This is the text extract for Consultation on proposals for bortezomib and thalidomide.; Closing Date: Closed; Contact: Jackie Evans, browse documents here.

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27 January 2011

Proposals to widen access to thalidomide and to fund bortezomib for patients with multiple myeloma

PHARMAC is seeking feedback on proposals to: 1) fund a new brand and strength of thalidomide (Thalomid 50 mg and 100 mg capsules), through a provisional agreement with Celgene Pty Limited, and to widen access to thalidomide to include funding for all patients with multiple myeloma; and 2) fund bortezomib (Velcade) for patients with treatment naïve and relapsed/refractory multiple myeloma (i.e. first and second line treatment) through a provisional agreement with Janssen-Cilag Pty Limited. PHARMAC also clarifies for which indications bortezomib funding has now been considered by PHARMAC. In accordance with criterion iv of the Cancer Exceptional Circumstances scheme, these indications will generally not be approved for funding under that scheme. Although these two proposals are separate, resulting from two separate agreements with two different suppliers; because they are both for multiple myeloma treatments and the market dynamics of each treatment is influenced by usage of the other we have included both proposals in this single consultation letter. Please note that the proposal for bortezomib supersedes PHARMAC’s previous proposal for bortezomib, consulted on 15 December 2010, and suspended on 12 January 2011. Further details of these proposals, including how to provide feedback and background information can be found below and on the following pages. All changes would be implemented 1 April 2011 unless otherwise stated.

Feedback sought

PHARMAC welcomes feedback on these proposals. You are welcome to provide feedback on either of the two proposals individually, or both the proposals combined, whichever you prefer. If you provided feedback on the previous proposal for bortezomib (consulted on 15 December 2010, and suspended on 12 January 2011) your previous submission will be considered when making a decision on this new proposal; however, you may provide additional feedback if you wish to. To provide feedback, please submit it in writing by 5 pm Wednesday, 9 February 2011 to: Jackie Evans Therapeutic Group Manager PHARMAC Email: jackie.evans@pharmac.govt.nz Fax: 04 460 4995 Post PO Box 10 254, Wellington 6143

All feedback received before the closing date will be considered by PHARMAC’s Board (or Chief Executive acting under delegated authority) prior to making decisions on these proposals.

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Details of the proposals

Thalidomide

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Thalomid (Celgene Pty Ltd) would be listed in Section B and in Part II of Section H of the Pharmaceutical Schedule at the following prices and subsidies (ex-manufacturer, excl. GST):

Presentation 50 mg Capsule 100 mg Capsule Pack size 28 28 Price and subsidy $504.00 $1008.00

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Thalidomide is a Class A controlled drug and can only be prescribed by registered prescribers in accordance with the supplier’s Risk Management Programme. The ‘Pharmaceutical Cancer Treatment – Only’ (PCT-only) restriction applying to all brands of thalidomide would be amended to a ‘PCT – Retail Pharmacy’ restriction so that retail pharmacies as well as DHB hospital pharmacies would be able to claim for its use when dispensed for the treatment of cancer. However, the regulatory requirements for the prescribing and dispensing of thalidomide would not be affected by this change. The main effect of this change would be to shift some expenditure on thalidomide from DHB budgets to the Community Pharmaceuticals Budget which is considered appropriate given that thalidomide is an oral therapy. The Special Authority criteria applying to all brands of thalidomide in Section B of the Pharmaceutical Schedule would be amended as follows (changes in bold and strikethrough):

THALIDOMIDE - PCT Only - Retail Pharmacy – Specialist Only on a controlled drug form Special Authority for Subsidy Initial application —(for new patients) only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid for 12 months where the patient has multiple myeloma. for applications meeting the following criteria: Both: 1 The patient has refractory, progressive or relapsed multiple myeloma; and 2 The patient has received prior chemotherapy. Initial application — (for patients receiving thalidomide prior to 1 January 2006) only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid without further renewal unless notified where the patient was receiving treatment with thalidomide for multiple myeloma on or before 31 December 2005. Renewal only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid without further renewal unless notified where the patient has obtained a response from treatment during the initial approval period.

