FDA should protect the American people, and Pharma should pay!

The Food and Drug Administration (FDA) regulates drugs, and, I guess, food, although I don’t know much about  what they do in that area. It also does not approve certain drugs because they are not classified as drugs, but rather “nutritional supplements” or in new jargon “nutriceuticals”. This is odd, because such a classification does not make them either safe or effective. If they ARE effective, do the good that is claimed for them, then of course they could have other effects, which could be bad. If they are biologically active, they could be harmful. The only way they can be presumed safe is if they have no effect. Oh, well.

The FDA has been prominent for several things in recent years, most commonly regarding the approval (or not) of drugs to treat COVID, and often for demonstrating that proposed treatments, even those endorsed by high-level elected government officials, were not effective. It also made news (and this blog, FDA approves Alzheimer's drug against the recommendation of its scientific panel. Be very concerned, June 21, 2021) by its approval of the Alzheimer’s drug, Aduhelm, against the recommendation of its committee of scientific experts (eventually Medicare, the largest payer, refused to routinely pay for it, although it will in some situations).

A recent article in the New York Times, F.D.A.’s Drug Industry Fees Fuel Concerns Over Influence, discusses the controversy over “user fees” that the agency charges drug and medical device makers to help fund its work. Well, “help” may be incorrect, because such fees account for 75% of its budget.  This requires annual negotiation between the agency and the trade organizations for the industry, and those negotiations often lead to concessions to the manufacturers. At the least, it creates a situation in which it appears that the manufacturers, rather than the public, are the agency’s clients. The Times notes that ‘The user fee program traces its roots to 1992, when AIDS activists pressed the F.D.A. to hasten drug approvals. About a decade later, drugs moved through the pipeline more quickly, averaging about 10 months from roughly 19 months,’ seen at the time as a big victory for AIDS patients. Of course, it is important to note that speedier approval is only a good thing if the drugs being approved work for their intended purpose; speedier (or any) approval is not a good thing if the drugs do not work, no matter how much people with AIDS or any other disease, or their advocates, or physicians or scientists or drug manufacturers, wish they did.

With the pharmaceutical and medical device industry paying for the costs of running the FDA, which should be high enough to ensure that adequate staff and time are available for thorough review of drugs. The agency would otherwise be funded by general tax revenue, and it seems entirely just that the industry that makes money from those approvals (an INCREDIBLE amount of money; the drug industry is regularly by far the most profitable in the US) should pay for them rather than the rest of us. What is wrong is for those payers to have any influence on how the agency operates, what it does, or certainly what drugs are or are not approved. It is an insane idea to think that they should have influence because “they are paying for it” as if it were a business deal, and yet this seems to be the perspective of some influential politicians, such as Sen. Richard Burr (R-NC).  ‘Mr. Burr, a business-focused conservative, complained that the program burdens companies with negotiating with the agency over the fees, which he predicted would rise even higher.’ They should rise as high as they need to in order to fund the agency and the industry should have zero input into their policy decisions (as, indeed, the tobacco industry apparently does not over the 1200 FDA employees in its tobacco division, although the division is entirely funded by user fees).

This issue with the FDA is one (important) example of how, when industries are unsuccessful in “persuading” the government (though large cash donations) to entirely privatize a public function, they seek control of it anyway. In some cases this is a win-win for the industry and the government: the industry not only gets effective control of policy but very large influxes of money from the government to their business, and also gets to deny complete responsibility since it is a "government program”. (See, for example,  Medicare Advantage and the DCE/REACH program, "Private Equity": Profiteers in nursing homes, Medicare Advantage, DCEs, and all of healthcare, September 16, 2022.) Of course, there is a lose-lose part of the equation that involves the other two parties: the sick people who need treatments that are both effective and affordable, and the rest of us who are funding these donations to corporate coffers. Guess which group, winners or losers, has more people? Guess which gives more money to politicians?

