The Paxlovid Story
It usually takes, on average, 11 years to develop a new drug. That is one reason why the introduction of an antiviral drug for Covid-19 treatment with the brand name Paxlovid is so remarkable: it was developed in just 20 months. The science that permitted this, as detailed in a STAT news article by Mathew Herper, was impressive indeed. The article quotes Eric Topol, the director of the Scripps Research Translational Institute, as calling the development of Paxlovid “the fastest development of a small molecule drug, with clinical validation and high efficacy, in history—no less in the midst of a pandemic.” In a study of unvaccinated people, Paxlovid reduced the risk of hospitalization for Covid-19 by 89%, leading the FDA to issue an Emergency Use Authorization (EUA) for the drug last December. It is now recommended for people with mild to moderate symptoms of Covid-19 who are at risk for developing more serious illness.
That impressive science makes the fact that the drug is, by all accounts, substantially underutilized, both perplexing and disturbing. The situation is highly reminiscent of what happened when the vaccines were first rolled out for Covid-19 under FDA EUA rules: brilliant science leading to a safe and effective vaccine in record time and then profound difficulties getting it into the arms of people in the U.S. and around the world. The roll-out of Paxlovid in the U.S. appears to be another story of dysfunctional healthcare and science communication systems.
Vaccines are highly effective at reducing the risk for serious illness, hospitalization, and death from Covid-19, but especially since the emergence of the Omicron variant it is clear that highly infectious mutants can readily infect even vaccinated people. More vulnerable people, especially the elderly, the immunocompromised, and those with underlying medical conditions like diabetes, are then more likely to develop significant symptoms. Developing drugs that can treat infected people and reduce the risk for this slide into serious illness has been a priority for scientists and pharmaceutical companies. One strategy is to administer antibodies specific to the virus that causes Covid-19, called monoclonal antibodies, as soon as someone is infected, but those require intravenous administration and therefore are not ideal.
Two oral medications have been granted EUA for preventing serious illness in people who have been infected with Covid-19, Paxlovid and molnupiravir, but the latter does not appear to work as well as Paxlovid. (We are breaking our usual policy and referring to Paxlovid by its brand name because it is not available as a generic drug and its generic name—nirmatrelvir with ritonavir—is a tongue-twister that almost no one seems to be using yet). Paxlovid is a combination of a drug invented by the Pfizer company (nirmatrelvir) and an older drug used to treat HIV infection (ritonavir). They are both in the category of medications called protease inhibitors, drugs that block a virus’ ability to assemble itself inside a human cell and then replicate.
If Paxlovid is so effective at preventing serious Covid-19 illness, then why isn’t it being widely used at a time when ever more infectious variants seem to be spreading? There are multiple reasons for this failure that fall into three main categories: 1. Lack of drug distribution, 2. Lack of awareness by the public, and 3. Lack of awareness and unwillingness to prescribe it by physicians.
Initial Distribution of Paxlovid was Problematic
In her New York Times article “Covid drugs save lives, but Americans can’t get them,” Zeynep Tufecki detailed on April 22 the travails people have gone through to find a pharmacy stocked with Paxlovid. Some pharmacies had no Paxlovid while others had stocks of unused doses. “Social media is also replete with stories of despondent patients unable to locate doses or managing to do so after much effort and paying extra when they ended up out of their insurance networks,” she wrote.
At the end of April, the Biden administration announced it would take a series of steps to increase the availability and use of Paxlovid, but that was four months after the EUA had been issued. It is still unclear why it has taken so long for Paxlovid to become widely available in hospitals, clinics, and pharmacies. The problem could rest with how much was initial manufactured and distributed by Pfizer or with the supply chain that links pharmaceutical companies to pharmacies. It is also unclear why it took federal and state governments so long to make a concerted effort to get Paxlovid to pharmacies. This all needs to be investigated because it seems absurd that a drug this effective should languish for four months off so many drug store shelves.
