The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved record numbers of new cancer drugs recently. This is extraordinarily good news for physicians, patients, and drug companies, but it raises important questions as to how effective these drugs are, whether everyone with cancer needs them, whether physicians are too enthusiastic about prescribing them, and why these drugs are so costly.
Robert Peter Gale, MD, PhD, DSc (hc), FACP, FRCPI (hon), FRSM
Hillard M. Lazarus, MD, FACP
First, do these new drugs improve survival to a clinically important degree, an obviously subjective measure? Some do. However, the magnitude of benefit of many of them is questionable. Consider, for example, pembrolizumab, which is approved by the FDA for advanced non–small cell lung cancer (among numerous other indications). In a randomized comparison with platinum-based chemotherapy in almost 600 patients with lung cancer, median progression-free survival increased by 0.2 months (2.9 vs 2.7 months), or about 6 days.1 Median survival increased by 2 months (13 vs 11 months), or 60 days. This is progress, and some people would rather receive immune therapy than chemotherapy, thinking the former is without adverse events; it isn’t. But the effect size is modest at best.
More troubling are accelerated approvals. For example, consider lurbinectedin, which recently received accelerated FDA approval based on data from a phase II study of 105 patients with advanced small cell lung cancer that failed to respond to platinum-based chemotherapy.2 The overall response rate was 30%, and the median response duration was 5 months, with no comparator arm.
Also, about one-half of conventional approvals were based on surrogate endpoints, not survival. For example, between 2009 and 2014, the FDA approved 83 cancer drugs, 55 based on surrogate outcomes, including 31 based on overall response rate and 24 based on progression-free survival.3 One review reported that fewer than one-half of drugs whose approval is based on a progression-free survival endpoint improved survival or health-related quality of life.4 Similarly, between 2009 and 2013 the EMA approved 48 cancer drugs, only one-half of which increased survival or improved health-related quality of life.5
Another problem with several new drug approvals is the choice of an inappropriate comparator therapy. For example, a phase III study in persons with chronic lymphocytic leukemia (CLL) older than age 65 compared ibrutinib with chlorambucil,6 an outdated approach. Another study compared low-dose cytarabine with or without venetoclax, despite several randomized trials showing azacitidine was better than low-dose cytarabine.7 Finally, many approvals have been based on analyses of hazard ratios rather than the preferred restricted mean survival time. This is because hazard ratios assume hazards between cohorts are proportional throughout the observation interval. Often, they are not.
Expertise and Endorsement
The next question is, given the modest effect sizes of many newly approved drugs, how and why do they gain favor with physicians and patients? One reason is because they are promoted by disease experts, referred to by pharma as key opinion leaders, who have considerable influence over where, when, and how a new drug is used.
Endorsements by patients and sometimes physicians (or actors dressed as physicians) are frequently promoted by drug companies in conventional and, more recently, social media. A two-page advertisement in the July 20, 2020, issue of The New Yorker magazine, not typically considered a high–impact factor medical journal, suggested that “adults with newly diagnosed non–small cell lung cancer that has spread” should consider the “first and only chemo-free combo.” The estimated cost of the advertisement was $120,000—less than the cost of one person receiving 1 year of nivolumab and ipilimumab (about $200,000). One wonders if the ad was directed to patients or physicians, given the New Yorker’s demographic. Television is filled with infomercials suggesting: “Ask your doctor if you need drug X,” followed by a litany of potential adverse effects, which seem to scare no one.
Is this collision of new drugs, physicians, and pharma a marriage of convenience, voluntarily entered into and benefiting all three? Sometimes.8 However, there are complex considerations.
“[A]lthough it is popular to disparage the drug industry for promoting new drugs with sometimes modest benefits and high costs, we and our patients benefit greatly from their investment.”— Robert Peter Gale, MD, PhD, DSc (hc), FACP, FRCPI (hon), FRSM, and Hillard M. Lazarus, MD, FACP
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Key opinion leaders are frequently investigators in the clinical trial(s) that result in new drug approvals. Often, they believe strongly the new drug is an important advance. In psychology, this heuristic is known as confirmation bias. Having invested several years studying a new drug, often requiring considerable effort and encountering problems with ethical committees, clinical research organizations, and study managers, physicians want to believe their efforts are worthwhile.
But we also need to acknowledge other considerations, such as the need to publish for academic advancement. Because of publication bias, it is much easier to publish a study claiming a new, more expensive drug is better than an older, less expensive drug than the converse.
