The British pharmaceutical company GlaxoSmithKline (GSK) has been forced to withdraw one of its innovative cancer therapies from the United States after the failure of a clinical trial of Blenrep, indicated against multiple myeloma. This drug was approved in 2020 through the so-called accelerated route —shorter and less expensive— and now it has not been able to demonstrate the expected efficacy results. This has motivated the US drug agency, the FDA, to have required the company to stop selling the treatment in the country.
The European Medicines Agency (EMA), which also approved the drug two years ago, affirms in a written response to this newspaper that it “is aware” of the results of the trial and the measures adopted by the FDA and that “the [nuevos] data will be evaluated to determine if it is necessary to take a decision in the EU”. This review will be done “at the beginning of 2023”, when the agency already planned to start the process of “annual renewal of the marketing authorization” of Blenrep.
The FDA measure comes less than two months after the Interministerial Commission on Drug Prices (CIPM), headed by the Ministry of Health, approved on September 29 the incorporation of Blenrep in Spanish public health for patients who have relapsed after receiving all available treatments for multiple myeloma.
Not all drugs approved by the EMA are necessarily introduced into public health. The decision to finance or not a treatment is made based on the available evidence on its efficacy and safety, the needs of hospitals and the price conditions offered by pharmaceutical companies.
Multiple myeloma is the second most frequent type of hematological cancer, with an estimated incidence of about five cases per 100,000 inhabitants. In Spain, a total of 3,200 patients were diagnosed in 2020, with an average age of between 65 and 70 years. It is a disease that has no cure, although the available treatments can slow its progress for a few months or years.
The FDA and the EMA approved Blenrep, whose active ingredient is the monoclonal antibody belantamab mafodotin, a few days apart in the summer of 2020. The former did so by the so-called accelerated route on August 5, a step that the latter had taken conditionally on July 24.
“Each agency has its system, but what is substantial in both cases is that a drug is approved faster than conventional procedures provide because it is considered to have significant potential benefits. This means that even if there are uncertainties about its effectiveness, it is considered worth taking the risk. In return, pharmaceutical companies must carry out new trials to confirm the possible benefits, something that Blenrep has not achieved now”, explains Eduardo Lopez Briz, coordinator of the Genesis group for drug evaluation of the Spanish Society of Hospital Pharmacy (SEFH).
The procedures of the two agencies are similar, but have some differences at the end. The two approve the drug on the fast track when clinical trials are still in the so-called phase II, which provides for shorter tests and with fewer patients, so they are also significantly cheaper to perform. After approval, pharmaceutical companies must carry out —also in the US and Europe— confirmatory trials with more patients, the so-called phase III trials.
The main difference between the FDA and the EMA is the reaction to a failure of these trials: while the US agency contemplates the automatic withdrawal of the drug, the European agency does not foresee this step immediately except for serious safety problems and analyzes the new results in the annual renewal of the drug.
The FDA’s decision does not mean that Blenrep may not have some clinical benefits. What it means is that, by failing to demonstrate them in the phase III trial, Blenrep is not deserving of the preferential treatment that the fast track gives it. This forces GSK to carry out new tests – the company has two more underway right now – before being able to market Blenrep again in the United States.
This greater number of investigations is especially important in treatments with significant side effects. 71% of patients who receive Blenrep develop keratopathy (vision problems and eye discomfort) and 38% thrombocytopenia (drop in platelets), according to the Therapeutic Positioning Report (IPT) prepared by the Ministry of Health.
Maria Victoria Mateos, president of the Spanish Society of Hematology and Hemotherapy (SEHH), is confident that Blenrep will continue to be sold in Europe after the reassessment of the EMA and will remain in Spanish public health. “It is true that Blenrep has failed to meet the primary endpoint of the trial, but this does not mean that it does not have some clinical benefits. The drug has a novel mechanism of action, different from that of pomalidomide and dexamethasone, and this may make it useful for multiple myeloma patients who have already exhausted this and other treatments to improve their disease-free survival”, she defends.
GSK is also confident in the future of Blenrep. “While we are disappointed that the study did not meet its primary endpoint, data from the DREAMM-3 trial show that the risk-benefit balance remains favourable. We are in talks with the health authorities of other regions, including the EMA, and currently the regulatory situation of the drug outside the US is not affected, ”says the company.
Irene Bernal, a researcher at Salud Por Derecho, an organization that advocates for universal access to drugs, believes that part of the regulatory problems for drugs such as Blenrep is due to the abuse of accelerated drug approval pathways. “A procedure that had to be exceptional has become a recurring and very interesting path for the pharmaceutical industry, because it allows them to put drugs on the market only with completed phase II trials. Thus, it obtains income and finances phase III research, a cost that it would have to assume in the conventional procedure. The agencies must ensure that confirmatory tests are always carried out, something that sometimes does not happen, and be expeditious when the tests do not confirm the necessary evidence, ”she defends.
An investigation of the prestigious magazine The British Medical Journal published last year showed that nearly half of the therapies fast-tracked by the FDA since 1992—112 of 253, or 44%—failed to subsequently be shown to be effective, yet the agency allowed remain on the market for years “despite its considerable price.”
A fundamental question, agree many of the experts consulted, is to determine who should take responsibility – if the public health or the pharmaceutical companies – of the uncertainty that surrounds many innovative treatments, both in their efficacy and in the high price that the companies pharmacists usually fix. A dilemma that has become evident in the process of incorporating Blenrep into the Spanish public health system.
In December 2021, when the Interministerial Commission on Drug Prices (CIPM) for the first time dismissed public financing of the drug, the reasons given were “uncertainties regarding its therapeutic value and criteria for rationalizing public spending and budgetary impact of the drug.” SNS”.
In April, with the second rejection, the arguments used were the same. And three months later, in July, the Ministry of Health published the Therapeutic Positioning Report (IPT) that included the following: “The response rates achieved are considered relevant, in the context of a population without alternatives [terapeuticas]. However, the results and the magnitude of benefit are limited by the design of the non-comparative phase II study from which they are derived. New phase III studies will complete the available efficacy and safety data, helping to establish its therapeutic position.”
One of these studies is the one that has now been made public with poor results for Blenrep. The CIPM, however, decided to change its previous criteria without waiting for these results and to approve the public financing of Blenrep on September 29 at an official price of 6,974.48 euros per vial. As the approved treatment provides for a dose every three weeks “until disease progression or unacceptable toxicity”, this implies a cost per quality-adjusted life year gained —ACAV, the unit of measurement used in these cases— of around 120,000 euros. . An amount much higher than the 25,000 euros that public management usually sets as recommendable, even if one takes into account that this criterion is usually made more flexible in rare diseases and oncological drugs.
The reasons that explain the commission’s turn are not public —the allegations and price offers from pharmaceutical companies are considered confidential—, although the experts consulted point out that it may be due to a lower price offer from GSK or a change in the criteria to be assessed by the Ministry of Health. He has declined to answer the questions raised by EL PAIS about this case.
Beatriz Gonzalez Lopez-Valcarcel, professor at the University of Las Palmas de Gran Canaria and specialist in health economics, considers that “with the new evidence, which reveals that Blenrep is not superior to the treatments already available in public health, it is possible that the public financing of the treatment will be reviewed”.
Although, in any case, this expert points out that everything that has happened with this drug illustrates “the difficulty of decision-making that health managers face, with a dynamic scenario and a lot of uncertainty.” All this, she concludes, “makes evident the need for all decisions to be adopted based on the evidence available at all times, but at the same time to be reviewable and flexible, since this can change as seen in this case ”.
