Cancer drugs: high price, uncertain value

Inadequate evidence

The research found that the EMA is basing many approval decisions on uncontrolled study designs or surrogate endpoints, which don’t always translate into outcomes which make a difference to patients.

Some of the cancer drugs were given “conditional marketing authorisations,” on the understanding that postmarketing studies would assess overall survival or quality of life. If the drugs are subsequently found to be clinically ineffective or unsafe, then the EMA can withdraw them. The study in The BMJ identifies 10 drugs approved under these fast track arrangements, but after four years of market entry none of them had good evidence that they either extended or improved life for patients.

Asked to comment on the research by The BMJ, an EMA spokesperson stated that is not agency practice to comment on research it has not seen. This is a topic that it has discussed widely and it welcomes taking part in further debate on the evidence underpinning cancer medicines.

The fact that so many of the new drugs on the market lack good evidence that they improve patient outcomes puts governments in a difficult position when it comes to deciding which treatments to fund.

In 2016, European health ministers issued a statement saying that new medical products “pose challenges to individual patients and public health systems in particular regarding their added value.” This, they said, affects patient access, affordability, and the financial sustainability of health systems.

As an example of the pressures put on health systems, a recent Bristol-Myers Squibb funded analysis compared licensed drugs for six different cancers across Europe and Canada and concluded that reimbursement decisions seem inconsistent. In an accompanying press release, the authors of the analysis stated: “There are potentially 200 000 patients in 12 countries who by licence should have access to drugs but are not getting them because of the reimbursement decision.”

Their underlying premise was that the EMA grants licences to “safe, effective cancer treatments where access to the drug can improve and prolong life” and these drugs should be paid for.2

In the eyes of industry the problem is with national reimbursement, yet the overwhelming picture now, from not only The BMJ study¹ but from studies published in Lancet Oncology and elsewhere, is that cancer medicines are being licensed that do not deliver clinically meaningful benefit.

The BMJ has found methodological problems with trials that EMA has either failed to identify or overlooked (box 1). This includes the trials’ design, conduct, analysis, and reporting.

Such flawed clinical trials can lead to bias and further difficulties in identifying the true effectiveness. Unless there’s thorough scrutiny of this regulatory evidence after approval, governments may make poor decisions about how to prioritise health budgets.

Unrealistic expectations

Perhaps most importantly, however, the fact the drugs have been given the imprimatur of regulatory approval may cause patients and doctors to have unrealistic expectations about their benefits and harms.

According to Richard Sullivan, professor of cancer and global health at King’s College London and director of the Institute of Cancer Policy, doctors cannot be expected to be gatekeepers. In many cases across Europe new cancer medicines with low clinically meaningful benefit continue to be prescribed.

“They may inappropriately script cancer drugs because of patient and family pressure; a lack of understanding of how new complex therapies work; or because of the culture of medical oncology in the absence of multidisciplinary decision making,” he says. “If patients are not offered alternative modalities, including palliative care, in end-of-life settings then the risk of inappropriate or futile treatment with chemotherapy and immunotherapy increases.”

Sullivan says the processes that allow a drug to be funded in national health services across Europe vary in their robustness and due diligence around judging clinical evidence. Some health technology assessment bodies view themselves as secondary gatekeepers to stop use of drugs that the EMA has licensed without evidence of benefit (box 2).

For example, the EMA approved vinflunine as a second line treatment for metastatic transitional cell carcinoma of the urothelial tract in 2009 (box 1) on the basis of a potentially biased analysis. But the UK National Institute for Health and Care Excellence (NICE) was less convinced, implying the evidence used for regulatory approval did not show the drug to be effective, and didn’t recommend it.

Although the exact reasons for rejection aren’t always clear, an assessment body analysis obtained by The BMJ shows that health technology assessments in most European countries have also taken a less favourable view of vinflunine than the EMA.

For patients, approval of such drugs may lead to unrealistic expectations, fuelled by patient organisations . In response to NICE’s decision, Action on Bladder Cancer, a charity supporting patients and promoting research, wrote to the agency to complain that: “Patients with metastatic bladder cancer are disadvantaged by the lack of a second line treatment option. Study 302 is the first trial to show a survival benefit and we feel that vinflunine should be available for this relatively small group of patients.”7

Uncertainty is compounded by unproved drugs being used as comparators. Despite the questions around vinflunine , for example, it is now being used as a comparator in trials for new drugs. On its website, the patient charity Fight Bladder Cancer has highlighted an ongoing study of a drug called PDL3280A for patients with advanced or metastatic bladder cancer.8 This, they say, compares chemotherapy with either paclitaxel or vinflunine. But regulatory sanctioning of a comparator that lacks robust evidence of efficacy, means the cycle of weak evidence and uncertainty continues.

