1.  EXECUTIVE SUMMARY

  1.1  Sirtex Medical was formed in 1997 to research and develop effective treatments for liver cancer using novel small particle technology.

  1.2  Selective Internal Radiation Therapy (SIRT) is a relatively new medical technique for the treatment of advanced primary and secondary (metastatic) liver cancer that cannot be removed by surgery. The safety and tolerability of SIRT is well established, with over 4,500 patients treated worldwide. The procedure normally requires an overnight stay in hospital with patients typically experiencing relatively minor side effects such as pain or nausea that resolve in a matter of days.

  1.3  At the time of the Interventional Procedure appraisal by NICE, Sirtex were the only manufacturer in Europe with an approved SIRT product—yttrium-90 labelled SIR-Spheres® microspheres—licensed for the treatment of unresectable primary and secondary liver cancer.

  1.4  At the time of the NICE appraisal of SIRT, the results of only one pivotal randomized clinical trial were available. This trial was halted prematurely after the FDA advised Sirtex that they would accept response rate and time to disease progression as endpoints for regulatory approval. The study demonstrated that adding SIR-Spheres microspheres to hepatic arterial chemotherapy (HAC) significantly increased the tumour response rate and significantly lengthened the time to disease progression. There was a trend towards prolonged survival, even though the study was not adequately powered to demonstrate a survival benefit and had been halted early. There was no major adverse impact on patients' quality of life.

  1.5  The results of a second pivotal randomized clinical trial were not in the public domain at the time of the NICE appraisal. Sirtex warned NICE that the timing of the appraisal was premature, but this was ignored. Sirtex offered to provide the results, in confidence, but NICE advised that the Interventional Procedures Programme did not accept "in-confidence" material. This is in direct contrast to NICE Technology Appraisals, where companies and clinicians can submit material "in-confidence". Once the appraisal process had started, updated clinical data from the second pivotal trial became available that demonstrated significant benefits, but NICE refused to accept this information.

  1.6  The guidance issued by NICE accepted SIRT as a therapeutic option for colorectal liver metastases in September 2004 (IPG 93), and advised that clinicians should audit and review clinical outcomes of the treatment, and ensure that patients are fully informed. However, the guidance noted that there was a lack of evidence of symptom relief or increased survival. Subsequent clinical trial data that was not reviewed by NICE showed a substantial and significant survival advantage—16 months extra survival—for patients receiving SIRT in addition to systemic chemotherapy.

  1.7  This second pivotal randomized trial compared the addition of SIR-Spheres microspheres to systemic 5FU/LV chemotherapy, demonstrating significantly longer survival for the combination compared to 5-FU/LV alone (29.4 months vs 12.8 months), plus significantly longer time to disease progression and higher response rates without any compromise to patients' quality of life.

  1.8  Subsequent clinical trials established the safety of SIR-Spheres microspheres in combination with the current standard of care first- and second-line chemotherapy regimens recommended by NICE, and demonstrated impressive efficacy. These studies reported that in some patients, tumours were decreased in size sufficiently to enable the remaining disease to be removed by surgery, which provides the best prospect of a long-term cure for colorectal cancer. A retrospective study of over 200 patients failing chemotherapy demonstrated a 6-month survival benefit for SIRT.

  1.9  The pathways for the NICE interventional procedures appraisal have proved to be extremely difficult, with NICE consistently adopting an adversarial approach and repeatedly deviating from their published procedures.

  1.10  Despite the proven effectiveness of SIRT, and the substantial potential benefits for patients in terms of survival, the process of adoption by the NHS in the UK has been difficult and tortuous. The majority of the 60+ patients treated in the UK have been funded by private medical insurance, self paid, or have had the SIR-Spheres microspheres donated by Sirtex, while only a handful have been approved by NHS fundholders. That the number of NHS patients treated has started to rise is a testament to the perseverance of NHS physicians in seeking the best treatment options for their patients.

  1.11  There is no mandatory funding for NICE interventional procedures guidance. Therefore PCT fundholders can easily deny funding of a treatment that a multi-disciplinary team has decided is the best option for the patient.

  1.12  In our experience, NICE appraisal of SIRT has done little, if anything, to enable patient choice for those under NHS care.

