NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE GUIDANCE EXECUTIVE (GE)

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1 NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE GUIDANCE EXECUTIVE (GE) Review of TA91: Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for the treatment of advanced ovarian cancer (for relapsed disease only). This guidance was issued in May 2005 with a review date of November Recommendation The decision to review the guidance should be deferred to November 2012, when NICE anticipates new data will be available. That we consult on the proposal. Consideration of options for recommendation: Options A review of the guidance should be planned into the appraisal work programme. The decision to review the guidance should be deferred to November A review of the guidance should be combined with a review of a related technology and conducted at the scheduled time for the review of the related technology. A review of the guidance should be combined with a new appraisal that has recently been referred to the Institute. A review of the guidance should be incorporated into an on-going clinical guideline. A review of the guidance should be updated into an on-going clinical guideline. Comment Clinical opinion suggests that there is no real clinical need to conduct a review at this point in time. A NICE appraisal at this time would not add value to the NHS. There are many ongoing clinical trials for both the existing technologies and the newer technologies. It would be most appropriate to defer the decision to review this guidance until November There are no other reviews of related technologies, We therefore reject this option. NICE is aware of several newer agents that are being investigated for this indication, some of which are already covered on our work programme. However, given that we are suggesting that no review is necessary at this point, this option is not suitable. No suitable guideline is currently on the work programme No suitable guideline is currently on the work programme Page 1 of 13

2 A review of the guidance should be transferred to the static guidance list. We are aware of several ongoing studies on these agents. We would therefore prefer to defer rather than static list this guidance. Original remit(s) To assess the clinical and cost effectiveness of topotecan (Hycamtin, GlaxoSmithKline), pegylated liposomal doxorubicin hydrochloride (Caelyx, Schering-Plough) and paclitaxel (Taxol, Bristol-Myers Squibb) in their licensed indications for relapsed ovarian cancer, relative to current standard treatments in the NHS, and to update as necessary, guidance issued to the NHS in England and Wales in August 2001, June 2002 and January 2003 Current guidance This guidance applies only to paclitaxel, pegylated liposomal doxorubicin hydrochloride (PLDH) and topotecan. For the purposes of this guidance, the following definitions are used: platinum-sensitive ovarian cancer: disease that responds to first-line platinum-based therapy but relapses 12 months or more after completion of initial platinum-based chemotherapy partially platinum-sensitive ovarian cancer: disease that responds to first-line platinum-based therapy but relapses between 6 and 12 months after completion of initial platinum-based chemotherapy platinum-resistant ovarian cancer: disease that relapses within 6 months of completion of initial platinum-based chemotherapy platinum-refractory ovarian cancer: disease that does not respond to initial platinum-based chemotherapy. 1.1 Paclitaxel in combination with a platinum-based compound (carboplatin or cisplatin) is recommended as an option for the second-line (or subsequent) treatment of women with platinum-sensitive or partially platinum-sensitive advanced ovarian cancer, except in women who are allergic to platinumbased compounds. 1.2 Single-agent paclitaxel is recommended as an option for the second-line (or subsequent) treatment of women with platinum-refractory or platinum resistant advanced ovarian cancer, and for women who are allergic to platinum-based compounds. 1.3 PLDH is recommended as an option for the second-line (or subsequent) treatment of women with partially platinum-sensitive, platinum-resistant or platinum-refractory advanced ovarian cancer, and for women who are allergic Page 2 of 13

3 to platinum-based compounds. 1.4 Topotecan is recommended as an option for second-line (or subsequent) treatment only for those women with platinum-refractory or platinum-resistant advanced ovarian cancer, or those who are allergic to platinum-based compounds, for whom PLDH and single-agent paclitaxel are considered inappropriate. 1.5 Within these recommendations, the choice of treatment for second-line (or subsequent) chemotherapy should be made after discussion between the responsible clinician and the patient about the risks and benefits of the options. Relevant Institute work TA55: Review of the clinical effectiveness and cost effectiveness of paclitaxel for ovarian cancer. Published January Proposal to add to the static list raised in August Note that this covers first line treatment, with the recommendations on second line treatment having been superceded by TA91. The recognition and initial management of ovarian cancer. Clinical Guideline (in progress). Expected publication April Trabectedin for the treatment of relapsed ovarian cancer. Technology Appraisal (in progress) expected publication September Diagnosis and management of metastatic malignant disease of unknown primary origin. CG in progress expected publication July **************************************************************************************** ***************************************. **************************************************************************************** ***************************. **************************************************************************************** *********. Phenoxodial (ovature) for advanced ovarian cancer resistant to platinum based drug treatment Topic 3035 status: NHSC considering. Bevacizumab for the treatment of Ovarian cancer (advanced). Topic 4534 status: CCPHA checking. Safety information Nothing new of note. Page 3 of 13

