LONDON – The majority of drugs paid for by a fund set up to provide access to the new wave of expensive cancer therapies failed to show any evidence of meaningful clinical benefit and may have resulted in patients suffering unnecessarily from toxic side effects, according to an analysis published in the Annals of Oncology on Friday.

The analysis looked at 29 drugs approved in 47 indications, which were paid for by the Cancer Drugs Fund (CDF) from 2011 to 2015. During that time, 100,000 patients were treated with drugs costing £1.27 billion (US$1.6 billion). That is equivalent to one year's expenditure on all other cancer therapies.

CDF was set up as a political move to quell the repeated public outcry each time the U.K. health technology assessment body, the National Institute of Health and Care Excellence (NICE), ruled a particular drug was not cost-effective and should not be reimbursed, and to give access to drugs in advance of NICE evaluations.

The research shows that overall – and despite statistically significant results – the 29 drugs had very limited benefits in terms of overall survival and progression-free survival, in the index trials supporting regulatory approval.

When other factors such as quality of life and toxic side effects were assessed according to European Society of Medical Oncology and American Society of Clinical Oncology criteria, the researchers considered that the majority of the 29 drugs had failed to show meaningful clinical benefits in the index trials.

In fact, the researchers said the benefits to patients in the real world were "probably" even less than in the clinical trials. Unfortunately, there is no way of confirming or refuting that claim, because the CDF did not require the systematic collection of outcomes data for patients who accessed drugs through the fund.

It was belatedly made mandatory to collect information on treatment cessation, side effects, date of death or relapse in 2014, but even so 93 percent of the outcomes data for 2014 and 2015 are incomplete. That represented a lost opportunity to understand how the drugs worked in practice, providing evidence of cost benefit (or not) and allowing indications to be expanded to patients with earlier-stage disease, who might be expected to see greater benefits.

Richard Sullivan, director of the Institute of Cancer Policy at King's College London, a co-author of the research, said the analysis demonstrates that setting up separate funds is not a rational approach to managing the introduction of high-cost health technologies.

"A ring-fenced drugs fund was created despite a lack of evidence that prioritizing drug expenditure would improve outcomes for cancer patients over and above greater investment in the whole cancer management pathway," he said.

In the clinical trials that formed the basis for the regulatory approvals, only 18 of the 47 indications that the CDF reimbursed had reported a statistically significant overall survival benefit. That ranged from 1.4 months for Zaltrap (aflibercept, Regeneron Pharmaceuticals Inc.) in metastatic bowel cancer, to 15.7 months for Perjeta (pertuzumab, Roche Holding AG) in metastatic HER2-positive breast cancer. The median increase in overall survival across the 18 indications was 3.2 months.

Of the remaining 29 indications, 17 won regulatory approval despite the index trials failing to show any statistically significant effect on overall survival, while 12 indications were approved for CDF funding without overall survival data being available.

Approval in 25 of the 29 indications was granted on the basis of progression-free survival; in four cases indications were approved based on noncomparator trials, meaning there was no evidence of progression-free, or overall survival.

The reliance on progression-free survival begs the question of whether that is a meaningful surrogate endpoint. "From a patient's perspective, a gain in progression-free survival may not equate to a clinical benefit given the serious toxicities that arise from many of these therapies, including those classified as targeted, and the fact that progression often occurs without any symptoms, [meaning] delaying progression is not delaying symptoms," Sullivan said.

Although there is no information on outcomes, the authors infer from prescribing data showing drug use was lower than expected compared to the doses and duration of treatment in clinical studies, that there was earlier disease progression or greater occurrence of severe adverse events in the real-world setting.

HEADWIND

Of the 47 indications covered by CDF, 26 had previously been rejected by NICE on the grounds of not being cost-effective.

It was lobbying by patients' groups against those NICE decisions that created the political headwind for CDF to be set up, and in response to the research, Delyth Morgan, chief executive of Breast Cancer Now, defended the formation of the fund.

"The analysis makes clear that the breast cancer drugs Perjeta and Kadcyla [trastuzumab emtansine] – which were not approved by NICE but which the CDF made available – provide a substantial improvement upon the current NICE-approved standard of care," she said.

Compared to current NICE-approved treatments, Perjeta can extend life by nearly 16 months, and Kadcyla by six to nine months. "In many cases, women will also be able to live relatively normal lives whilst taking these life-extending drugs, including working," said Morgan. "For many living with incurable breast cancer, the CDF has had a totally transformational impact on their lives."

UNSUSTAINABLE

The original budget for CDF was £50 million (US$64.7 million) per annum. By 2015 that had risen to £340 million, prompting two internal CDF reviews that saw the number of indications it funded cut to 23.

Notably, 18 of those reversals were based on the same evidence used by NICE to rule the treatments were not cost-effective, causing the clamor that led to CDF's formation.

For co-author of the report, Ajay Aggarwal, academic clinical oncologist at the London School of Hygiene & Tropical Medicine, that not only suggests CDF wasted resources, "but equally that drugs were given that were ineffective and probably resulted in unnecessary toxicities."

By 2016, CDF was viewed as financially unsustainable and its remit was reduced to managing access in advance of compulsory NICE appraisals of all new cancer drugs.

At the same time NICE began reappraising drugs that previously were available only through application to CDF, and in July announced Bosulif (bosutinib) for treating chronic myeloid leukemia, would be the first drug to move over to general NHS coverage.

When NICE first looked at Bosulif in November 2013, it was not considered cost-effective. Despite that, the drug was made available through CDF. NICE's change of heart in the reappraisal came after the manufacturer, Pfizer Inc., agreed to offer a discount to the £45,000 per patient, per year list price.