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Notes: Prescription must be written by a registered prescriber in the thalidomide risk management programme operated by the supplier. Maximum dose of 400 mg daily as monotherapy or in a combination therapy regimen.

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It is anticipated that this proposal would result in up to 150 multiple myeloma patients accessing funded thalidomide earlier in their treatment pathway. Some patients who would receive first line thalidomide may go on to receive further thalidomide in subsequent lines of therapy but it is considered that the number of patients who would be retreated with thalidomide would be small and the duration of treatment is expected to be shorter than currently funded second, or subsequent line usage. PHARMAC seeks specific feedback from DHBs on the resource implications of this proposal to widen funded access to thalidomide (see background section below for more details regarding dosing and administration).

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Bortezomib  Bortezomib (Velcade) would be listed in Section B and in Part II of Section H of the Pharmaceutical Schedule at the following prices and subsidies (ex-manufacturer, excl. GST):

Presentation Inj 1.0 mg Inj 3.5 mg Inj 1 mg for ECP Pack size 1 vial 1 vial 1 mg Price and subsidy $540.70 $1,892.50 $594.77

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Bortezomib would be listed in the Pharmaceutical Schedule as a Pharmaceutical Cancer Treatment Only (PCT only - Specialist), meaning that only DHB hospitals can claim for its use. The 3.5 mg vial and 1 mg for ECP presentations would be listed from 1 April 2011, whereas the 1.0 mg vial would be listed from 1 June 2011. Please note the proposed price and subsidy for the 1 mg for ECP presentation assumes 10% wastage based on the expected average dose, dosing schedule and number of patients treated. Bortezomib (Velcade) would be listed in Section B of the Pharmaceutical Schedule subject to Special Authority criteria as follows:

BORTEZOMIB – PCT only – Specialist Special Authority for Subsidy Initial application – Treatment naïve multiple myeloma - only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid for 15 months for applications meeting the following criteria: Both: 1. The patient has treatment-naïve symptomatic multiple myeloma, and 2. Maximum of 9 treatment cycles.

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Initial application – relapsed/refractory multiple myeloma - only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid for 8 months for applications meeting the following criteria: All of the following: 1. The patient has relapsed or refractory multiple myeloma; and 2. The patient has received only one prior front line chemotherapy for multiple myeloma; and 3. The patient has not had prior publicly funded treatment with bortezomib; and 4. Maximum of 4 treatment cycles. Renewal – relapsed/refractory multiple myeloma - only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid for 8 months for applications meeting the following criteria: Both: 1. The patient’s disease obtained at least a partial response from treatment with bortezomib at the completion of cycle 4; and 2. Maximum of 4 further treatment cycles. Note: Responding relapsed/refractory patients should receive no more than 2 additional cycles of treatment beyond the cycle at which a confirmed complete response was first achieved. A line of therapy is considered to comprise either: a) a known therapeutic chemotherapy regimen and supportive treatments or b) a transplant induction chemotherapy regimen, stem cell transplantation and supportive treatments. Refer to datasheet for recommended dosage and number of doses of bortezomib per treatment cycle.

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DHB clinicians would be able to apply directly to PHARMAC for Special Authority approvals for existing patients (i.e. those being treated with bortezomib on 30 March 2011); clinicians would need to demonstrate that the patient would have met the proposed Special Authority criteria for initial applications prior to starting treatment with bortezomib and, if the patient had relapsed/refractory multiple myeloma and had been on bortezomib for longer than 4 cycles at 30 March 2011, that the patient would also meet the proposed Special Authority renewal criteria. A confidential rebate would apply to all subsidies payable for bortezomib which would reduce its net price to DHBs. It is anticipated that this proposal would result in approximately 300 multiple myeloma patients accessing funded bortezomib annually; either as first or second line treatment. Bortezomib would be administered by bolus injection in DHB hospital outpatient departments (see background section below for more details regarding dosing and administration). As well as the service required to administer bortezomib (see background section below for more details) and monitor disease response, there would also be increased resource implications for DHB hospitals for blood monitoring in patients with multiple myeloma receiving bortezomib. PHARMAC seeks specific feedback from DHBs on the resource implications of this proposal to fund bortezomib.

