Antimicrobials are special amongst classes of pharmaceuticals for several reasons, including their use in the treatment of infections and prevention for myriad medical procedures that range from chemotherapy to organ transplantation.
Antimicrobials also have a national security role as they are a vital component of the medical countermeasures to be used during a biological attack. The public health police power of the government may also require antimicrobials to intervene during contagious infectious disease outbreaks effectively.
To be useful as countermeasures, high levels of resistance existing — or being engineered — amongst the pathogen in question could render countermeasures ineffective.
On an almost daily basis, there are warnings regarding the real and alarming rise of antimicrobial resistance. Among the reports detailing the detection and spread of a new resistant species, are proposals for reversing the situation, buying time for new antimicrobials to be developed, and finding long term solutions to this seemingly insoluble problem.
A fundamental problem — which is often not mentioned or analyzed — is the relative societal value that is placed on antimicrobials as compared to other medical interventions.
Duration, stewardship, and resistance: Unique forces
The contexts in which infectious diseases are treated differs from those in which other medical conditions are treated in ways that give rise to unique challenges in creating and monetizing effective treatments.
The shortage of new anti-microbials to fight the resistance crisis is often regarded as a case of “market failure” and to require non-market-based solutions, such as the creation of a non-profit government-sponsored entity for their development.
Several characteristics of antimicrobials underlie this situation. The relatively short duration of therapy with antimicrobials limits the total amount of revenue a product can generate relative to medications taken for more extended periods.
We are facing a march of resistance leads to the predictable obsolescence of any antimicrobial over a period of time. Also — and unparalleled — is the unique issue that the use of an antibiotic by one individual (including an animal) having a potential negative impact on the future use of that same (or related) medication by another individual.
Lastly, stewardship is required of newly developed antimicrobials, for which resistance has not increased, to preserve the future use of these products when they become drugs of last resort. These factors all act in concert to limit revenue generation and investment recuperation before patent expiry.
Most proposed policy solutions to the problems above take the form of creating special incentives for industry to produce new antimicrobials. These solutions are divided into “push” incentives (which provide support for early research and development with less emphasis on commercial development and financial return) “pull” incentives (which offer a financial performance for a successful event through market entry rewards or guaranteed purchase).
Market entry rewards granting prolonged market exclusivity (e.g., The GAIN Act) have been put into place but still have not appreciably lessened the crisis. Push awards have also been introduced that fund early antimicrobial development. Such an approach is exemplified by the public-private partnership CARB-X, which has seen some early success.
There is a growing consensus that to profit from new antimicrobial drugs without encouraging their misuse, pharmaceutical companies will need to “decouple” the revenues derived from these drugs to their use.
One plan for such decoupling that has garnered widespread support from policymakers is to adopt a subscription model, where a purchasing entity would pay for access to a company’s portfolio of antimicrobials for a fee that is independent of the volume of use of any particular drug.
Government policy reform can also help alleviate the crisis. For example, the proposed DISARM Act seeks to allow antibiotics to be paid for separately from a bundled payment for hospitalization. The current practice of including medicines as part of the bundle encourages the use of cheaper antimicrobials versus newer, more expensive alternatives that may be more effective.
No reform can work without addressing the root cause
All of the reform measures discussed operate within the current paradigm of healthcare and, as such, do not treat what is likely the root problem. The immense value of potential new microbial depends on intelligent stewardship and continued use over a prolonged period.
This requires innovation (and experimentation with) not only new drugs but new business models. Such changes are better discovered by industry than prescribed by policymakers. But the industry is not in a position to invest in their discovery because the current regulatory and IP regime allows them no way to capture the value of such innovations monetarily.
As an example of the sort of policy that would enable such innovation, one of us has proposed extending the IP protection of new antimicrobials indefinitely, so long as specific levels of antimicrobial susceptibility are maintained in clinical isolates.
Such a policy would make it possible for companies to find ways to capture the long-range value of new microbial and new business practices for their responsible stewardship monetarily. It would, therefore, make it possible for them to invest in developing such drugs and such methods.
However, at least some of the business plans that we expect would be developed where such a policy in place would require high prices for new drugs that are seldom used. However, many of the prevailing cultural and political trends eschew any talk of raising the price of pharmaceutical products, and there are active policy proposals to limit the number of pharmaceuticals.
Affording the development of new antimicrobials requires the industry to able to achieve a return on investment. If a drug is to offer this ROI, while being seldom used, it will need likely need to be expensive.
Why is it that antimicrobials — which are unquestionably one of the most important innovations in all of medication history — are priced the way they are?
Effective antimicrobials were first developed in the 1910s (arsenic derivative for syphilis) and 1930s (sulfonamides) and 1940s (penicillin) in an era when drug pricing was in its infancy, drug discovery was relatively uncomplicated, and ineffective therapies abounded. Bringing a drug to market in those eras did not involve the estimated $1 billion investment that is required today.
Moreover, the price of drugs as such was relatively low, and no drugs had prices comparable to those seen with, for example, CAR-T therapies. By contrast, when any new antimicrobial is released, there is often an alarming concern regarding its price. For example, such concern was expressed for hepatitis C curative therapies.
There are have been discussions of breaking patents on anti-infective therapies. By contrast, there is much less controversy generated for similar products used to treat leukemia, hypercholesterolemia, and neurodegenerative diseases.
Moreover, when an antimicrobial producer raises prices to increase ROI, villainization invariably occurs. It is non-controversial to spend $475,000 for a course of CAR-T therapy to rescue someone from leukemia, but it is considered beyond the pale to pay $1000 for a 7-day course of an antibiotic to save someone from septic shock.
Recognizing this paradox, Ezekiel Emanuel wrote:
As a society, we seem willing to pay $100,000 or more for cancer drugs that cure no one and, at best, add weeks or a few months to live. We are ready to pay tens of thousands of dollars for knee surgery that, at best, improves function but is not lifesaving. So why won’t we pay $10,000 for a lifesaving antibiotic?
Interestingly, much like the drugs they prescribe, infectious disease doctors themselves, despite the cognitive complexity of their work, command less in salary than other specialists and subspecialists, a point made in a recent piece arguing for compensation reform.
Remedying the problems with the antimicrobial market requires us to reframe the philosophical and moral case for it completely. We can do this by emphasizing that the treatment and control of infectious diseases is historically one of the most civilizing and life-enhancing activities undertaken by humans and deserves to be recognized and monetarily valued as such.
Dr. Amesh A. Adalja is an infectious disease physician and senior scholar at the Johns Hopkins Center for Health Security. Greg Salmieriais, Ph.D., is a philosopher and fellow at the Anthem Foundation.