4 Details of new indications Drug (manufacturer) Gemcitabine (Eli Lilly and nonproprietary) Details Licensed for patients with locally advanced or metastatic epithelial ovarian carcinoma, in combination with carboplatin, in patients with relapsed disease following a recurrence-free interval of at least 6 months after platinum-based, first-line therapy. Details of new products Drug (manufacturer) Details Trabectedin (PharmaMar) EU positive opinion (September 2009). On NICE work programme ( Plevitrexed (AstraZeneca) Phase II in refractory or recurrent epithelial ovarian cancer. Pazopanib (GSK) Phase I/II. VEGF-R inhibitor. Patupilone (Novartis). ***************************************************************************** Irofulven (MGI) Phase II for recurrent or persistent platinium-sensitive ovarian cance Idronoxil (Novogen) in platinum-resistant, recurrent epithelial ovarian cancer. U Farletuzumab (Eisai ) Phase II for relapsed platinum sensitive ovarian cancer. Canfosfamide (Telik). Has failed to meet primary endpoints in ASSIST 1, 3 & 5 On-going trials Trial name Topotecan vs. Topotecan + Etoposide vs.topotecan + Gemcitabine in Ovarian Cancer Therapy Efficacy Study of Chemotherapy to Treat Ovarian Cancer Recurrence and to Prolong the Platinum Free Interval Caelyx Plus Carboplatin Versus Paclitaxel Plus Carboplatin in Patients With Epithelial Ovarian Cancer in Late Relapse Platinum-Based Chemotherapy With or Without Paclitaxel in Treating Patients With Relapsed Ovarian Cancer Details Completed (early expected completion date December 2009) Currently recruiting Estimated primary completion date: May 2009 Ongoing Estimated completion date: November 2012 Ongoing Estimated completion date: Not stated Page 4 of 13

5 TLK286 (Telcyta) vs. Doxil/Caelyx or Hycamtin in Platinum Refractory or Resistant Ovarian Cancer AURELIA: A Study of Avastin (Bevacizumab) Added to Chemotherapy in Patients With Platinum-Resistant Ovarian Cancer Hycamtin Plus Carboplatin Versus Established Regimens for the Treatment of Ovarian Cancer Relapse Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer Completed Yet to open for participants Estimated completion date: September 2013 Currently recruiting Estimated primary completion date: June 2009 Yet to open for participants Estimated primary completion date: October 2014 Paclitaxel in Treating Patients With Advanced Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Remission Carboplatin and Paclitaxel With or Without Cediranib in Treating Women With Relapsed Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer Ongoing Estimated completion date: Not stated Currently recruiting Estimated primary completion date: December 2013 Ph 3 Randomized Study of Telcyta + Liposomal Doxorubicin Vs Liposomal Doxorubicin in Platinum Refractory or Resistant Ovarian Cancer Carboplatin and Paclitaxel With or Without Bevacizumab After Surgery in Treating Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer TLK286 (Telcyta) in Combination With Carboplatin (Paraplatin) Versus Doxil in Platinum Refractory or Completed Currently recruiting Estimated primary completion date: December 2009 Completed Page 5 of 13

6 Resistant Ovarian Cancer Carboplatin With or Without Liposomal Doxorubicin in Treating Patients With Recurrent Ovarian Epithelial or Primary Peritoneal Cancer Patupilone Versus Doxorubicin in Patients With Ovarian, Primary Fallopian, or Peritoneal Cancer A Randomized Trial for Patients With Platinum Resistant Ovarian, Fallopian or Primary Peritoneal Cancer. Ongoing Estimated completion date: none given Ongoing Estimated primary completion date: May 2010 Completed New evidence The search strategy from the original assessment report was re-run on the Cochrane Library, Medline, Medline(R) In-Process and Embase. References from April 2004 onwards were reviewed. Implementation A submission from Implementation is attached at the end of this paper. Equality and diversity issues No equality and diversity issues have been identified. Appraisals comment There are new circumstances which could have impact on the existing guidance in TA91. New evidence has become available on pegylated liposomal doxorubicin (highlighted by the manufacturer) which shows that PLD in combination with carboplatin has a superior therapeutic index (benefit/risk ratio) versus the current standard, paclitaxel-carboplatin in patients with platinum-sensitive ovarian cancer. This could provide evidence for a broader recommendation for PLDH than is currently in the guidance, and may change the sequencing of the treatments in the current recommendations. However, clinical opinion suggests that PLDH is, to some extent, currently being used for platinum-sensitive disease. Page 6 of 13

