Σάββατο, 16 Μαΐου 2020

NEGATIVE STUDIES AND COSTLY DRUGS

As we approach the American Society of Clinical Oncology 2020 Annual Meeting — one of the biggest cancer meetings in the world, to be held virtually May 29-31 — it is somewhat sobering to read about "spin" disguising negative results.

Researchers sometimes spin negative results in an ambiguous, or even positive, light in their conclusions sections, say a group of Italian authors. Disseminating conclusions that are unjustified by results could be misleading and, in some cases, even harmful in clinical practice, they warn.

The team undertook a systematic review of oral presentations at two major cancer meetings (held by ASCO and the European Society of Medical Oncology [ESMO]) over 3 years. They found that 13% to 47% of studies with negative results were not reported as such. "Despite the formally negative trial result, the authors' conclusions are not negative," they report.  

The study was published online on April 16 in JAMA Oncology.

"Many slides at important meetings like ASCO and ESMO are tweeted or shared on social media in real-time, and this could contribute to the diffusion of questionable scientific messages," said lead author Massimo Di Maio, MD, from the division of medical oncology at Ordine Mauriziano Hospital in Turin, Italy.

"In our analysis we found that, in several cases, authors defined the experimental treatment as an option for clinical practice," Di Maio said.

Some studies failed to show superiority for the experimental treatment but had similar outcomes for the experimental and standard treatments. However, that does not prove non-inferiority for the experimental treatment compared to standard therapy, and it does not mean the experimental treatment may be an option for clinical practice, Maio commented. Proving noninferiority would require a prespecified, clinically "nonrelevant" margin of difference. Using a post-hoc noninferiority interpretation is methodologically questionable, he added.

"If the drug is already available in clinical practice, as is the case for treatments tested in many academic trials, applying that questionable conclusion to clinical decisions could result in patients potentially receiving an inferior treatment," he said.

He added that he is not against presenting negative results, which may have value and deserve attention.  

"I strongly believe that a formally negative or inconclusive result does not imply that the study deserves less attention compared to a positive result," he said. "Negative trials can represent important evidence. They can be used as part of meta-analyses, and can offer important suggestions for further research."

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Di Maio said he came up with the idea for this study last year while attending oral sessions at the ASCO 2019 annual conference in Chicago, Illinois. He noticed that several trials with a primary analysis that had negative results were presented with ambiguous or non-negative conclusions. So he discussed the issue with his colleagues back in Italy, and they decided to see how big the problem really is.

How Big Is the Problem?

The team reviewed oral presentations of phase 3 randomized controlled trials (excluding noninferiority trials) presented at ASCO and ESMO from 2017 through 2019. They separated trials based on whether the primary endpoint had positive or negative results. Then they evaluated the wording of the conclusions sections. Conclusions were considered non-negative when the authors "more or less explicitly" brought up the idea of using the experimental treatment in a clinical setting and did not provide clear conclusions about the negative results.

The analysis included 208 trials, of which 91 had negative primary endpoint results. Among trials with negative results, 29% had non-negative conclusions, of which 22% were presented in 2017, 13% in 2018, and 47% in 2019.

Among the studies with negative results and non-negative conclusions:

The team also compared for-profit and academic (nonprofit) studies and found similar percentages of non-negative conclusions among studies with negative results: 30% (17/57) among nonprofit studies and 26% (9/34) among for-profit studies.

"One could hypothesize that the tendency to present results in a non-negative way is related to economic interests of the study sponsor. However, our results tell us that this is not the case," Di Maio said. "Many researchers tend to present their study as positive, maybe because they are 'in love' with the hypothesis and truly convinced of the efficacy of the treatment they have tested."

Overall, the results imply the need for caution when listening to oral presentations, whether or not the study is sponsored by "big pharma" or a nonprofit.

"Practicing physicians should not read authors' conclusions as pure gold, but should question whether the conclusions are actually supported by the results. I suggest always looking carefully at the study design, primary objectives, and hypothesis," he said.

"We believe that more attention should be paid to the statements included in the conclusions of oral presentations at meetings, and the discussants' role is crucial," the team concludes. In addition, "when the primary endpoint is not met, the word negative should be explicitly used."

Di Maio has reported receiving personal fees from AstraZeneca, Eli Lilly, Bristol Myers Squibb, MSD, Eisai, Takeda, Pfizer, and Janssen. Several coauthors have also reported receiving fees from various pharmaceutical companies.

JAMA Oncol. Published online April 16, 2020. Letter

Follow Medscape Oncology on Twitter for more cancer news: @MedscapeOnc.


The cost of cancer drugs continues to escalate with each new product that comes on the market, often presenting formidable challenges to both patients and healthcare systems. But a new analysis suggests these high costs cannot be justified with respect to clinical benefit.

The analysis considered 65 oncology drugs launched in the past decade and found no association between clinical benefit and monthly treatment cost.

The study was published online May 1 in the Lancet Oncology.

"Prices of cancer drugs should be better aligned with their clinical benefit to improve access to beneficial medicines and enable limited resources to be used for treatments that offer patients improved outcomes," said lead author Kerstin Noëlle Vokinger, MD, JD, PhD, LLM, assistant professor for public law and digitalization, health law, and regulatory sciences at the University of Zurich, Switzerland.

Clinician "Tough Discussions" With Patients

The findings of this study are similar to findings of previous studies, noted an expert who was approached for comment.

