Roche responds to the ‘Herceptin or deception’ article

Roche acknowledges that independent evaluations are required for fair and balanced consideration of the costs and benefits of Herceptin® for New Zealand women.

First results of independent assessments overseas have recently become public, with the National Institute for Health and Clinical Excellence (NICE) in the UK and the Scottish Medicines Consortium (SMC) recommending the use of Herceptin in early breast cancer on 9 June 2006.1

These evaluations are based on transparency and the ability to ensure systematic critical appraisal of the results. However Martin Rosevear’s article published in NZMJ on 2 June 2006 (http://www.nzma.org.nz/journal/119-1235/2014) is limited in the information it provides, and a number of its cost estimates are based on inaccurate assumptions in regard to the funding review currently underway in New Zealand.

The Medsafe-approved indication is specifically for the use of the three-weekly administration regimen upon completion of chemotherapy2 as used in the HERA trial.3 It is this three-weekly regimen with Piccart-Gebhart et al as the primary source of evidence, which PHARMAC has been asked to consider for funding. Three other trials (NSABP N9831, NCCTG B-31, BCIRG 0064) have been provided as supportive evidence. The paper by Romond et al reported the two-year combined results of NSABP N9831 and NCCTG B-31.5

The once-weekly administration schedule used in the NSABP N9831 and NCCTG B-31 studies forms the basis for the author’s simplistic evaluation. However the drug acquisition and administration costs are higher when Herceptin is administered once-weekly with chemotherapy, as is the rate of cardiotoxicity, (which will have associated treatment costs). The three-weekly regimen, as per the New Zealand indication, was considered by the NICE appraisal committee as better use of healthcare resource.1

Rosevear also used the NICE 2001 cost/QALY estimate of £19–38k in metastatic breast cancer,6 which is not appropriate for early breast cancer. In the adjuvant setting, treatment with Herceptin significantly improves disease-free and overall survival.7 The costs associated with a patient being disease-free are minimal.8,9

The quality of life values have also been inappropriately adjusted by the author using the NICE metastatic breast cancer guidance, a significant decrease of 30–50%. The MEDTAP study commissioned by Roche UK and validated by the School of Health and Related Research (University of Sheffield) on behalf of NICE, adjusted the quality of life for the disease-free state after diagnosis of early breast cancer by 15%.10

Rosevear’s analysis over-estimates the costs for patients treated with Herceptin for HER2 positive early breast cancer. This is supported by the release of the draft NICE Guidance in the UK. Whereas the 2001 cost/QALY estimate for use of Herceptin in metastatic breast cancer was £19–38,0006, the estimate in early breast cancer is between £2,387 and £18,000, with the upper limit assuming patients that go on to develop metastatic breast cancer would be retreated with Herceptin.1

The public and medical support for the funding for Herceptin has been generated by the strength of the clinical evidence and the significant advance Herceptin offers women with HER2-positive early breast cancer.10

It is important that the real benefit adjuvant Herceptin offers for women with HER2-positive early breast cancer does not get lost in the debate over the costs of providing this treatment.

Svend Petersen
Managing Director
Roche Products (New Zealand) Limited
Auckland

References:

Final Appraisal Determination – Trastuzumab for the adjuvant treatment of early breast cancer. London: National Institute for Health and Clinical Excellence (NICE); 2006. Available online. URL: http://www.nice.org.uk/page.aspx?o=328476 Accessed July 2006.
Herceptin (trastuzumab) Data Sheet. 15 March 2006. Roche Products (New Zealand) Ltd. 8 Henderson Place, Auckland.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72. Available online. URL: http://content.nejm.org/cgi/content/full/353/16/1659 Accessed July 2006.
Slamon D, et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Abstract presented at San Antonio Breast Cancer Symposium 8–11 December 2005.
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005; 353:1673–84. Available online. URL: http://content.nejm.org/cgi/content/full/353/16/1673 Accessed July 2006.
National Health Service. TA34 Breast cancer – trastuzumab: Guidance. London: National Institute for Clinical Excellence (NICE); 2002. Available online. URL: http://www.nice.org.uk/page.aspx?o=29280 Accessed July 2006.
Smith IE, et al. Trastuzumab following adjuvant chemotherapy in HER2-positive early breast cancer (HERA trial): disease-free and overall survival after 2 year median follow-up. Scientific Special Session, American Society of Clinical Oncology (ASCO) Annual Meeting 2006.
Butler JRG, Furnival CM, Hart RFG. The costs of treating breast cancer in Australia and the implications for breast cancer screening. Australian and New Zealand Journal of Surgery. 1995;65:485–91.
Hurley SF, Huggins RM, Snyder RD, et al. The cost of breast cancer recurrences. British Journal of Cancer. 1992;65:449–55.
Ward S, Pilgrim H, Hind D. Trastuzumab for the treatment of primary breast cancer in HER2 positive women: a single technology appraisal. School of Health and Related Research (ScHARR); May 2006. Available online. URL: http://www.nice.org.uk/page.aspx?o=282270 Accessed July 2006.

Martin Rosevear’s response

My article was one of a series which examined the ‘equity’ of PHARMAC’s funding for a range of new pharmaceuticals. The intent of these articles is to encourage rational debate and equity in our funding of health interventions, and we suggested that Herceptin® is expensive and we questioned whether it is affordable.

In summary:

It is a promising new drug, but the evidence for its economic value is still being determined, although subsequent to my article the NICE group in the UK have found it is affordable in the UK setting for early breast cancer2.
If funded, Herceptin would have a significant budgetary impact, similar to the total funding of a small provincial hospital, and current budgets will struggle to cope with this.