2.  INTRODUCTION TO SIRT

  2.1  SIRT (also known as radioembolisation) is a new medical technique for the treatment of primary and secondary (metastatic) liver tumours that cannot surgically resected.

  2.2  SIRT utilises SIR-Spheres microspheres—biocompatible resin microspheres labelled with radioactive yttrium-90 that emits high-energy pure beta radiation. SIR-Spheres microspheres are administered by an Interventional Radiologist by infusion through a catheter placed in the hepatic artery. Liver tumours derive ®90% of their blood supply from the hepatic artery, whereas normal liver tissue derives ®90% of its blood supply from the portal vein. SIRT uses this trait against the tumour to selectively target radiotherapy at the liver tumours.

  2.3  The SIR-Spheres microspheres become trapped in the small blood vessels of tumours, delivering high doses of beta radiation to the tumours while maintaining the a tolerable radiation dose to the normal liver. The half-life of yttrium-90 is 64.2 hours. By two weeks, 97% of the radioactive dose has been delivered to the tumours.

  2.4  SIR-Spheres microspheres gained CE Mark approval in October, 2002, and are fully approved in Europe for the treatment of unresectable liver tumours.

  2.5  SIR-Spheres microspheres is also approved by the US FDA for treating colorectal liver metastases and is fully reimbursed by the Center for Medicare and Medicaid Services (CMS).

  2.6  The safety and tolerability of SIRT is well established, with over 4,500 patients treated worldwide using SIR-Spheres microspheres since its approval. The procedure is currently used in over 100 centres worldwide. The procedure normally requires an overnight stay in hospital with patients typically experiencing relatively minor side effects such as pain or nausea that resolve in a matter of days.

  2.7  At the time of appraisal by NICE's Interventional Procedure Advisory Committee (IPAC), Sirtex were the only manufacturer in Europe with an approved SIRT product licensed for the treatment of unresectable primary and secondary liver tumours.

  2.8  At the time of the NICE appraisal, only the results of one pivotal randomized clinical trial were available. This trial had been halted prematurely after the FDA advised that they would accept response rate and time to progression as endpoints for regulatory approval. The study investigated adding SIR-Spheres microspheres to HAC using FUDR, demonstrating:

2.8.1    a statistically significant increase in the tumour response rate (44% vs. 17%), and in median time to disease progression (15.9 months vs 9.7 months) compared to FUDR HAC alone;

2.8.2    a trend towards prolonged overall survival, although the study was not powered to show survival and had been halted early; and

2.8.3    these positive results were achieved without deterioration in quality of life of patients, with patients in both groups demonstrating an improvement in QoL.

  2.9  The results of an additional pivotal randomized clinical trial were not in the public domain at the time of the NICE appraisal. Sirtex offered to provide the results, in confidence, since public disclosure would jeopardise publication in a peer-review scientific journal, but NICE advised that the Interventional Procedures Programme did not accept in-confidence material. Sirtex believe that this was incorrect and that NICE are bound to accept in-confidence material for both Technology Appraisals and Interventional Procedures. Sirtex warned NICE that the timing of its appraisal was premature, but this was ignored.

  2.10  This second study compared the addition of SIR-Spheres microspheres to systemic chemotherapy with 5FU/LV, demonstrating:

2.10.1    significantly longer median overall survival for the combination of SIR-Spheres microspheres plus 5-FU/LV compared to 5-FU/LV alone (29.4 months vs 12.8 months);

2.10.2    significantly longer median time to disease progression for those receiving SIR-Spheres microspheres (18.6 months vs. 3.6 months);

2.10.3    significantly higher response rate for patients receiving SIR-Spheres microspheres (73% vs 0%); and

2.10.4    quality of life of patients was not compromised by adding SIR-Spheres microspheres.

  2.11  Subsequent clinical trials have established the safety of SIR-Spheres microspheres in combination with current standard of care first- and second-line chemotherapy regimens recommended by NICE, and have demonstrated impressive efficacy. Investigators reported that in some patients, the tumours were decreased in size sufficiently to enable the remaining disease to be removed by surgery, which provides the best prospect of a long-term cure for colorectal cancer.