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Consideration of Cancer Exceptional Circumstances applications for bortezomib

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The funding of bortezomib has now been considered by PHARMAC for: o multiple myeloma (various subgroups); and o AL amyloidosis. Because funding for these diseases has been considered by PHARMAC, the funding of bortezomib for patients with these diseases will not generally meet the current Cancer Exceptional Circumstances criterion iv. As a result, unless the individual is distinct from others with these diseases such applications will generally be declined. We note that the majority of CaEC applications we are currently receiving would be funded under the proposed Special Authority criteria for bortezomib.

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Background

Multiple Myeloma Multiple myeloma (MM) is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies. Collections of abnormal cells accumulate in bones, where they cause bone lesions, and in the bone marrow where they interfere with the production of normal blood cells. The annual incidence of MM in New Zealand has increased by approximately 150%–200% over the last 40 years (Cancer in New Zealand: Trends and Projects (2002)1); some of this increase may be due to better diagnostic methods and classification systems. Forecasts indicate approximately 300 new cases of MM in 2009, increasing to approximately 320 by 2014. MM predominantly affects older individuals, with a median age at diagnosis of 65–68 years. The risk of MM is approximately 40% higher in males than females, and Maori have a substantially higher risk of being diagnosed with, and dying from, MM than non-Maori. Initial treatment of patients with MM is dependent on the age of the patient and eligibility for peripheral blood stem cell or bone marrow transplant. In New Zealand currently, newly diagnosed patients with MM aged under 65 years and otherwise healthy patients with MM aged over 65 years would typically receive high dose induction chemotherapy (e.g. vincristine, adriamycin and dexamethasone) followed by a stem cell transplant. Transplantineligible patients generally receive prednisone and melphalan. Following relapse, patients would receive thalidomide (second line) usually in conjunction with steroids (often dexamethasone) and sometimes with oral chemotherapy (e.g. cyclophosphamide). Patients who subsequently relapse may receive a range of third line salvage regimens. Third-line options include re-use of second-line options (or combination thereof) or high-dose dexamethasone. MM treatment algorithms are rapidly developing and PHARMAC has recently considered multiple funding applications for new treatments for MM (bortezomib and lenalidomide) and widening of access to existing treatment (thalidomide). These proposals to widen access to thalidomide and to fund bortezomib do not preclude the future funding of lenalidomide for MM patients.

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http://www.moh.govt.nz/moh.nsf/82f4780aa066f8d7cc2570bb006b5d4d/8e1d731682cab3d9cc256c7e00764a23/ $FILE/25-myeloma.pdf

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There is a high unmet medical need for effective and curative MM treatments. Treatments including bortezomib and thalidomide are not curative; therefore, treatment goals in this setting are limited to delaying disease progression and extending and/or improving quality of life. Thalidomide background The mechanism of action of thalidomide has not been fully clarified but may involve direct inhibition of myeloma cell growth and survival. Thalidomide is indicated in New Zealand:    in combination with melphalan and prednisone in untreated MM patients ≥ 65 years or ineligible for high dose chemotherapy; in combination with dexamethasone in untreated MM for induction therapy prior to high dose chemotherapy with autologous stem cell rescue; and as monotherapy after failure of standard therapies.