7 There has been no substantial new evidence identified for paclitaxel or topotecan that would affect the current recommendations. However, since the original appraisal was undertaken, gemcitabine (generic) in combination with carboplatin has received a marketing authorisation for patients with relapsed locally advanced or metastatic epithelial ovarian carcinoma following a recurrence-free interval of at least 6 months after platinum-based, first-line therapy. Clinical opinion suggests that there is already some use of gemcitabine in combination with carboplatin in clinical practice for this population. It may be useful for the technologies included in this review to be compared with gemcitabine in combination with carboplatin at an appropriate time. Trabectedin is another potential comparator for the technologies in this review. Trabectedin in combination with PLDH received an EU positive opinion in September 2009 for the treatment of patients with relapsed platinum sensitive ovarian cancer, and this is in the current work programme to be appraised though the STA process (invitation to submit November 2009, submission due in January 2010 and 1 st committee meeting April 2010). Including this STA within the MTA review of TA91 would not be a feasible option, as this would delay guidance on trabectedin in combination with PLDH to the NHS. There are other technologies undergoing clinical trials for the treatment of ovarian cancer, but these are not likely to affect the guidance in TA91 at this point in time. Summary All of the above information could support a review of TA91. However, the current guidance does give positive recommendations for all 3 technologies and they are all now off-patent/generic. Gemcitabine (in combination with carboplatin) is also off-patent/generic and is already being used in clinical practice. Clinical opinion also suggests that there is no real clinical need to conduct a review of guidance TA91 at this point in time. A NICE appraisal at this time would not add value to the NHS. As there are many ongoing clinical trials for both the existing technologies and the newer technologies, it would Page 7 of 13

8 be most appropriate to defer the decision to review this guidance until November GE paper sign off: Nina Pinwill, Associate Director, CHTE 8 December 2009 Contributors to this paper: Clinical opinion from: Information Specialist: Technical Lead: Technical Adviser: Implementation Analyst: Project Manager: Prof Peter Clark, Consultant Medical Oncologist, Clatterbridge Centre for Oncology, Wirral Tom Hudson Raphael Yugi Helen Knight Mariam Bibi Adeola Matiluko Page 8 of 13

9 NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE IMPLEMENTATION DIRECTORATE Guidance Executive Review Technology appraisal 91: Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for the treatment of advanced ovarian cancer 1. National Hospital Prescribing Data Data showing trends in prescribing costs are presented below. Unfortunately this data does not link to diagnosis so needs to be treated cautiously in relation to the specific recommendations of the guidance. Estimated costs are also calculated by IMS using the drug tariff and other standard price lists. Many hospitals receive discounts from suppliers and this is not reflected in the estimated cost. Page 9 of 13

10 2. External literature Page 10 of 13

11 The Information Centre for Health and Social Care (2008) Hospital Prescribing, 2007: England Data showing the use of topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for the treatment of advanced ovarian cancer in primary care, in hospitals and those prescribed in hospitals, but dispensed in the community. Cost ( 000s) Primary care % growth primary FP10HP* % growth Hospital % growth hospital Total % growth total Topotecan , , Pegylated liposomal doxorubicin , , hydrochloride Paclitaxel , , *FP10HP = prescriptions written in hospitals but dispensed in the community Overall the data shows that the majority of prescribing for advanced ovarian cancer is carried out in a hospital setting. Richard M (2009) Uptake of NICE approved cancer drugs 2007/2008 Department of Health: London An analysis of prescribing data across cancer networks showed a 76% increase in prescribing of topotecan, a 39% increase in prescribing of pegylated liposomal doxorubicin and a 31% increase in prescribing of paclitaxel. Variations in usage between cancer networks were wider for some NICE approved drugs than others. There was a 61% reduction in variation across networks for pegylated liposomal doxorubicin and a 4% increase in variation for paclitaxel. (NB data is not linked to diagnosis). Page 11 of 13

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13 A literature search was carried out using the following databases: Cinahl (EBSCO Host) Embase (Ovid) HMIC (Search 2) Medline (Ovid) Medline in Process (Ovid) The search found no results that linked directly to the uptake of this piece of guidance. Page 13 of 13