The Dangers of Incentivizing Mediocrity With 'Me-Too' Drugs

H. Jack West, MD


April 16, 2021

Earlier this year, the US Food and Drug Administration (FDA) announced the approval of cemiplimab-rwlc for the first-line treatment of patients with advanced non–small cell lung cancer (NSCLC). Although such approvals are typically cause for celebration, oncologists reading the news could be forgiven for instead feeling a frustrating sense of déjà vu.

Cemiplimab is now the third immune checkpoint blockade therapy targeting programmed cell death 1 and programmed cell death ligand 1 (PD-L1) approved in this indication. Pembrolizumab first demonstrated a highly significant improvement over chemotherapy back in 2016,leading to its remarkably quick approval and establishment as our preferred first-line standard of care for such patients. Last year saw atezolizumab's approval in the same setting, after it was reported to provide remarkably similar efficacy and tolerability to what we already had with the pembrolizumab monotherapy. And now the charitably named EMPOWER-Lung 1 trial has shown that cemiplimab monotherapy is superior to platinum doublet chemotherapy as first-line treatment in patients with advanced NSCLC and tumor PD-L1 expression ≥ 50%. This gives us essentially redundant offerings that confer no incremental benefit over existing alternatives.

We've seen this all before. It is yet more evidence of the FDA's flawed approach to judging redundant therapies: "Me-too" drugs must only surmount the dubiously low bar of producing a superior outcome to the lowest justifiable standard therapy, with no consideration of incremental benefit or potential cost.

Some might argue that by taking this inherently libertarian position, the FDA is simply expanding the options to oncologists and patients. What's the harm in that? However, incentivizing a lack of innovation is ripe with peril for our field.

The Dangers of Redundancy

There are clear ethical dilemmas in running trials that knowingly administer obsolete standards of care.

The EMPOWER-Lung 1 trial randomized patients with high tumor PD-L1 expression to receive chemotherapy alone well after pembrolizumab had established highly significant superiority over a chemotherapy doublet. The design of this international trial exploited poor access to the best-known treatments in certain healthcare systems. This is a trial that would have been clearly considered unethical to conduct in the United States and many other countries.

The opposing argument is that such trial designs benefit half of the patients by giving them a treatment more reflective of our best global standard. But should the international oncology community tacitly enable and capitalize on these disparities rather than address them more directly? Is this the best way to overcome substandard care in these parts of the world?

The FDA has developed several extremely valuable programs for treatments that offer promise for serious diseases with an unmet need, including priority review, recognition of breakthrough therapy, accelerated approval, and fast-track status. What they lack, however, is a designation to deprioritize therapies that offer little or no perceptible clinical benefit.

The FDA faces the practical, yet enviable, challenge of needing to review and regulate a wide array of agents, alone and in combination, all of which are competing to be approved first. Time spent reviewing redundant offerings inevitably comes at the cost of more promising therapies. The unnecessarily tragic outcome of this equation is on display for the many patients with advanced NSCLC that harbors a KRAS G12C mutation who will literally die waiting for the approval of sotorasib, an agent that will be the first with proven activity in this setting.

I would similarly argue that oncologists' limited time and mental energy could be better spent learning about nearly any other topic in cancer care than about the availability of cemiplimab for advanced NSCLC. Instead, they become a hapless audience to the argument that "new" equals "improved."

Finally, we cheat ourselves of true innovation by allowing pharmaceutical companies to scrap for a sliver of market share without offering true benefit over our best current options.

Trials that ask a question that has already been answered direct patients away from new opportunities. The EMPOWER-Lung 1 trial could have been designed to at least ask a novel question about less frequent dosing of immunotherapy after 6 or 12 months, or perhaps have incorporated randomization by duration of therapy. This would have opened up the possibility for an otherwise redundant trial to still provide fresh insights. But because we demand so little, the trial design had no such ambition or courage.

By not asking "me-too" therapies to exhibit improved efficacy, better tolerability, and/or lower costs than the current best options in that setting, we continue a failed status quo. Although we may have additional competition in the market of cancer therapies, it does nothing to staunch the inexorable increase in drug pricing in the United States. Our healthcare system, by far the least cost-efficient in the world, is a reflection of these policies, which we need to work together to overturn. You get what you incentivize. We can do better.

H. Jack West, MD, associate clinical professor and executive director of employer services at City of Hope Comprehensive Cancer Center in Duarte, California, regularly comments on lung cancer for Medscape. Dr West serves as web editor for JAMA Oncology, edits and writes several sections on lung cancer for UpToDate, and leads a wide range of continuing education programs and other educational programs, including hosting the audio podcast West Wind.

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