Post-launch, pre-cliff: The R&D congress ignores

Post-launch, pre-cliff: The R&D congress ignores

Written by

Article originally published in

Small molecule therapeutics make up roughly 70% of all new medicines approved by the FDA. The current drug pricing legislation being considered by the Senate would tilt incentives away from small molecule drug development by introducing price negotiation for small molecules at nine years, as opposed to 13 years for biologics.

That would certainly result in fewer new small molecule drugs, particularly for diseases of aging, like cancer, that affect Medicare beneficiaries – many fewer than currently mis-estimated by the Congressional Budget Office. We endorse the arguments for creating a parity of incentives for small molecules and large molecules in any new drug pricing legislation by making both classes of drugs eligible for negotiation only after 14 years on the market, which is the average duration before drugs go generic.

Our opposition to the nine-year period is not just about fewer drugs being approved, though that would be reason enough not to start price controls so soon after launch. Often, a drug’s initial approval only hints at its full therapeutic potential and the eventual number of patients who may benefit over time. Continued R&D investment can unlock much more utility before the drug ultimately goes generic, but those investments require adequate incentives.

A generic drug is only as useful to us as we know what it’s good for, and most of what we learn about any medicine is learned before it goes generic. With that in mind, we wanted to provide some additional data on why we believe in the need for longer protection of small molecules; nine years is not enough.

Stunning progress, incrementally

We’ve seen huge progress in recent years for patients in oncology and immunology, the top two areas for drug development. So, we thought it might be useful to explore the development process and the role of small molecules in these areas specifically.

Over the past three years (2019-2021), the FDA has approved 177 new drugs. Fifty-one of those were in oncology and more than half of those (27) are small molecules. The standard approach for cancer drug development, where one medicine may end up treating multiple tumor types, is to first seek approval in one initial tumor type among patients who have not responded to any available treatments. It is only after this initial FDA approval that extensive research begins to explore the drug’s benefit in additional tumor types and settings, gradually increasing the number of patients who might benefit.

The table below shows examples of leading small molecule cancer drugs and the time from each drug’s first approval to its most recent approval (Fig. 1).

Fig. 1. Source, FDA; authors’ analysis.

Let’s drill down into one specific example from this table. Tafinlar, a kinase inhibitor originally developed by GlaxoSmithKline, was first approved for a subset of melanoma patients in 2013 (Fig. 2). Over the following nine years GSK and Novartis, which acquired rights to the drug, completed the extensive R&D necessary to prove Tafinlar’s value in combination regimens with existing drugs, then in lung cancer, then to prevent cancer recurrence, ultimately proving its effectiveness in all tumor types with a particular mutation known as BRAF-V600E (more than 20 different kinds of cancers).

Fig. 2. Source: FDA; authors’ analysis.

Tafinlar isn’t unique in that regard. Each line in Figure 1 above describes a similar, systematic process for expanding a drug’s usefulness from an initially narrow indication so it can benefit many more patients. And this broadening-of-utility phenomenon occurs outside oncology drug development as well.

Immunology is also an active area of new drug development, and drug development there follows a similar trajectory. Take for example Pfizer’s Xeljanz, the first small molecule inhibitor of the JAK enzyme. FDA first approved Xeljanz for refractory rheumatoid arthritis patients in 2012 (Fig. 3). It took an additional nine years of research to ultimately prove its value for multiple additional unmet autoimmune disease needs, including ulcerative colitis, psoriatic arthritis, and ankylosing spondylitis.

Fig. 3. Source: FDA; authors’ analysis.

While Tafinlar and Xeljanz are just two examples, this is a familiar and lengthy development path, similar to that of many other drugs that treat chronic autoimmune conditions.

Drug development doesn’t happen all at once

The only reason that the private sector would invest more money into trials to study what new uses a drug might have is if there will be enough time before generic entry for these new uses to justify the investment required to discover them. And it’s not like every trial looking at a new use of a marketed drug is destined to succeed. Companies run a portfolio of trials probing for new uses; many fail. So the ones that succeed have to compensate for the cost of running that whole portfolio of trials. Spending nine years to find new indications might be worth it if you expect to still have six more years to profit from such findings. But few would bother to fund all that post-launch R&D if there was little time to generate a return.

And often the first indication for which a drug is approved is not what made it worthwhile to develop in the first place; it was just a warmup, with the bigger market to come later. When you know you have enough patent life to get 14 years on the market post-launch before generics compete, launching in a small indication and generating some revenue while working on a bigger goal makes sense. If the drug turns out not to work in the larger indication, then the smaller market ends up a consolation prize. But if you were limited to only nine years from launch regardless of your patent life, then you wouldn’t want to start the clock by launching in a small indication. You would either go for the big, risky indication or not bother to develop the drug at all, since the small indication can’t justify the cost of development on its own.

Less common tumor types in particular, like metastatic melanoma, certainly would not have seen the dramatic increase in cure rates we have today had price controls after nine years been the policy these last several decades. So you can’t even assume that you would get the drugs we have on the market if companies couldn’t count on having the time to both complete a portfolio of trials searching for more uses and profit from those findings.

The long-term damage to innovation that would result from limiting protection of small molecules to nine years should be self-evident. We’d know much less about Tafinlar and Xeljanz, those drugs would be helping far fewer patients, and we’d be giving up on two of the most significant sources of progress in cancer and immunology in the last several years. Just imagine the impact of this limit on drug development overall.

Turning the current bill into policy would result in drug developers opting not to make the significant investments needed to understand the value of medicines in multiple diseases, how they should be used with existing therapies, or make them available to patients with less severe forms of disease.

There are so many problems we have yet to solve, and we’re making progress. It is not a given that we must die as early as we do of cancer or suffer the indignities of Alzheimer’s. Why must we give up on the biomedical advances we have yet to make and all the patients who will need them?