There are also less altruistic considerations. Everyone likes to lecture to a large, admiring audience, have one’s headshot (typically from 20 years ago, in a coat and tie, no beard, a stethoscope draped across your neck) projected on a huge screen, travel abroad—the SARS-CoV-2 pandemic notwithstanding—be fêted at a reception, and dine at an exclusive restaurant. This behavior is human nature we cannot fault. Generic drug makers are more likely to take you to Nathan’s Famous Hot Dogs in Coney Island for dinner (excellent, but $7.99 without soda or fries).
On the Other Hand
Consider a world where drug companies do not develop new drugs for diseases with unmet medical needs. We would be left with melphalan to treat plasma cell myeloma and methotrexate to treat lung cancer. Almost all new drugs in the past 30 years have come from biotechnology and drug companies, not academia. Our point is that, although it is popular to disparage the drug industry for promoting new drugs with sometimes modest benefits and high costs, we and our patients benefit greatly from their investment. Much of our medical education in diverse areas is indirectly supported by the drug industry.
There are other far-reaching implications. For example, barring the SARS-CoV-2 pandemic, large annual scientific/educational hematology/oncology meetings would generally expect to welcome between 25,000 and 42,500 attendees, of whom about 15% to 20% are drug company employees or sponsored physicians. Considerable funding for these meetings comes from drug companies in the means of attendance, exhibition space, and product theaters.
Consider, too, that peer-reviewed oncology and hematology journals are filled with advertisements for new drugs. These publications would likely be unable to achieve widespread distribution at a reasonable cost to oncology professionals without advertising income. The same holds true for the publication websites.
Our lives would be entirely different if drug companies developing and promoting new drugs ceased to exist. Remember, the estimated cost of bringing a new cancer drug to approval is about $1 billion USD but could be as low as $800 million or as high as $2.9 billion.9 These costs come from a high rate of failures and acquisition costs and need to be returned to stockholders with a profit.10 Drug company earnings are higher than most industries but much lower than technology companies like Alphabet and Google. Recent data suggest a decreasing return on research and development investment for drug companies and increasing pressure to reduce drug prices. A collison may be inevitable.
Rays of Hope
Have we a solution to these potential conflicts of interest? No. But there are rays of hope.
In the United States, several federal organizations are charged with enforcing the Physicians Payments Sunshine Act, which requires drug companies to collect and track all fiscal relationships with physicians and teaching hospitals. The goal of the law is to increase transparency of financial relationships between health-care providers and drug companies and uncover potential conflicts of interest. The legislation also allows states to enact additional requirements. Think again if you are from Minnesota and expect to eat lunch at an educational session. I [RPG] was with a distinguished Mayo Clinic oncologist at one such session where I had to swear under oath he would not eat lunch.
Another positive step is that some universities have limited or completely restricted participation of their faculty in promotional activities. However, data on the effectiveness of this ban are far from promising.11 For example, in a cohort of academic oncologists at U.S. public medical schools, two-thirds received payments from the drug industry in 2017, accounting for more than 20% of their annual salary.
None of these developments is surprising.
The truth is, physicians, medical schools, and the drug industry have symbiotic relationships. What ultimately saves us from these liaisons dangereuses is the moral compass of most physicians who want what’s best for their patients.
Our bottom line is that some of these new drugs are important advances, such as imatinib and other tyrosine kinase inhibitors in chronic myeloid leukemia, osimertinib in adjuvant non–small cell lung cancer, and chimeric antigen receptor T-cell therapy in adult B-cell non-Hodgkin lymphoma or childhood acute lymphoblastic leukemia. However, the impact of many newly approved drugs on cancer outcomes is mostly modest, and not everyone needs them. The cost of most anticancer drugs does not pass conventional cost-effectiveness criteria.12
Health-care resources need to be used to reduce infant mortality, increase childhood vaccination rates, eradicate malaria, and most recently to combat the SARS-CoV-2 pandemic and treat COVID-19. Many new cancer drugs are unlikely to be the most
effective investment of health-care resources, especially in developing countries and those with limited health-care resources.
Dr. Gale is Visiting Professor of Haematology at the Imperial College London and is on the medical staff at the University of California, Los Angeles. Dr. Lazarus is Professor Emeritus in the Department of Medicine, Division of Hematology and Oncology, Case Western Reserve University, Cleveland.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
DISCLOSURE: Dr. Gale has received research funding from the UK National Institute of Health Research funding scheme. Dr. Lazarus is a consultant for Jazz Pharmaceuticals, Seattle Genetics, Partner Therapeutics, Actinium, Pluristem, AstraZeneca, and BioSight.
REFERENCES
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