  2.12  A retrospective study of SIRT as salvage treatment in over 200 patients who had failed chemotherapy demonstrated a significant survival benefit for patients treated with SIR-Spheres microspheres (10.5 months in responders vs 4.5 months in non-responders or historical controls).

  2.13  Unlike the guidance issued by NICE, the clinical benefits from SIRT for patients with liver tumours are not restricted to colorectal cancer. Clinical studies have demonstrated benefits following SIRT using SIR-Spheres microspheres for patients with hepatocellular carcinoma (primary liver cancer), and liver metastases from neuroendocrine tumours, breast cancer, pancreatic cancer, lung cancer and various other cancers.

3.  TERM OF REFERENCE: NICE'S EVALUATION PROCESS

  3.1  When it commenced the Interventional Procedures appraisal, NICE failed to confirm formally to Sirtex that our technology was to be appraised. As the only manufacturer in the world with a SIRT product approved for colorectal cancer, Sirtex was disappointed and concerned that NICE failed to advise us that the procedure was being assessed.

  3.2  It was clear from the speed with which NICE began the investigation that the main stakeholders were not consulted adequately, if at all.

  3.3  The refusal of NICE to accept the results of clinical trials, in confidence, in order to avoid jeopardising publication in a peer-review scientific journal or disclosure of commercially sensitive information is in direct contradiction of the policies NICE adopts for its appraisals, where companies and clinicians can submit material in-confidence to NICE.

  3.4  NICE initially refused to delay the timescale of the Interventional Procedures Advisory Committee in order to allow them to consider interim data from the second pivotal randomised trial. Following the eventual acceptance of our data, once the appraisal process commenced, NICE refused to accept more mature, updated data from Sirtex despite the significant clinical benefits that were demonstrated.

  3.5  Sirtex's warnings to NICE that the timing of the Interventional Procedure appraisal on SIRT was premature were ignored by NICE. As forewarned by Sirtex, data from the second pivotal randomized clinical trial—demonstrating a 16-month survival benefit by adding SIR-Spheres microspheres to systemic chemotherapy—should have made a substantial difference to the guidance issued by NICE.

  3.6  NICE appear to be under the illusion, in oncology at least, that use in a clinical trial of a product in isolation is desirable since this makes interpretation of the results easier. NICE noted in its guidance on SIRT that "combination with other treatments makes interpretation of the published literature difficult." Where there is a clear benefit from combining different treatments, it would be unethical to conduct a clinical trial one element in isolation. The clinical reality is that there are synergies from combining different treatment modalities ie radiotherapy plus chemotherapy, that provide greater clinical benefits for patients due to the radiosensitising effects of some chemotherapy agents that translate into improved survival and quality of life benefits for patients. In its Assessment Report for the Technology Appraisal on the management of advanced colorectal cancer using 5FU, FA (or LV), irinotecan and/or oxaliplatin, NICE noted that interpretation of results from trials is complicated by the fact that the disease is often managed with sequences of either mono- or combination therapy, with frequent use of unplanned second- or third-line salvage chemotherapy. This understanding of oncology needs to be shared more broadly within NICE.

3.7  The NICE Interventional Procedures appraisal process has proven to be extremely difficult for Sirtex to negotiate, and we repeatedly had to remind NICE of its own published procedures to ensure that these were followed.

  3.8  Throughout, we were confused by NICE's use of terminology and its inconsistency. We were informed that NICE was assessing SIRT as "a procedure" under the Interventional Procedures Programme. However, SIR-Spheres microspheres is licensed as a "medical device" and not as a "procedure".

  3.9  In this context, the NICE appraisal of SIRT therefore appeared to us to amount to a review of the product (or medical device), something that is explicitly excluded from NICE's own terms of reference ("The programme looks at procedures and not the devices (or drugs) used during the performance of the procedure" About Interventional Procedures, NICE Website).

  3.10  Alternatively, if the Advisory Committee intended to focus on the benefits and risks of SIRT as an interventional radiological procedure for treating hepatic tumours by introduction of anticancer agents through the hepatic artery, then this principle is already well established, both in medical practice and the scientific literature. It is the same procedure used in Trans-Arterial Chemo Embolisation (TACE), which is not a novel treatment strategy but standard practice in most countries, including the UK. NICE has announced that they will not perform any appraisal on TACE.