Thalidomide is a Class A controlled drug and can only be prescribed by a registered prescriber in accordance with the supplier’s Risk Management Programme. Thalidomide has caused severe birth defects when taken during pregnancy. Thalidomide should never be used by women who are pregnant or who could become pregnant whilst taking the drug or could become pregnant within 4 weeks after stopping the drug. Even a single dose can cause birth defects. Thalidomide (Thalidomide Pharmion 50 mg capsule) is currently funded on the Pharmaceutical Schedule under Special Authority criteria for patients with refractory, progressive or relapsed MM who have received prior chemotherapy. Currently, approximately 250 patients per year are accessing funded thalidomide. The Thalidomide Pharmion brand of thalidomide is to be discontinued by the supplier. Under this proposal, two strengths (50 mg and 100 mg capsules) of a new brand of thalidomide (Thalomid) would be funded at a higher per mg price than the currently funded Thalidomide Pharmion brand. Under this proposal funding for both the Thalidomide Pharmion and Thalomid brands of thalidomide would be widened to include all patients with MM, including treatment naïve patients. In this setting the recommended dose of thalidomide in transplant ineligible patients is 200 mg per day for up to 12 cycles of six weeks given in combination with melphalan and prednisone. In transplant eligible patients, the recommended dose of thalidomide is 200 mg per day for 4 cycles of four weeks in combination with dexamethasone. This proposal to widen funded access to thalidomide is expected to improve overall survival, progression free survival and treatment response in patients with MM compared with currently funded treatments. PTAC consideration - Thalidomide An application for the funding of thalidomide to be widened to include treatment of patients with newly diagnosed (treatment naïve) MM (transplant eligible and transplant ineligible) was considered by the Pharmacology and Therapeutics Advisory Committee (PTAC) and its

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Cancer Treatments Subcommittee (CaTSoP) at their August 2009 and November 2009 meetings respectively. A summary of the recommendations made are provided below (full copies of PTAC and CaTSoP minutes are available on the PHARMAC website at www.pharmac.govt.nz/PTAC/PTACminutes and www.pharmac.govt.nz/PTAC/PTACSCMinutes).

August 2009 – PTAC recommended that application for thalidomide to be used in stem cell transplant eligible patients be declined. PTAC considered that in this whilst the studies generally demonstrated an improvement in response with thalidomide containing induction regimens, interpretation of longer term outcome data, including overall survival, was confounded by patients having received a transplant and subsequent (uncontrolled) treatments. Therefore, members considered that the inability to determine the benefit of thalidomide on longer term outcomes prevented the Committee from making a positive recommendation for its use in this setting. PTAC recommended that the Special Authority for thalidomide should be widened to include first line treatment of multiple myeloma in patients ineligible for stem cell transplantation. The Committee gave this recommendation a high priority. The Committee considered that despite heterogeneity of the studies, overall the data indicated that the addition of thalidomide to melphalan and prednisone resulted in statistically significant improvements in overall survival, progression free survival and the proportion of patients with a treatment response. November 2009 – CaTSoP agreed with PTAC’s view for transplant eligible patients and considered that PTAC’s decline recommendation for this population was reasonable. The Subcommittee considered that, overall, the evidence indicated that the addition of thalidomide to MP treatment in transplant ineligible patients resulted in statistically significant improvements in progression free survival and the proportion of patients with a treatment response. CaTSoP recommended that thalidomide should be funded for the first line treatment of multiple myeloma in patients ineligible for stem cell transplantation with a high priority.

Bortezomib background On 15th December 2010, PHARMAC consulted on a previous proposal to fund bortezomib. However, during consultation on that proposal PHARMAC received several enquiries about the proposed Special Authority criteria. Respondents considered that the proposed criteria did not make it clear which patient population(s) (first and/or second line) were being proposed for funding. PHARMAC considered these responses and have reached a new agreement with the supplier which is the basis of this new proposal. Under this new proposal, bortezomib funding would be available for: 1) treatment-naïve patients with symptomatic MM (i.e. first line treatment); and 2) patients with relapsed/refractory MM where the patient has received only one prior front line chemotherapy and is bortezomib treatment naïve (i.e. second line use). It is not proposed that funding would be available for third, or subsequent line, use at this time. Funding for this patient population was considered by PTAC and CaTSoP in 2006 (see below for summary of recommendations). Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells.

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Bortezomib is indicated in New Zealand for:

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the treatment of patients who have received at least one prior therapy and who have progressive disease (relapsed/refractory MM); and the treatment of patients with previously untreated MM in combination with melphalan and prednisone in patients who are not suitable for high dose chemotherapy..