No one wants to say no to a cancer drug

Vinflunine isn’t an isolated example of questionable decision making. In 2011, the EMA licensed panitumumab in combination with other drugs as a second line treatment for colorectal cancer. This was despite the agency questioning whether the primary analysis showing a borderline statistically significant benefit in progression-free survival was robust (box 1). Indeed, the EMA initially rejected the drug but later reversed its opinion.9 In the words of one EMA adviser who spoke to The BMJ, however, “no one wants to say no to a cancer drug.” When NICE invited Amgen, panitumumab’s manufacturer, to submit evidence for approval to use on the NHS, the company declined to do so. They intimated that there wasn’t sufficient evidence to determine the cost effectiveness. Again NICE didn’t recommend it.10

Most European funding bodies have also turned down panitumumab for second line treatment for colorectal cancer. However, the published study does not reflect the questions over the statistical analyses, concluding that panitumumab “significantly improved” progression-free survival and there was “a trend toward” improved overall survival.4

Subsequent hype and misleading reporting can put pressure on governmental bodies to reimburse a drug. Health technology assessors are in an invidious position—if they refuse to reimburse and a drug later turns out to be an important therapeutic advance, then patients have lost out because of the delay. If they reimburse and the drugs later turn out to be ineffective, have no clinically meaningful effects, or not to be cost effective then patients may have been unnecessarily subjected to toxic drugs and scarce healthcare resources have been wasted.

The combination of this hype coupled with underlying concerns about the quality of trials can cause confusion. In England, pomalidomide, an immunomodulatory drug for refractory multiple myeloma wasn’t available, then was, then wasn’t, then was again.

The drug was approved by the drug regulators both in Europe and the US despite questions over trial design (box 1).

Correspondence between the FDA and Celgene, the trial sponsor, shows the US agency cautioning the company that its choice of comparator was unsuitable for regulatory decision making.1112 The FDA ultimately ignored its own advice and approved the drug regardless. The EMA approved it several years later.

When NICE rejected the drug for use in the NHS because of the poor comparator, Celgene claimed that it was chosen only after consulting with the regulators. Pomalidomide subsequently went onto England’s Cancer Drugs Fund, an extra source of funding, only for budgetary constraints eventually leading to it being removed in 2015. It was one of 17 drugs for 23 different indications to be included in the cull.13

The delisting prompted both companies and charities to call for all interested parties to work together to find a better solution for patients, putting pressure on NICE. Noticeably, however, this did not necessarily include better evidence generation and better oversight from the EMA.

“This has been a unilateral decision by NHS England. What is missing is a willingness for all stakeholders to take part in collaborative discussion and work together,” Wim Souverijns, general manager at Celgene UK and Ireland, said. “There is a role for companies to put pressure on stakeholders, including NICE and NHS England, to point out the implications of these changes.”13

This pressure may have worked for patient access and cost purposes. In 2016—after the company offered a confidential discount—NICE approved the drug because it then became cost effective. But that does not mean the evidence of efficacy is robust; other European countries continue to deem it not worth paying for.

Regulator fit for purpose?

The inability of EMA to uphold its current policies on drug approval has implications for patients and budgets, and the scientific advice the agency gives is coming under increasing scrutiny (box 2).

The example of bevacizumab (Avastin) is a cautionary tale about how well the EMA can monitor, evaluate, and learn about products even after they are on the market. Yet the agency wants to push ahead with a programme allowing quicker access to drugs with immature data.14

In June 2011, the FDA announced it had revoked bevacizumab’s indication for metastatic breast cancer because it “has not been shown to provide a benefit, in terms of delay in the growth of tumors, that would justify its serious and potentially life-threatening risks. Nor is there evidence that [it] will either help women with breast cancer live longer or improve their quality of life.”15

But the drug is still licensed in Europe for metastatic breast cancer; the EMA withdrew the licence for only some uses. It said this was because the available data on use in combination with paclitaxel have “convincingly shown [the drug] to prolong progression-free survival of breast cancer patients without a negative effect on the overall survival.”16

Again the EMA’s decision caused challenges for funders. Bevacizumab was rejected by NICE and was one of the most requested drugs under the Cancer Drugs Fund.17

It was another of the drugs delisted in 2015, leading to disappointment of patient groups. “People with incurable breast cancer can only watch from the sidelines as life-extending treatments are debated again and again and vital options disappear,” the charity Breast Cancer Care said in a statement.18 But patients will continue to have their hopes dashed if regulators approve drugs using designs that are not methodologically rigorous.