The life story of a drug is told over years, even decades. To begin with, from when the first idea arises or the final molecule is designed until it is approved and reaches the patient, it can take about 10 years. And then, on the street, he gets to have as many lives as his abilities (and regulatory agencies) allow. Pembrolizumab, for example, was a highly innovative immunotherapy that turned around, first, the prognosis of melanoma and now it is also indicated for lung cancer, lymphoma, kidney, breast and colon tumors, among others. Regulatory agencies have been giving their approval and the drug is used in clinical practice for these clinical pictures. But not all drugs have that full life and the endorsement of the authorities does not imply, de facto, great real benefits for patients.
A study published in The BMJ precisely describes that the therapeutic value of approved drugs is not always so great: the research concludes that less than half of the new drugs that are approved for the first time add substantial therapeutic value to treatments already existing; and only a third of the drugs that achieve complementary approvals (they are different therapeutic approaches from the first) add significant therapeutic value to what already existed. “The fact that new does not necessarily mean better must be clearly communicated to patients and doctors,” warns Beate Wieseler of the German Institute for Quality and Efficiency in Health Care in an editorial accompanying the article.
Researchers from the Universities of Zurich, Harvard, and Yale, led by Professor Kerstin Vokinger, analyzed, through clinical benefit scales used by independent centers in France and Germany, the therapeutic value of new drugs approved in the United States and Europe. between 2011 and 2020, both for first indications and for supplementary therapeutic approaches, and compared them with existing treatments. In total, the study cohort included 124 first indications and 335 supplements approved by the US Food and Drug Administration (FDA) and another 88 first indications and 215 supplements validated by the European Medicines Agency ( EMA, in English). Most were cancer drugs.
The authors explained that neither the FDA nor the EMA “require data on the magnitude of the efficacy of a drug compared to other treatments” for the same condition, and they set out to compare the therapeutic value of early and supplementary indications. They did this through therapeutic value rating mechanisms used by two health technology assessment agencies in France and Germany, which typically measure the additional benefits of an approved drug indication compared to existing therapies. The criteria to evaluate the therapeutic value are, in the German case, the improvement of health, the reduction in the duration of the disease, the increase in survival, the decrease in side effects or the improvement in quality of life. The French agency also looks at the severity of the disease or its priority in the country’s therapeutic strategy.
The results drew a scenario where the novelty does not always provide strong benefits compared to those generated by other drugs already available. “When indications do not offer additional therapeutic benefit over other available treatments, that information must be clearly communicated to patients and reflected in the price of drugs,” the authors also warned in the article.
“When indications do not offer additional therapeutic benefit over other available treatments, that information must be clearly communicated to patients and reflected in the price of medicines”
Study at BMJ
Specifically, the researchers found that only 41% of the first indications approved by the FDA and 34% of the complementary ones were classified as having high therapeutic value. In those of the EMA, only 47% of the first indications and 36% of the complementary ones had high ratings. “What we have done is describe what happens: first, the primary indications have a low added value with respect to what already exists, and second, the supplementary ones have an even lower relative value,” says Miquel Serra-Burriel, postdoctoral researcher. from the University of Zurich and co-author of the study.
The study does not go into the reasons, why this happens, but Serra-Burriel suspects that it is “multicausal”. And he suggests several explanations, such as an economic part, in which the industry takes advantage to “maximize benefits with the products it already has” developed and, on the other hand, he adds, also “it is natural that it is increasingly difficult to find truly innovative therapies ”.
Josep Maria Suñé, Professor of Pharmacy and Pharmaceutical Technology at the University of Barcelona, also pronounces himself along these lines: it is complex to continuously discover new molecules that revolutionize therapeutic results. “New original molecules are harder to find. The industry continues to investigate what exists and seek added value and provide a small detail that improves the treatment, but sometimes, that improvement will not be noticeable. For example, that it has fewer side effects or that it can be administered every 12 hours instead of every eight.”
Contextualize each drug
Oncologist Andrés Cervantes, president of the European Society for Medical Oncology (ESMO), appeals for caution in interpreting these study results and invites the evaluation of therapeutic value to be “put into perspective”. “Not all drugs that are approved add exceptional value, but I do not share the idea that medication degrades when indications increase: I believe that in oncology we have many needs and when a drug proves effective in diseases with low prevalence and reaches diseases with higher prevalence, the benefit is global”.
Each drug must be contextualized within the situation of a specific pathology, it is convenient. “The first indications for immunotherapy were in melanoma and there we started from a place where there was nothing, it was a deserted area, with testimonial treatments. When we go to second indications, we also see that there are subgroups of lung cancer that benefit. But melanoma is not on the list of the 10 most incident tumors and benefiting 2% of the population with lung cancer has a greater social impact. You have to see these things in their value and meaning”, defends the specialist, who is head of Medical Oncology at the Hospital Clínico Universitario de Valencia and a researcher at the INCLIVA Health Research Institute.
Sometimes, that improvement will be little noticeable: that it has fewer side effects or that it can be administered every 12 hours
Josep Maria Suñé, University of Barcelona
Precisely, ESMO has developed a scale of magnitude of clinical benefit to assess clinical trials: “Once the agencies approve a drug, ESMO takes that study (of the drug) and puts it in context: is that treatment to cure or to palliate? Does it cure or prolong survival? We have different classifications for both cases. One thing that stood out to us is that regardless of the magnitude of the benefit, it was priced no differently whether it increased life by one month or 10. Most important is the value that is brought to the patient when given administers a drug”, explains Cervantes. Apart from survival, the scale also takes into account quality of life or toxicity.
Cervantes appeals to dialogue to land the value of drugs. “It may be that a drug in a trial shows an important effect, but if it is applicable to a small proportion of patients, it limits its usefulness. The expert who participates in the trial, the regulatory agency and the actors who have to implement it do not have the same perception”, agrees the oncologist. And he adds: “A dialogue is necessary between the professionals who know the diseases, the regulatory agencies and the payers. And I think the ESMO scale can help. If we had an enormously rich country, we would not have to prioritize; but since resources are limited, it has to be done.”
A spokesman for Farmaindustria, the employers’ association of the pharmaceutical sector, defends, for his part, that a new indication of a medicine, “even if its efficacy or safety are not a revolution over the existing ones, they are always useful as a competitor of the already existing ones and as a drug that increases the therapeutic options of patients and physicians”. Through an email, the industry representative points out that the benefit for a specific population of patients within a pathology may be greater than the overall gain for the group of patients, and claims the convenience that public health finance, even drugs that have a lower contribution of clinical value: “Because they have a contribution to improve survival that can be significant in certain groups of patients; because they increase the possibilities of treatment for doctors and patients, and because they introduce price competition in said pathology, which is good for financiers and payers”, Justifies Farmaindustria.
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