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The funding of bortezomib is expected to result in a delay to disease progression in patients with MM compared with the most commonly used currently funded treatments. Bortezomib is administered in hospital as a bolus intravenous (IV) injection. In patients with previously untreated MM who are not suitable for high dose chemotherapy, it is recommended that bortezomib be administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles. In cycles 1 to 4, bortezomib is administered twice weekly and in cycles 5 to 9, bortezomib is administered weekly resulting in a total of up to 52 doses per patient. Bortezomib is not indicated in New Zealand for use in the first line treatment of patients with MM suitable for high dose chemotherapy and stem cell transplantation. However, under this proposal, it would be funded if a clinician wishes to use it in this setting. As this is an ‘offlabel’ indication, clinicians would need to comply with Section 25 of the Medicines Act to prescribe it in this setting. Section 25 prescribing is not an unusual situation for cancer treatments; it requires that clinicians obtain informed consent from their patients for ‘offindication’ use. In this setting, we anticipate that bortezomib would be administered at a dose of 1.3mg/m2 twice weekly for two weeks (days 1, 4, 8, and 11) in combination with dexamethasone for 4 cycles, followed by high-dose melphalan prior to stem cell transplantation (a total of 16 doses). However, other dosing regimens could be used at the clinician’s discretion (up to a maximum of 9 treatment cycles). The recommended dose of bortezomib in relapsed/refractory MM patients is 1.3mg/m2 twice weekly for two weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). Patients would receive a maximum of 8 treatment cycles. It is recommended that patients with a confirmed complete response receive 2 additional cycles of bortezomib beyond confirmation of response. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 treatment cycles. It is estimated that in this setting, on average, patients would receive 6.5 cycles of treatment (26 doses). PTAC consideration - Bortezomib The funding of bortezomib has been considered by PTAC and CaTSoP on multiple occasions for various indications (including first, second and third-line treatment in various patient groups with MM). In summary, PTAC has recommended that bortezomib be listed as a second-line agent for patients with relapsed/refractory MM with low priority and as a firstline treatment in MM in patients unable to be treated with high dose chemotherapy and transplant with medium priority. A summary of the applications reviewed and recommendations made are provided below (full copies of PTAC and CaTSoP minutes are available on the PHARMAC website at www.pharmac.govt.nz/PTAC/PTACminutes and www.pharmac.govt.nz/PTAC/PTACSCMinutes ):

May 2006 – PTAC considered an application from the supplier for bortezomib in patients with MM who have received at least two prior therapies (3rd line therapy). PTAC recommended that a

