Patents, Medicines, Public Funding–2

We have distinguished four sorts of medical interventions–prevention, cure, facilitation, and alleviation. We have also argued that from a public health point of view, prevention and cure are tops, and facilitation and alleviation are great when they support prevention and cure, and less interesting if they serve to make acute conditions chronic. A vaccine that prevents tetanus is great. A vaccine that is facilitated by a better injection system is even better. An injection that doesn’t hurt so much is nice, too. No doubt anesthesia in its various forms is one of the great facilitators of all sorts of medical interventions.

Absolutely there’s still interest in making acute conditions bearable. Dialysis keeps those with kidney failure alive. And insulin is critical for treating diabetes. Such alleviators are tremendously important–it’s just that they are not cures, and so those suffering from kidney failure or diabetes are dependent on the interventions for the rest of their lives. They are rescued but also become a reliable “market” for for-profit products. Dialysis, for instance, runs about $89,000 per year, according to UCSF’s “The Kidney Project.” At 750,000 patients in the US, that’s a “market” worth $42 billion a year–7% of annual Medicare expenditures. As for diabetes, the American Diabetes Association estimates the cost of diabetes treatments in the US in 2017 were $237 billion. That’s also, er, a “market” value. The drug portion of that total is 15%. The rest is hospital care (30%), doctor’s visits (13%) and medications to treat complications (30%). If one thinks about the multipliers for estimating company valuations based on revenues in a “market” growing by 5% a year–say 9.36 for healthcare services or 15.42 for healthcare products or 22.87 for biotechnology–call it 10 because we can be lazy–we are looking at combined biomedical company valuations in the trillions that would be severely depressed if diabetes as a market just went away because of the reckless and untimely introduction of an effective prevention or cure.

Another thing. If acute conditions become bearable, then also there’s less pressing need for prevention or cure, no? If a drug can extend suffering life another six months, then there’s hope that a better drug in the future, with research, will be developed to extend life twelve months, maybe more. Once there’s a market in alleviation–fewer symptoms, lesser symptoms, longer time of response, slowing the progress of disease–then it would be a great shame if not injustice to make the private investment in that market vanish with a prevention or cure. For public policy–for where our governments choose to support programs for prevention or cure, say, relative to alleviations and facilitations.

From a market point of view developing and improving alleviators and facilitators for alleviators is the source of continuing, reliable value. If the incidence of disease is reliable, then there will be a “market” for the alleviation of the disease. If one eradicates the disease, then one also eradicates the “market” for alleviation. Wherever we see reports of billions of dollars in sales revenue for a drug that alleviates, there are people whose livelihoods depend on the continuing incidence of the disease and investors whose wealth depends on the profitability of the alleviation. Prevention or cure would, to these people, be devastating.

The implicit policy argument then is that government should not spoil the “value” of “innovation” in these “markets” for alleviation medicine by making any push for prevention or cure. If there’s no maximum value to be obtained, then investors won’t put their capital into alleviation opportunities and we won’t get alleviation medicines developed. The folks who advocate for Bayh-Dole, or for patent monopolies in medicine, or who insist on private development of medicines as a profit-seeking activity never report outcomes based on prevention-cure-alleviation-facilitation. It’s just “210 new medicines” as if all medicines were equal. But all new medicines are not equal, in terms of public health.

I went through the list of new drugs approved by the FDA in 2018. Here’s the FDA list. Here’s Centerwatch’s list. Here are drug trial “snapshots” with more information than Centerwatch’s descriptions. 

My category definitions are coarse. (The aim is to get an accurate sense of things, not getting lost in weird definitional precisions and then study the nature of the categorization).

Preventions include vaccines and medicines that prevent a disease or injury from arising. Prevention may lead to the extermination of a disease, such as has been the case with smallpox. Prevention of course will miss all those non-medicine ways that one might avoid a disease–through limitation of exposure, change in lifestyle or diet, and the like. If we destroy all diseased rats and mice, we could expect to have less problems with plague. We might say that with better prevention we would have less need for medicines, other than medicines that prevented.

Think about that–we have a multi-hundred-billion dollar biomedical industry built on the expectation that we cannot or will not prevent disease and injury. It’s one thing to hope that there will always be disease–folks can hope for what they want; but it’s another thing to create public policy to ensure that it is always the case that we will have diseases that otherwise might be prevented. There are weird cases of prevention, too, that game the expectations of categories–for instance the annual flu vaccine that often doesn’t work and when it does won’t be effective next year but most everyone is supposed to get vaccinated anyway.