  3.11  Since the procedure itself is well established, Sirtex was left with the distinct impression that NICE appeared to be undertaking an assessment of the device itself rather than the procedure of treating hepatic tumours via agents introduced through the hepatic artery.

  3.12  To our knowledge, none of the growing number of UK Interventional Radiologists or Medical Oncologists experienced in the use of SIRT or cancer organisations with direct knowledge of SIRT were contacted by NICE or by the IPACmembers. In addition, no charities or patient organisations in the UK that we were in contact with were approached by NICE.

  3.13  This suggested to us that "adequate consultation" as defined by NICE had not taken place.

4.  TERM OF REFERENCE: THE IMPLEMENTATION OF NICE GUIDANCE

  4.1  NICE issued Interventional Procedures Guidance on SIRT for colorectal metastases in the liver in September 2004. Since this time, Sirtex has noted much ignorance about the existence of NICE guidance on SIRT. NICE has a regulatory duty to inform all stakeholders of its own decisions and it appears that this responsibility is discharged by simply posting the decision on the website and emailing Trust CEOs etc.

  4.2  Despite their apparent antipathy towards industry, it would appear that NICE abdicates its responsibility of ensuring wide understanding of its guidance amongst the appropriate medical specialists who would conduct an interventional procedure, and instead leaves industry to perform this task. We note that it can be very difficult and expensive for a small company to effectively inform all UK stakeholders. Over two years after NICE Guidance was isssued, there is still considerable lack of knowledge among healthcare professionals, Trust personnel and the general public on the existence and nature of the Guidance. Effectively, the Guidance is only implemented when Sirtex actively pursues the issue with Trusts.

5.  TERM OF REFERENCE: WHETHER PUBLIC CONFIDENCE IN NICE IS WANING, AND IF SO WHY?

  5.1  There is no mandatory funding for NICE interventional procedures guidance. If a MDT determines that SIRT is the best treatment for a patient, an already overworked consultant is forced to apply on a case-by-case basis to PCT fundholders to get approved funding for treatment. This can easily be denied by fundholders, and delays to the process can result in patients missing the opportunity to receive a treatment that could extend their lives and improve their quality of life.

  5.2  Despite NICE guidance on the use of SIRT for the treatment of colorectal cancer liver metastases, NHS patients are still dying prematurely in the UK because their physicians are unable to secure funding from PCT fundholders. How can patient choice be a cornerstone of NHS policy when the majority of patients with liver-dominant cancer are not offered a treatment option that could provide the possibility of downstaging the tumour to permit surgical resection or extending overall survival as well as time to the progression of their disease?

6.  RECOMMENDATIONS

  6.1  Sirtex experienced great difficulties negotiating with NICE. We recommend that NICE ensures that they proactively identify all key stakeholders before undertaking an assessment and include the manufacturers in that exercise.

  6.2  NICE should adopt a less adversarial negotiating position and should stop treating manufacturers and clinicians with suspicion and mistrust.

  6.3  NICE should listen to advice from manufacturers and clinicians when they advise the Institute that they may be reviewing a technology prematurely.

  6.4  NICE should ensure that adequate procedures are in place to monitor their own published procedures and that NICE keeps to those procedures during the appraisals process.

  6.5  The NICE Interventional Procedures Programme should be more transparent and stakeholders should be able to enter into dialogue with NICE at the start of the process to discuss the assessment.

  6.6  The NICE process should be flexible enough to allow the Advisory Committees to accept relevant published data as the assessment progresses.

  6.7  The dissemination of NICE Guidance needs to be more structured and owned by NICE. It needs to consist of more than publication of its guidance on the NICE website.

  6.8  The Select Committee should give strong consideration to recommending to Government that funding for interventional procedures that have been appraised by NICE be made mandatory where a multidisciplinary team of specialists has determined that the recommended treatment is in the best interests of the patient, and particularly where the treatment is for cancer.

Nigel Large, Chief Executive, and David Turner, Director of UK Operations

Sirtex Medical Europe

March 2007