do you have any comments on the proposal No comments. under a) above that a change in intended purpose of an IVD CDx would require an application to vary the ARTG entry and submission of evidence which supports the new intended purpose?

Q24 Do you have any comments on the proposal Amgen supports the development of guidance for sponsors on the requirements for under b) above that any IVD CDx that was not clinical evidence and analytical performance requirements that would be applicable to

used in the clinical trials of a targeted therapy IVD CDx, including in house IVDs.

must demonst rate equivalent performance to the In a given development program, initial clinical studies (phase 1/phase 2) may reference test in concordance studies? commence using an in-house IVD to make cl inical decisions such as stratifying patients for inclusion/exclusion in a trial. Traditional phase 3 registrational studies may subsequently be conducted using alternative in-house or commercial IVD CDx solutions, in line with current cl inical practice. In such instances, the availability of guidance documentation to clearly address how to meet the requirement for demonstrating equivalent performance to the reference test in concordance studies will be of benefit to sponsors.

General Comments

TGA will develop guidance materials Amgen welcomes TGA developing guidance material to assist sponsors of therapeutic goods, whether medicines, biologicals or IVDs, impacted by this proposed change and expects that such guidance material will undergo consultation with relevant parties.

Whilst a major impact of the proposals in this consultation paper will fall on sponsors and manufacturers of existing commercial and in-house IVD CDx, there is potential for impact on sponsors of medicines due to a historically inconsistent approach to inclusion of information concerning IVDs essential for the safe and effective use within the Product Information of medicines. Amgen suggests that revisions of labelling for medicines should not be required solely for the purpose of introduction of the revised regulatory regime for IVD CDx.

ARTG entries vs available in the market Amgen would like to make the point that there is a distinction between registration and inclusion of a medicine and device in the ARTG and their ready availability to healthcare practitioners and consumers, which is largely driven by the reimbursement processes for medicines and medical services. Has consideration been given to situations where there may be inconsistency between the ARTG and the availability

Potential unintended consequences of proposal

of therapeutic goods and their associated IVD CDx?

Further, Amgen would encourage TGA to consider the situation where IVDs might be bein su lied under rovisions such as the S ecial Access Scheme SAS . Amgen notes that introduction of compulsory audit of all IVD CDx presently included in the ARTG, and associated costs, could potentially lead to withdrawal of IVDs from the Australian market.

Amgen encourages TGA to ensure that it is adequately resourced in order that the intended concomitant evaluation occurs in a timely manner for both the medicine/biological and device evaluations. This could be particularly impactful durin the ro osed 2- ear transition eriod for IVD CDx.