The FDA Delivered A Big Win For Innovation Against Foreign “Me-Too” Drug Makers

On 19 February 2022, the FDA’s Oncologic Drugs Advisory Committee (ODAC) dealt a serious blow to China’s “me-too” drug-makers hoping that China-derived data will grant them access to the US market. In a near-unanimous decision, ODAC recommended against approving Eli Lilly and Innovent’s PD-1 antibody sintilimab in lung cancer despite positive Phase 3 data from a trial that enrolled patients in China. 

Sintilimab is a checkpoint inhibitor that inhibits the same PD-(L)1 pathway as Keytruda (marketed by Merck), Opdivo (marketed by Bristol Myers Squibb), and Tecentriq (marketed by Roche) –– all of which are approved for the treatment of lung cancer. However, sintilimab wasn’t compared to any of those drugs in its Phase 3 ORIENT-11 trial. Instead, it was added onto chemotherapy and compared to chemotherapy alone –– a study design that isn’t only unhelpful but is unethical in the US. In the US, PD-(L)1 inhibitors, like Keytruda, are a standard of care for the treatment of lung cancer. Denying patients access to these checkpoint inhibitors, including in the control arm of a clinical trial, would be considered malpractice.

The “me-too” model of drug development has been a favorite of the pharmaceutical industry for decades. For too long, pharmaceutical companies have joined the bandwagon based on the success of a drug from another company that validates a new mechanism of action. These “me-too” drugs have an identical primary mechanism of action to the initial first-in-class drug but are chemically distinct enough to allow for patent protection without patent infringement. Unfortunately, they also possess little potential to improve the efficacy or safety profile of the first-in-class drug.

Why is “me-too” drug development so popular? It enables a comparatively low risk, high profit endeavor that ensures that multiple drug companies have a seat at the table. In a sense, it’s more cost-effective for a pharmaceutical company to invest resources to circumvent another company’s patent rather than manage the clinical risk associated with developing a first-in-class drug candidate. Today, more and more pharmaceutical resources are dedicated to me-too drug development focused on large patient populations; drugs that can be aggressively marketed to grab a slice of an existing profit pie.

Drs. Pazdur and Singh from the FDA put the problem plainly in an editorial in Lancet Oncology: 

“Many current applications that rely on clinical data from China are similar to previously conducted multi-regional clinical trials that led to US approval and, hence, do not fulfill an unmet need. Most of these drugs are checkpoint inhibitor antibodies; China’s Centre for Drug Evaluation cites more than 100 investigational new drug applications for this class.”

The biggest losers of the “me-too” model are patients, who rarely see a single benefit from the billions of dollars that are poured into copy-paste drug development. While one might reasonably expect that the availability of multiple drugs with a similar mechanism of action would drive down drug prices, this hasn’t been the case. A year of treatment with a checkpoint inhibitor in the US costs ~$150,000 regardless of the marketing company.  In fact, the price of Opdivo is higher today than when it was initially approved in 2014, despite the fact that six other PD-(L)1 checkpoint inhibitors have been approved since that time.

Patients only benefit when “me-too” drug development moves beyond simply carving out a piece of the profit pie established by the first-in-class therapy and results in development for patient populations not served by the initially approved drug. Until a me-too drug demonstrates that clinical benefit compared to the first-in-class drug, it is essentially a “who cares” drug: an approved drug based on a known mechanism that does not improve patient outcomes. 

In oncology, there are abundant unmet-need-patient populations with less common cancers in desperate need of more effective treatments. However, these cancer populations may be much rarer than lung cancer, and therefore not a high priority of pharmaceutical companies. As noted in Unnecessary Expense, TRACON Pharmaceuticals takes a different approach. Rather than developing a me-too drug in an indication already well served by an approved checkpoint inhibitor(s), TRACON is developing the potential best-in-class checkpoint inhibitor envafolimab in sarcoma, where no checkpoint inhibitor is approved and where the most effective “drug” is a chemotherapy discovered more than 50 years ago. Envafolimab’s best-in-class potential derives from the fact that it is given as a thirty-second injection under the skin in the physician’s office (akin to a flu shot). 

This is a much more convenient method of administration compared to the half-day visit to an infusion center required for all currently approved checkpoint inhibitors because they are administered intravenously. TRACON’s goal then is to approve the first checkpoint inhibitor for sarcoma patients that also represents a best-in-class treatment by virtue of its convenience of administration, and show it is safer and more effective compared to currently approved sarcoma treatments.

Hopefully, the FDA’s recent admonition of Eli Lilly and Innovent will receive a healthy reception from pharmaceutical companies and refocus their priorities, with cancer patients being the beneficiaries.