Cures as I account for them bring about, in an individual, the eradication of a disease or the healing of injury or restoration of function that otherwise would not return to health, all without the need for continuing (daily, weekly, monthly) interventions or laboratory testing. An antibiotic, for instance, might do that (though there are times when an antibiotic might create conditions for re-infection as a side effect–that’s in the 2018 list as well. Yupelri, for instance, treats cough but a side effect is, ahem, more coughing). A cancer drug that eliminates the cancer once for all is a cure. A cancer drug that slows the progress of the disease is not a cure, even if the progress becomes so slow that one is much more likely to die of some other cause.

Alleviation drugs are ones that lessen symptoms or delay the progress of a disease. They don’t prevent, they don’t cure–they make less acute, they prolong, they maintain. Unlike preventions, which may require “boosters” from time to time, and unlike cures, which do their work and then are no longer needed, alleviation drugs often require regular maintenance doses until their effectiveness wanes, toxicity becomes unacceptable, or the patient dies. Alleviation of suffering is compassionate. There’s not much one can say against alleviation. And if there’s huge market value in alleviation, how can anyone criticize companies from focusing their efforts on compassion? One would think it is a confluence of interest made in heaven–the most compassionate thing turns out to also be the most profitable. Isn’t that how ethics is supposed to work?

Yet, from a public policy perspective–perfidious public policy–doesn’t it appear that prevention and cure ought to be our focus whenever possible, and that alleviation is a sort of stopgap only until prevention and cure have been fully explored and implemented? If we support a stable if not growing and profitable industry in alleviation at the expense of prevention and cure, then we have, in effect, made a virtue of suffering so we can profit from compassion–which is dysfunctional and in its way morbid and much less heavenly than a first impression might suggest.

Facilitators contribute to the effects of other medical interventions. The new drug Akynzeo, for instance, controls nausea induced by chemotherapy. On its own, it alleviates nausea–doesn’t prevent it or cure it–it suppresses “delayed nausea” in 75% to 90% of those who take it. That’s a nice facilitation that makes the chemotherapy more tolerable and effective (and therefore expands and extends the market for those chemotherapy drugs). There are facilitators that are not medicines–devices, methods, lab tests–that won’t show up here. Indeed, many alleviator medicines require regular monitoring in the form of lab tests, some of which may be expensive in their own right. In some cases, even if the alleviator medicine itself was free of charge, the monitoring cost (doctor’s visits, blood draws, imaging, lab tests) would still run to tens of thousands of dollars a year. Facilitators improve other interventions and aren’t themselves of much use if there’s no other intervention. In one sense, facilitators make medical practice better. That’s good! In another sense, however, facilitators make it less attractive to search for alternatives, which now have to be better than (or at least not inferior to) the alleviator and its facilitators. Facilitators can take the pressure off the search for prevention or cure. That’s in its way not so good.

In a similar way, one might see generally that the effort to “solve” “society’s problems” by mitigating the effects of the status quo serves to preserve the status quo. “We make an awful mess of things the way we like to do them, but look at these nice people, these facilitators, who have devoted their creative talents to cleaning up after us so what we do isn’t nearly so bad after all.” The facilitation of alleviation is the status quo’s dream of improvement. If this analogy depicts a status quo as a disease, then there’s something to ruminate upon for later.

Of the 59 new medicines for 2018, here’s what I see:

4 Prevention

6 Cure (or 7)

45 Alleviations

4 Facilitations (of alleviations)

Let’s work through preventions and cures, since these are short lists. For prevention, we have:

Tpoxx–no price, developed by Siga Technologies as a prevention for smallpox in the case of bioterror attack. There’s no current “market” for bioterror-attack-caused smallpox, so perhaps that’s why there’s no price information readily available.

Krintafel–$45 for a single injection, developed by GSK with the nonprofit foundation Medicines for Malaria Venture using “open source” research to prevent malaria relapse, resulting in 76% to 84% of patients not experiencing relapse at six months–about twice as effective as chlroquine with a placebo.

Annovera–$1320/yr, developed by TherapeuticsMD (funded by nonprofit foundations, WHO, USAID, and NICHD) as part of a vaginal ring contraceptive device, with a “failure” rate twice that of other methods, but is reusable and can be self-managed.

Biktarvy–$35,352/yr (one pill a day, forever), developed by Gilead, reduces HIV to “undetectable” levels in 89% to 92% of patients. Is this a prevention for developing AIDS or is it an alleviator that maintains HIV at sufficiently low levels that HIV becomes a manageable chronic condition? Let’s call it a prevention.

Of the 6 (or 7) cures, we have:

Moxidectin (that’s its generic name, no proprietary name)–no price, developed by Medicines Development for Global Health (a nonprofit), to cure and prevent river blindness. We could list it with prevention, too, but once is enough.