The letters from Breast Cancer Advocacy Coalition and Roche raise valid issues on some technical details.

However the letters are mute on what we understand is the big issue of budgetary impact and our ability to fund such drugs. If new drugs such as Herceptin provide better value for money than other health interventions, then funding should be available to give patients access to these drugs. We are aware of a number of interventions provided routinely by hospitals where the $/QALY far exceed an agent such as Herceptin, according to our understanding, and the mechanisms to re-prioritise DHB funding between these ‘competing’ interventions are very weak. If existing funding mechanisms are getting in the road of good health governance, these structures should be changed.

As the respondents point out, the NICE findings suggest Herceptin is relatively affordable and our understanding of the final NICE findings is that they quote a base-case of approximately £18k ($55k) per QALY. However it should be noted that many of the assumptions in these findings are subject to debate and other interpretations would lower this value to £8k ($24k) per QALY.

As a result of new information received, I have revised the cost/benefit analysis in my original article, the details of which are set out in Figure 1:

Figure 1. Herceptin survival estimates; hypothetical results

The model above is simplistic and intended to capture the major issues in the debate. As we understand them, these issues are:

The Chemotherapy arm has been generated based on a 10 year study of HER2 patients3 and adjusted to fit the survival data reported by Romond4 at four years+. We note that the Chemotherapy arm may give better survival advantage than nominally achieved in New Zealand since it includes the impact of taxanes which are not currently approved for use in New Zealand. Hence these findings are arguably conservative for local conditions.
The default Herceptin arm has been generated by giving a 50% survival advantage to patients, based on disease free survival findings from HERA5 and overall survival results from Romond. Hence this line sits midway between the Chemotherapy arm and the the average population.
The persistence of Herceptin is perhaps the most important issue in the economic analysis. Does the 50% survival advantage observed in the trials last? Her2 patients tend to relapse within 5 years and given the action of Herceptin which prevents relapse to metastatic disease, it would seem reasonable to expect the impact of Herceptin on survival to be reasonably persistent. However uncertainties remain over long-term effects and the possible toxicity (especially in women with reduced cardiac capacity) which could reduce longer term survival. The NICE evaluation assumed no survival advantage after 5 years. Our model above is less conservative and uses a 10%/annum decline of persistence.
Metastatic disease impacts approximately 40% of patients and Herceptin reduces its impact by 50%. The model does not account for the avoidance of this cost and suffering, hence our results are conservative.
We have used treatment cost provided by Roche as a base-line. However we are aware that these are under negotiation and changes in clinical practice, especially in the duration of treatment, could change these.
The quality of life adjuster has been set to 80%7 derived from Roche submission to NICE. Patients receiving Herceptin have generally had surgery and chemotherapy, and generally will have lost disfigurement and loss of quality of life.
How many years should be used to estimate benefits? We have counted benefits up to them age of 70, since many other disease processes start impacting people over that age.

The life years gained is the area between the Chemotherapy arm and the options above (Herceptin with declining persistence and Herceptin with 100% persistence). These results are shown in Figure 2:

Figure 2

Item	20 years persistent	20 years declining	40 years persistent	40 years declining
Life-years enhanced Quality of life adjuster QALY* Cost per QALY ($NZ)	2.23 80% 1.78 $30,625	1.18 80% 0.94 $57,780	3.82 80% 3.06 $17,853	1.34 80% 1.07 $50,785

*Quality adjusted life year.

We have chosen to use the results over 20 years as our base-line results (ignoring the avoidance of metastatic disease):

$31k per QALY (assuming persistent survival) to $58k per QALY (assuming 10%/annum decline in survival)

This result is lower than our original study. Furthermore we are aware of clinical developments which may lower these estimates further:

Patient selection. An interview with Dr Piccart6 discusses work intended to improve the economic effectiveness by identifying sub-groups within the HER2 patient group who will respond more strongly to the drug.
Shorter treatment. The Piccart interview above identifies trials where shorter duration treatments have been explored to find an ‘optimum’ treatment protocol which weigh up clinical effectiveness and cost.

We agree with the respondents that it is important for the real benefit of adjuvant Herceptin to be aired. But we also suggest that it is equally important to understand the challenges in funding these new treatments, and the need to re-prioritise interventions provided by the wider health system.

Martin Rosevear
Director
Outcome Management Services (a consultancy specialising in health and public sector economics)
Wellington

References and endnotes:

Rosevear M. PHARMAC and Herceptin for early-stage breast cancer in New Zealand: Herceptin or deception? N Z Med J. 2006;119(1235). URL: http://www.nzma.org.nz/journal/119-1235/2014
National Institute for Health and Clinical Excellence (NICE). Final appraisal determination: trastuzumab for the adjuvant treatment of early-stage HER2-positive breast cancer. London: NICE; June 2006. Available online. URL: http://www.nice.org.uk/page.aspx?o=328476 Accessed July 2006.
Pritchard KI, Shepherd LE, O'Malley FP, et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med. 2006;354:2103–11. Abstract available online. URL: http://content.nejm.org/cgi/content/abstract/354/20/2103
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–84. [This trial involved concurrent use of chemotherapy and Herceptin and hence is not directly relevant to the sequential method approved for use in New Zealand.]
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72 [An interim analysis after 1 year of a planned 2-year study.]
Dr Piccart interview posted 01 Mar 2006 at http://www.medscape.com (registration required)
See reference 2 above. We have been advised by Roche (personal communication) that the quality of life adjuster should be 85%, but at the time of writing we have not received the material supporting this, hence we have used 80% which is in the public domain.