Public Poorly Informed about Paxlovid
But even as Paxlovid does become more available, people may not know enough about it to ask for it or know how to access it. Paxlovid must be prescribed by a physician, nurse practitioner, or physician’s assistant, and it needs to be taken within five days of first exhibiting symptoms. Not all Americans have such relationships with prescribers or even if they do are able to get through to them fast enough to make taking Paxlovid possible. Furthermore, because Paxlovid is not an FDA-approved drug yet but rather only available under the EUA program, Pfizer is not allowed to advertise it, either to the public or to prescribers. That leaves it up to local, state, and national public health authorities to ensure that people know that a pill is available that they can take to prevent serious illness if they develop symptoms and test positive for Covid-19. In some places, like New York City, frequent television ads about drugs to treat Covid-19 are appearing, but this is not the case throughout the U.S., and we are unaware of any systematic CDC or FDA programs to inform the public about it. Thus, the disjointed American healthcare system has not been able to provide sufficient public information about Paxlovid or to come up with a viable plan for getting it to people who need it.
Prescribers are Reluctant to Prescribe Paxlovid
The prohibition against drug company advertising about Paxlovid extends to prescribers. As Tufekci notes “In the United States, such doctor outreach is often, sadly, left to pharmaceutical companies, which spend tens of billions of dollars each year marketing their drugs to physicians. This has led to heavily promoted drugs getting prescribed even when cheaper, effective alternatives exist.” Once again, there has been a lackluster attempt on the part of public health agencies to educate physicians and other prescribers about Paxlovid. Our healthcare system appears content to default to drug companies to provide physicians with information they need about newly available medications.
This lack of prescriber education about Paxlovid may explain one of the main reasons physicians appear to be reluctant to offer patients the medication: what are called drug-drug interactions. Most medications we take are broken down (that is, metabolized) by the liver, thus controlling how high the blood levels of the drug can go. The liver has a set of enzymes called the cytochrome P450 system that is responsible for metabolizing drugs. The activity of these enzymes is controlled by our genes, so that activity varies from one person to the next depending on the individual’s genetic make-up. Some people are faster metabolizers of specific drugs than others.
Some drugs we take can inhibit the activity of these metabolic enzymes, and Paxlovid is one of them. Its ritonavir component inhibits an enzyme called 3A4 in the cytochrome P450 system, making metabolism of a host of other medications less efficient. That means that there are many drug interactions with Paxlovid that can lead to significant increases in blood levels of certain medications. Since elderly people are considered among the important candidates to take Paxlovid and they are most likely to be taking multiple other medications, prescribing Paxlovid can be tricky.
A doctor or other prescriber about to give someone a prescription for Paxlovid may see the long list of potential drug-drug interactions and become wary. Some of the medications that interact with Paxlovid might be stopped for the five days a person takes Paxlovid, but others, like drugs to control heart rhythm disturbances such as atrial fibrillation, cannot be stopped so easily. There are probably ways to handle these situations (such as temporarily lowering the dose of a drug with which Paxlovid interacts), but prescribers have not been given sufficient information about what to do in such instances and we hear anecdotally that this is discouraging some physicians from prescribing it. How widespread a reason this is for the lack of Paxlovid uptake is unknown at present, but again speaks to the failure of public health agencies like CDC and FDA to conduct timely and meaningful prescriber education campaigns.
On three levels then—supply, public information, and prescriber education—our healthcare system has failed to get Paxlovid into the hands of people who should take it. This is another example of the shortcomings of the American healthcare system, a system that is based on some of the world’s most outstanding biomedical research but nevertheless routinely fails to make the progress of modern science available to its constituents. In the case of Paxlovid, we see a disjointed drug distribution system and a failure of vital health science communication to both the public and healthcare providers. We also see the results of years of default to pharmaceutical companies for critical public health education to both groups.
The Paxlovid story is a case in point, then, of some of the things that are wrong with the American system. What should have happened was three-fold. First, the moment Paxlovid was first presented to FDA for an EUA, federal authorities should have planned for the drug’s rapid distribution to pharmacies and hospitals around the country. Second, federal, state, and local public health agencies should have developed a comprehensive plan to provide the public with information about Paxlovid, including who should take it and where to get it. Third, the same public health authorities, along with medical and nursing associations, should have developed an education campaign aimed at prescribers, informing them about the benefits of prescribing the drug and providing them with algorithms for what to do in complex situations such as those that arise because of drug-drug interactions. Once again, we have witnessed the benefits of great science vitiated by poor public science communication.
criticascience 