Zemdri–$3,300 for a 4 to 7 day course, developed by Achaogen to treat urinary tract infections, with a 72% to 88% cure rate.

Oxervate–$96,000 for an 8 week course, developed by Dompe, a startup, to treat neurotrophic keratitis, an eye condition, with 62% to 72% of patients experiencing complete corneal healing. A cure for some, not for others. Complete healing, though, for some–that’s got to be a good thing.

Xerava–$500 for 4 to 14 day course, developed by Tetraphase (formed in 2006–this appears to be its first and only product) to treat intra-abdominal infections, with 87% to 91% cure rate (effective but less so than other alternatives).

Lumoxiti–$37,800 ($2,100 per infusion, 3 infusions per 28 days, up to 6 cycles) for a course of treatment, developed by AstraZeneca to treat hairy cell leukemia, providing for 30% of patients a “durable complete remission” for at six months or more. Perhaps this is not a cure–only works some of the time, and we are talking remission for a pretty short time–but still, there must be an elation in those that see their blood counts go to normal and stay there for a while. So let’s call it a cure, if only for some.

Nuzyra– $3,140 (or double for a longer treatment), developed by Paratek (formed 1996) to treat bacterial pneumonia and skin infections, with a 81% to 83% effective cure rate–a rate “statistically non-inferior” to other treatments.

I don’t know quite what to do with Elzonris, a drug for treating a rare bone marrow cancer called blastic plasmacytoid dendritic cell neoplasm. The clinical trial had remission rates of 54% to 72%, and 45% of patients in one group then went on to receive stem cell transplants. So it’s sort of a cure, and it’s sort of a facilitator to get patients in condition for a stem cell transplant that might offer a cure–apparently folks don’t believe that Elzonris induced remission is necessarily lasting. The price for Elzonris appears to be north of a million dollars per year–my calculation is $1.5 million ($25,000 for a vial, 5 treatments per 21 days, so $125,000 per treatment cycle and there appear to be multiple cycles: “Continue treatment with Elzonris until disease progression or unacceptable toxicity”–that language in the prescribing information doesn’t sound much like a cure–annual cost would be $125K x 12 or $1.5 million–but does anyone stay on the drug for 17 cycles?).

Of the rest, 45 are alleviation medicines. I won’t go through them all. But here’s some observations. First, the average price of the alleviations is just over $200,000 per year. The range is from $150/course of treatment to reduce the duration of flu symptoms by a day (Xofluza), and $159 to reduce the duration of traveler’s diarrhea by 22 hours (Aemcolo), to $574,ooo per year for Takhzyro, to treat hereditary angioedema (73% to 87% reduction in HAE episodes–but you will still have episodes); $458,000 per year for Alexion, for homoglobinuria (73% of patients avoided transfusions, 7% better than a competing treatment)–and $450,000 per year for Onpattro to treat polyneuropathy and amyloidosis (reducing symptoms and a levels of the TTR protein). The median price of the alleviators on the 2018 list is $120,000 (per year, or if shorter than a year, per course of treatment or if even course of treatment is highly variable or not readily reported, based on my estimate of a typical course of treatment).

Here are median cost (per course/year/typical) estimates, then, for our four categories:

$682       Prevention

$3,140    Cure

$91,250  Alleviation

$2,000   Facilitation

These are coarse estimates, with incomplete information based on public sources. But the main point leaps out. Alleviation prices–the market for alleviation drugs–is 30x or more the market for any other category. Among alleviators, 26–over half–cost more than $100,000. Only two other drugs in the other categories cost more than $50,000 (Omegaven, a fish oil derivative to provide supplemental nutrition, a facilitator; and Oxervate, a cure for keratitis). Clearly, the “market” is in alleviators. By comparison, there’s “hardly any money” in prevention or cures, and hardly anyone is bothering.

While the price differential between new alleviator drugs and all other new medicines is obvious, other things may not be so obvious.

First, alleviators involve dependency. The idea is to provide a statistically demonstrated benefit with tolerable adverse side effects, available only if the medication is taken regularly–to slow disease progression, to reduce symptoms–in frequency or acuteness, to reduce the duration of an illness. Without context, alleviation sure seems to be a good thing. If alleviation was all there were, then alleviation would be the only goal. And without context, if the only available option was to find chemicals that, if taken repeatedly–chronically–provided at least statistically demonstrable relief, would not that be a heaven-sent confluence of innovation and profit? Sadly, there is also prevention and cure–things that generally do not rely on regular–daily, weekly, monthly–repeated applications of a chemical. The sweet spot for medicinal profit is the alleviator that relies on dependency.