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PHARMAC cost-utility analysis be performed and the application be referred to the Cancer Treatments Subcommittee (CaTSoP) for further advice regarding targeting criteria and the acceptability of the side effect profile of bortezomib as third-line treatment for patients with multiple myeloma. October 2006 – CaTSoP considered an application from the supplier for bortezomib in patients with MM who have received at least two prior therapies (3rd line therapy). CaTSoP recommended that, given its side effect profile and uncertainty surrounding long-term benefit, bortezomib should not be listed on the Pharmaceutical Schedule. CaTSoP considered that there may be a place for bortezomib in combination with HDD or other drugs in earlier treatment of multiple myeloma; however, more data in this area are needed. November 2008 – PTAC considered an application from the supplier for bortezomib for the second-line treatment of patients with multiple myeloma. PTAC requested that it reconsider this application following review by the Cancer Treatments Subcommittee and a PHARMAC costutility analysis. February 2009 - CaTSoP considered an application from the supplier for bortezomib for the second-line treatment of patients with MM and recommended it be funded with a medium-to-high priority. CaTSoP recommended that initial applications be valid for three months, with the requirement for a partial response to be demonstrated after four cycles for further approval to be granted. August 2009 – PTAC considered a cost-utility analysis prepared by PHARMAC regarding the funding of bortezomib for the treatment of patients with relapsed/refractory multiple myeloma. PTAC also considered information from clinicians regarding the use of bortezomib in MM patients with renal impairment. PTAC recommended that bortezomib be listed as a second-line agent for patients with relapsed/refractory MM with a low priority. PTAC recommended that initial applications be valid for three months, with the requirement for a partial response to be demonstrated after four cycles for further approval to be granted. The Committee gave this recommendation a low priority. PTAC also considered that although renal impairment was relatively common in MM patients and although there was some evidence of benefit of bortezomib for these patients, the evidence was weak comprising small non randomised studies (largely case series). November 2009 – CaTSoP reviewed a paper prepared by PHARMAC staff regarding applications for funding of cancer treatments which had been considered under the Cancer Exceptional Circumstances Scheme (CaEC). CaTSoP specifically reviewed a number of treatments that PHARMAC staff had identified as being the subject of a number of Cancer EC applications including bortezomib for amyloidosis and bortezomib for IgA/IgG/t(4:14 translocation) MM / Plasma Cell Leukaemia. CaTSoP noted that bortezomib is currently being funded under the CaEC scheme for a small population of patients with amyloidosis or various genotype-specified plasma cell disorders. CaTSoP considered that specifying patient groups, and even individuals, at a molecular level (ie by genotype) is likely to be seen more in future funding applications as more therapies are being targeted in this way. CaTSoP considered that dealing with such applications under the Cancer EC scheme was problematic since all people are, in some way, unique; however, this does not mean that all cases are exceptional. CaTSoP considered that it was appropriate for PHARMAC to consider funding applications for bortezomib in patients with amyloidosis or various genotype-specified plasma cell disorders and amyloidosis and recommended that PHARMAC staff request funding applications from the Haematology Society. November 2009 – CaTSoP considered the cost-utility analysis prepared by PHARMAC regarding the funding of bortezomib for the treatment of patients with relapsed/refractory multiple myeloma. CaTSoP noted that the CUA compared bortezomib plus dexamethasone with thalidomide plus dexamethasone. CaTSoP noted that since there have been no clinical trials directly comparing bortezomib with thalidomide, the CUA necessarily included a number of assumptions regarding

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the relatively efficacy of the two treatments. CaTSoP considered that the PHARMAC CUA model was legitimate. CaTSoP considered that given that MM is incurable, most patients would require second-line treatment; therefore, it would be expected that uptake would be rapid such that by year 4, up to 250 patients would access second line treatment and that, if funded, bortezomib would likely replace thalidomide as the preferred second-line treatment. February 2010 – PTAC considered an application from the supplier for the funding of bortezomib, in combination with melphalan and prednisone, as first-line treatment for patients with MM who are unable to be treated with high dose chemotherapy. PTAC recommended that bortezomib be funded for these patients with a low priority. PTAC further recommended that the application be reviewed by CaTSoP for advice regarding appropriate Special Authority criteria, including initial number of treatment cycles, and cost-utility analysis inputs. April 2010 – CaTSoP considered an application from the supplier for the funding of bortezomib, in combination with melphalan and prednisone, as first-line treatment for patients with MM who are unable to be treated with high dose chemotherapy. CaTSoP noted that the application was for the same population that it had recently recommended for funding with thalidomide i.e. stem cell transplant ineligible patients and that it gave this thalidomide recommendation a high priority. CaTSoP considered that effective, curative, treatment of MM was an area of high unmet need. Members noted that with current treatments, including bortezomib, MM was not curable and, therefore, treatment goals were principally to extend and/or improve quality of life. CaTSoP recommended that bortezomib should be listed in the Pharmaceutical Schedule subject to Special Authority criteria for patients with newly diagnosed MM not eligible for high dose chemotherapy and transplant, CaTSoP gave this recommendation a medium priority. This recommendation was accepted by PTAC at its August 2010 meeting. November 2010 – PTAC considered an application from [a clinician] for the funding of bortezomib on for the treatment of patients with systemic AL amyloidosis. PTAC recommended that the application be deferred until Phase III trial data is available. November 2010 – CaTSoP considered applications from [clinicians] for the funding of bortezomib for the treatment of patients with systemic AL amyloidosis and patients with t(4:14) multiple myeloma. CaTSoP also considered a paper from PHARMAC staff regarding Cancer Exceptional Circumstances applications for bortezomib in patients with MM for use as a bridge to stem cell transplantation. Minutes are not yet available from this meeting.

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