It is tempting, when the nation’s people want something done right (like protecting them from unsafe and ineffective drugs) but do not want to pay more taxes to make it work, to enact things like “user fees”. This is certainly fairer; it is why, for example, semi-trailers pay higher highway taxes than cars --  because they travel so many more miles and are so much heavier they cause far more damage to the roads. (You used to see bumper stickers on them that announced how much, until, presumably, they realized, that the other folks driving on the highway had little sympathy and probably cheered and felt it wasn’t enough!) Thus charging the pharmaceutical companies who make so much money on drugs to pay for the FDA makes sense and is the way it should be, as long as they have no influence on the process. But that lack of influence is what irks Mr. Burr, and the drug makers who fund him.

Obviously, Burr is wrong, and so is the current process. Of the two sets of interests – the health of the American people and the profits of Big Pharma, the first should be the sole responsibility of the FDA, and the money to fund it should come from the second. Pharma will still make an exorbitant amount, no matter how much they and Sen. Burr cry that they do not have enough clout in the process to make even more, and they will continue to spend far more on marketing than on research and development.

And this should be the process for all government agencies. Fund them to protect the people from the profits of the companies that benefit.

FDA approves Alzheimer's drug against the recommendation of its scientific panel. Be very concerned.

Early in June, an article in the NY Times discussed the possible approval of aducanumab, a recombinant DNA (the “-ab” is always clue!) drug intended to treat Alzheimer’s disease. The FDA approved the drug a few days later, going against the recommendations of its advisory committee of scientific experts, and generating this “Quotation of the Day” in the Times from one of its members, G. Caleb Alexander: “There’s no way to recover the opportunity to understand whether or not the product really works in the post-approval setting.” Almost immediately, three members of the advisory committee, Joel Perlmutter of Mayo, David Knopman of Washington University in St. Louis, and Aaron Kesselheim of Harvard, resigned in protest of the decision. Dr. Kesselman, along with his colleague, Dr. Jerry Avorn, presents a strong indictment of the FDA in an Op-Ed guest essay in the Times, and they are not alone. Most neurologists, including those that I know who are experts on and leading researchers in Alzheimer’s, echo these concerns.

This is pretty unusual. Not just the resignations, but the reason for them – the decision by the FDA to approve a new drug based on evidence of effectiveness so weak that the scientific advisory panel recommended against it. It raises a number of questions, the foremost one of which is “why?” Also: Is this a precedent, and will it happen again, or more regularly? What was the reason that the advisory committee recommended against approval? Who were the people at the FDA who overruled them, and what were their reasons?

First let’s start with cui bono? – who benefits. This is certainly Biogen, the company that developed aducanumab and will market it, under the tradename Aduhelm. It is estimated that it will cost $56,000 a year. This is not a record; there are other recombinant DNA drugs – including several for neurologic conditions – that cost even more. In fact, as indicated in recent study by the American Academy of Neurology, “Medicare paid 50% more for neurology drugs over 5 years while claims rose only 8%”. Still, it is a tidy chunk of change, and since Alzheimer’s is a far more common disease than most of the rare one that are ostensibly treated by more expensive drugs, Biogen expects to make a bundle. And, because only the very very rich could afford this much, most of it will be paid by you. That is, by insurance companies that collect your premiums, and especially by Medicare, the insurer for the majority of Alzheimer’s patients, which is funded by your tax dollars. This is described in another article, with the subhead: ‘Despite scant evidence that it works, the drug, Aduhelm, is predicted to generate billions of dollars in revenue, much of it from Medicare.’  If people are not insured, or rich, they can forget it. Which, in this case, might be just as well.

Making a lot of money, as much as they possibly can wring out of patients and insurers, is the core business of pharmaceutical companies (and most companies, although pharmaceutical companies have been particularly good at making outrageous profits, always ranking as the #1 industry for profit). It is not, despite their ads (and they spend much more on marketing than on research and development) about improving your health.  You are just the coincident vehicle for generating their profits. Their drugs do not have to actually help you get better; as long as they don’t harm you too much – and, of course, as long as the FDA approves them – they are golden. This is why they spend so much on marketing, and lobbying, and specifically lobbying the FDA. Indeed, the “golden parachute” of many FDA staffers is to retire from the agency and get a job lobbying for a drug company. Sigh. So that one is obvious. Corrupt and despicable, yes, worthy of complete anger and condemnation, yes. But obvious. Not, heretofore, however, predictable.