To demonstrate statistically significant alleviation, a drug candidate has to show (in many cases) that it outperforms a placebo, or outperforms (or at least is not inferior to) a comparator drug that has in its turn been shown to outperform a placebo. And here’s an interesting thing about the 2018 alleviator drug approvals–those that have clinical trials that show activity relative to a placebo, the new drugs outperformed placebos. Galafold–52% of 25 patients saw at least a 50% improvement in inclusions per kidney interstitial capillary compared with only 45% of 20 patients given a placebo. Orilissa reduced endometriosis pain–cramps  were down 27% to 56% over a placebo that reduced cramps by nearly a quarter; pelvic pain was reduced 14% to 18% over a placebo that reduced pelvic pain 37%. With Diacomit, 67% to 71% of patients “responded” with greater than 50% decrease in seizures, while only 5% to 9% of patients on the placebo responded. Seizure frequency overall reduced with Diacomit by 81% to 91%, and with a placebo overall seizure frequency was up 7% in one trial and down 27% in another. Ajovy reduced monthly migraine days by 4, while the placebo achieved a reduction of but 2 monthly migraine days.

There are two ideas going here. First, the drugs do better than the placebo. But second, the placebos do remarkably well on their own. Think about it–one can reduce migraine days per month by 2 simply by taking a placebo, or pay $7,000 per year for Anjoy to double the number of days per month without a migraine. Reduce endometriosis pain by a third with a placebo, or pay $10,000 per year for Orilissa to reduce pain by half. Get a reduction in kidney inclusions with a placebo or pay $315,000 per year to get a slightly better reduction with Galafold (-0.04 median change from baseline with  Galafold compared with -0.03 with placebo).

It’s worth pointing out that some of these alleviator drugs also come with adverse side effects–Galafold carries risk of headache (35% of patients, compared to 21% for placebo), urinary tract infection (15% of patients, 0% for placebo), and nausea (12% of patients, 6% for placebo). Diacomit reduces seizures, but causes sleeplessness (67% of patients; 23% placebo), decreased appetite (46%; 10% placebo), nausea (15%; 3% placebo). One pays for the drug in more ways than just price. Some patients gain the benefits of the drug and avoid the worst of the side effects–but others don’t fare so well. It’s an expensive crap shoot to find out.

We might wonder about the benefits of taking placebos as a first line of medical response to symptoms. Of course, there is the argument that offering placebos is unethical because it plays on a patient’s trust. One cannot inform a patient that they should take a placebo and expect the placebo to have the same effect. Following this line of reasoning, one can talk oneself into the idea that offering drugs, even with serious side effects, is “ethical” while placebos, with much fewer side effects, are not. Isn’t reasoning strange?

There’s another issue wrapped up quietly in the cost of drugs. Alleviators for 2018 are priced 30x higher than the new 2018 drugs in other categories. Why? If the high price reflects the cost of development, then why is it that a drug that’s a preventor or cure or facilitator costs so much less to develop? Think about it–if the cost to develop cures is so very much less than the cost to develop alleviators for the same disease, then why should federal research policy not focus entirely on prevention, cures, and facilitators? These would appear to have a much, much lower cost of development and a greater likelihood of proving themselves in clinical use. Or, if the price of an alleviator drug is not tied to the cost of its development, then perhaps we have a case of pricing what the “market” will bear–and the offer to reduce suffering–make something acute less acute with a chronic dependency–apparently is a market willing to pay tens of thousands to hundreds of thousands a year for a moderate improvement over a placebo. We might then ask–if this is so, if there’s a market for relieving suffering, if only in marginal statistical ways that carry their own set of induced ailments, is this the market that we should subsidize with public funding–not just for research but also to pay the prices charged by the companies exploiting the market for profits? Should public retirement funds invest in the companies doing the exploiting of this market, speculating on whether the next alleviator drug in a company’s “pipeline” will be a huge (financial) success–that is, capable of extracting yet more 30x payments from the “market” in alleviating suffering (even if just by a bit)?

These are tough questions with tough answers. But it’s also an answer to leave things as they are–30x higher prices for alleviators that exist to extract maximal financial response from those willing to alleviate suffering, even at a huge price compared with prevention, cure, and facilitation. We might come to think that those handling alleviation payment budgets compete with those seeking prevention, cures, and facilitation. Perhaps it is as simple that prolonged suffering creates a greater emotional pull than prevention or cure. High drama invites high prices. But is high drama–and the financial success of companies playing on high drama–the standard of success in a national health care policy? That’s what AUTM, PhRMA, and BIO appear to suggest. A wealthy biomedical industry is good for America. But is it also so good for health?

This entry was posted in Innovation and tagged , , , , , , , . Bookmark the permalink.