There is already considerable evidence that the price of new drugs does not reflect the drug's value, said Yousuf Zafar, MD, MHS, FASCO, associate professor of medicine and public policy at Duke University in Durham, North Carolina.

"Because price is not linked to value, manufacturers are incentivized to develop more drugs in an existing class or drugs with limited benefit," he told Medscape Medical News. "If value played a role in the drug pricing and approval process, we could disincentivize the production of the tenth checkpoint inhibitor or the drug that improves survival by just weeks."

Existing value frameworks (such as those used in the current study) provide a good start for this process, he noted, but payers will ultimately need to make difficult decisions about coverage.

"But that responsibility does not end with payers," Zafar emphasized. "Clinicians should have the tough discussion with patients about how much benefit is actually expected from the drugs we prescribe.

"In many instances, I have had patients decline drugs like regorafenib [Stivarga, Bayer] for colorectal cancer when I explain the magnitude of expected benefit vs the potential for toxicity ― both physical and financial," he added.

Details of the Findings

Drug prices have been a hot topic of discussion for some time, especially in the United States, where they are the highest in the world. Determining the value of a drug by pegging cost to benefit has been proposed by experts and the two major professional organizations.

The American Society of Clinical Oncology (ASCO) developed a value framework (ASCO-VF) that defines the value of a drug on the basis of clinical benefit, toxicity, and cost. The European Society of Clinical Oncology (ESMO) released a Magnitude of Clinical Benefit Scale (MCBS), which offers a "rational, structured, and consistent approach" to stratifying drugs' clinically meaningful benefits.

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The new study used both of these frameworks to assess the association between the clinical benefit of approved cancer drugs and their cost in the United States and four European countries (England, Switzerland, Germany, and France).

The researchers identified all new drugs indicated for adult cancers that were approved by the US Food and Drug Administration between January 1, 2009, and December 31, 2017, and by the European Medicines Agency through September 1, 2019. Because the ESMO-MCBS tool can only be used with regard to solid tumors, the evaluation of clinical benefit was restricted to drugs indicated for nonhematologic cancers.

The median monthly treatment costs for the included cancer drugs was highest in the United States ($13,179), followed by England ($6202), Switzerland ($5696), Germany ($5121), and France ($4866).

When the team assessed the 46 drugs approved for solid tumors, there was no significant difference in monthly treatment costs between drugs that had high clinical benefit and those of low benefit (using the ASCO-VF, two-sided = .25; using the ESMO-MCBS, = .25).

As an example, for the treatment of prostate cancercabazitaxel (Jevtana, Sanofi-Aventis) had lower clinical benefit scores than abiraterone (Zytiga, Janssen) (ESMO-MCBS score, 2 vs 4), yet the cost of the two drugs was similar in the United States ($10,531 vs $10,887) and Germany ($3311 vs $3340) and was slightly higher in England ($4554 vs $3568) and Switzerland ($5292 vs $3475).

With regard to individual countries, no significant associations were observed between cost and clinical benefit using the ESMO-MCBS (for the United States, = .16; for England, = .98; for Switzerland, = .54; for Germany, = .52; and for France, P =.40). The same was true when the team used the ASCO-VF except for France, where there was a correlation (for the United States, = .56; for England, = .47; for Switzerland, = .26; for Germany, = .23; and for France, = .037).

The authors conclude that the prices of cancer drugs should correspond more closely with their clinical importance, "such as by prioritizing drugs with low or uncertain benefit for price negotiations, to improve access to beneficial medicines and enable finite resources to be used for treatments that offer patients improved outcomes and optimal value."

"I recognize two explanations for the lack of strong association between price and clinical benefit seen in this paper," said Scott Huntington, MD, MPH, of Yale School of Medicine, New Haven, Connecticut, who was approached for comment.

"First, this work and others provide compelling evidence that prices of recent cancer therapeutics are not strongly tied to clinical utility, particularly in the US, where payers have little leverage over coverage or pricing of cancer drugs," he told Medscape Medical News.

In countries such as the United Kingdom, formal cost-effectiveness analyses do inform negotiations, drug prices, and ultimately coverage decisions, thus, "we would expect cancer drug prices in the UK to be more closely associated with clinical benefit, but that is not seen in this analysis," Huntington pointed out. "It is likely that the cost measure — using monthly drug cost — and clinical utility — framework composite scores — in this study is less precise than what is typically used in formal cost-effectiveness analyses."

The bottom line, he added, is that it is probably safe to conclude that there's a long way to go before cancer drug prices are strongly associated with their clinical benefit.

"Incorporating the spirit of available value-based oncology frameworks, particularly concepts of treatment-related toxicity and degree of innovation, alongside traditional cost-effectiveness modeling is likely an important step towards value-based pricing of cancer therapeutics," he said.

The study was funded by the Swiss Cancer Research Foundation (Krebsforschung Schweiz). Vokinger received grants from Swiss Cancer Research Foundation during the conduct of the study. Several coauthors also report receiving various grants. Huntington is employed at an academic medical center with 340B status; he has consulted for Celgene, Bayer, Genentech, Pharmacyclics, and AbbVie and has received research (institutional) funding from DTRM Biopharma, Celgene, and TG Therapeutics. Zafar has relationships with Shattuck Labs, AIM Specialty Health, Copernicus WCG, Discern Health, Family Reach Foundation, McKesson, RTI Health Solutions, Vivor, and AstraZeneca (institutional).

Lancet Oncol. Published online May 1, 2020. Abstract

Follow Medscape Oncology on Twitter for more cancer news: @MedscapeOnc.


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