There is another stakeholder group involved, Alzheimer’s advocacy groups. The FDA still has an acting chief, Janet Woodcock, and another article notes these groups supported her becoming permanent. It says “Woodcock’s nomination back in February when the application for the drug, aducanumab by Biogen, was pending, its approval was a sign that they backed the right candidate.” Wow. Shouldn’t we be paying them attention? After all, they are not the drug manufacturers who will be making a mint. And Alzheimer’s is a terrible disease, and we need effective treatments, right?

Not so fast. Yes, Alzheimer’s is a terrible disease. Those who have it suffer greatly, at least until it is so advanced they no longer recognize what is going on. And their loved ones continue to suffer, more and more. A drug that would cure it, or mitigate it, or make it progress more slowly would be wonderful (although it shouldn’t cost $56,000 a year!). But is aducanumab that drug? Not according to the scientific panel, who know. But the advocacy groups are pushing for it anyway. Why? Well, they make not be making most of the money, but they have to justify their existence. And they almost certainly are getting donations from those drug makers. And maybe, even, they care so deeply about the disease that their hope and optimism overcomes appropriate caution. It wouldn’t be the first time that this has happened (e.g., the continued promotion by breast cancer advocacy groups for decreasing the age and increasing the frequency of screening even when science showed the opposite).

It also wouldn’t be the first time that those advocating for victims of terrible disease pushed strongly for approval before studies were completed. One meaningful and important example is the efforts of groups such as ACT-UP to get early approval for anti-retroviral drugs, as people were dying in droves from AIDS.  But there are differences. One is the disease; Alzheimer’s is not killing people quickly as did AIDS, and no one is claiming that aducanumab or any other drug will change its eventual downhill course. Another is health equity. In the political and social landscape of the 1980s, AIDS was a disease primarily affecting gay men and IV drug users, definitely not the mainstream. Leaders such as Ronald Reagan refused to offer support. And, perhaps most importantly, the anti-retrovirals were showing a definite positive effect in studies, and the calls were to speed up the approval process. In the current case, the trials are complete and the evidence showing a positive effect is not sufficient.

This is in no small part due to the fact that the “positive effect” studies show involves changes in biomarkers, not changes in people’s lives. That is, they look at lab tests rather than whether people die less soon or suffer less. Yes, there is evidence, as there is evidence in many diseases, that these intermediate markers are related to long-term outcomes, but the problem is that the further out they get the more it becomes like a game of “telephone” (well, our drug affects A, and A is related to B, and B may be related to long-term outcomes). We need studies that look at patient-oriented not disease-oriented or laboratory-test-oriented effects.

Sometimes an intermediate marker improves but the patient does not, or gets worse. It could be from a side effect of the drug (drug safety) but it can also be from the desired positve effect of the drug!  For a time diabetes groups pushed to lower the target hemoglobin A1c (HbA1c) -- a measure of long term glucose level, to be 5 rather than 6, because people with diabetes with lower HbA1c levels had lower levels of diabetes complications. Makes sense. But when the average blood sugar over several months is lower, it increases the risk of significant hypoglycemia (low blood sugar), which can be more dangerous than higher sugar. Indeed, if you pass out from low blood sugar, fall and break your hip, and die, the lower rate of complications from your diabetes in the long term is irrelevant. There is an old medical joke about Harvard doctors being very insistent that their residents keep patients’ lab values in the normal range, so that even when the patient died, they died in “perfect Harvard balance”.

This is not what we want. We want diseases to be cured, or ameliorated; for lives to be lengthened and improved in quality. We certainly do not want drug companies to make billions off of people’s suffering. When the FDA approves a drug over the recommendations of its scientific panel, it should be of great concern to all of us. 

And don't forget cui bono?