Analysis: The FDA Is a Melting Iceberg – GovExec.com

The byzantine world of pharmaceutical regulation has recently broken into the public consciousness, causing a bit of a panic. Aducanumabthe first new Alzheimers treatment in nearly two decadeswas approved by the Food and Drug Administration on June 7 despitescantevidence of benefit, and against thenearly unanimousadvice of the agencys expert advisers. Op-eds called the decision, which could triggerbillions of dollarsin new government spending, a false hope, bad medicine, and a new low. (FDA officials have said that their decision was based on rigorous science, and that it reflects the willingness of people with Alzheimers and their families to accept a treatment that might help, despite some degree of uncertainty.) On Thursday, the FDA tried to clarify that the drug should be used only for patients with mild dementia; the next day, amid concerns about inappropriate interactions between the drugmaker and FDA officials, Acting Commissioner Janet Woodcockcalledfor her own agency to be investigated.

This isnt the firstor fifthrun ofbad pressthe agency hasreceived, but one gets the sense from recent coverage that some crucial threshold has now been crossed, that the rising floodwaters of ineptitude have finally yielded a catastrophe. But even if this blunders inner workings are more public than those of the past, theres little reason to believe well see systemic change at the FDA. The long-standing and gradual erosion of the agencys scientific standards makes me think instead of the eroding coastlines and thawing icebergs associated with climate change. For decades now, alarmed scientists have been crying out for action as things have gotten worse and worse. And for decades now, little has been done.

The FDAs standards began to slide in the late 1980s and early 90s.AIDS activists, desperate to slow a devastating and mysterious illness, hadpushedfor the creation of new pathways for approving treatments more quicklyand, effectively, on thinner evidence. A new program in 1992 allowed for accelerated approval on the basis of surrogate markers, which are indirect measures of a drugs benefit, assessed via laboratory or imaging tests, that stand in for more meaningful outcomes such as life expectancy. But the implementation of these accelerated processes was criticized by some scientists and patients, even at the time. In 1994, for example,TheNew York Timescited skeptics who worried that no one can tell if the drugs work. Eight months later, the AIDS activist organization ACT UP San Francisco called Anthony Fauci a pill-pushing pimp for supporting CD4 immune-cell counts and viral loads as surrogate markers. They were completely invalid, the activists wrote, and nothing more than a marketing execs wet dream.

[Read: Before Occupy: How AIDS activists seized control of the FDA in 1988]

That early change in standards worked out for the best. We now know that CD4 counts and viral load are excellent markers of HIV/AIDS status, and the types of HIV drugs that were being questioned at the timereverse-transcriptase inhibitors and protease inhibitorsdid turn out to be effective. Newer versions still form the backbone of lifesaving, multidrug regimens. In fact, their success has been used to wave off criticism of the FDAs declining standards for years.

But that level of success is not at all the norm. Most treatments in medicine will prove onlymodestly effectiveand come with real risks. The use of regulatory shortcuts has grownmore commonanyway. In 1992, about 40 percent of all drugs qualified for at least one of the FDAs expedited programs for approval. By 2018, that rate had doubled. Use of surrogate endpoints has now become routine60 percent of approvals in recent years have relied on them. The repeated protests of agency critics along the way have done nothing to slow the trend. In May 2000, for example, the government approved the use of saline breast implants despite safety concerns. This decision really sets the FDA standard of safety ata new low, the health-policy expert Diana Zuckerman said at the time. More than 20 years later, she continues to decry the agencys still-declining standards: The aducanumab approval sets a very dangerous precedentthat could harm patients health, she said recently. (Acting Commissioner Woodcock has disputed the idea that evidence standards are declining; in her view, we know far more nowabout a drug when it is approved than in the past.)

Indeed, public controversies over drug approvals have only proliferated. In 2015, the FDA approved flibanserin, a treatment meant to improve female libido, after havingrejected it twice. This is a product that isneither very effective nor particularly safe, one former FDA official told reporters at the time, and it sets a precedent that a drug for womens sexual health has to be treated in a very special way. The agencyreachedanother low the following year, when its leaders overruled their own staff to approveeteplirsen, a treatment for a rare genetic condition called Duchenne muscular dystrophy. The drugs poor quality of evidence led a dissenting official to declare that it was nothing more than a scientifically elegant placebo. The 21st Century Cures Act easilyclearedCongress a few months after that, though two former ACT UP members and a former FDA commissioner had declared in aTimesop-ed that the new laws encouragement of even-lower low standards was potentially placing patients at unnecessary risk of injury or death. In 2019, the bioethicist Ezekiel Emanuel warned about the approval of a slew ofnew cancer therapieswith uncertain or very limited benefits, noting that drugs with unproven effectiveness sellfalse hopeto desperate patients.

[Read: In between the FDA and Pharma, people wait for treatments]

The FDA says that it must balance the importance of meeting rigorous standards with the need to provide timely access to potentially lifesaving medicines. Commentators have noted FDAs increasing use of these programs over the last decade, often with a view that the increase is driven by a loosening of our approval standards, Woodcock and the FDA official Peter Marks wrote in 2019. In reality, the FDAs standards have not changed. Instead, the increased use of expedited approval pathways is directly related to the increasing numbers and scope of these programs provided by Congress, as well as the kinds of medicines that are being developed, and the types of diseases that are being studied.

For all the panicky commentary, the problem is a diffuse and slowly growing one, with specific harms that are tricky to assess. Thats why the approval of yet another costly, ineffective drug on the basis of asuspect surrogate markerends up being like another deadly set of wildfires in the West: Were told that it has to do with long-standing changes in the climate, but responding to the immediate crisis distracts from broader fixes. Even the agencys historic and ill-advised sign-off on aducanumab might not move the needle of public opinion toward favoring greater scientific rigor over quicker access, according to Daniel Carpenter, a government professor at Harvard who hasstudiedthe FDA. Its hard to feel invested in medical regulation without tangible, personal reminders of what happens when it fails. If aducanumab were to prove really dangerous for patientsif it ended up killing peoplethat would certainly grab attention. (Theres currently no evidence of major harm from aducanumab, though the FDAs expert advisers didraise concernsabout brain swelling in some clinical-trial patients.) The experience of children who were born with severe disabilities from thalidomide in the 1950s and 60s, like that of the victims ofsulfanilamidepoisoning in the 30s, prompted significant strengthening of government oversight. Thalidomide had that influence, Carpenter told me, precisely because the nature of the deformities the victims had was so visceral, so evocative. But the approval of a merely ineffective and expensive drug simply wouldnt have the same effect. You need to see the health-care systems version of a starving polar bear, he said, or else most people wont care.

Even aducanumabs staggering price tag of $56,000 a patient per year may not be conspicuous enough, because few will pay the full cost themselves. Most of the expense incurred for each new drugwhich, for aducanumab, could belarger than NASAs yearly budgetends up being quietly subsumed into strained public-health budgets and rising health-insurance premiums. The actions of drug regulators, like those of industrial polluters, are often freighted with unacknowledged externalities. The FDA specifically does not really worry about those larger societal issues and doesnt really worry about cost, Walid Gellad, a drug-policy researcher at the University of Pittsburgh, told me. Instead, the agency is judged by howmanydrugs it can approve. No regulator wants to go before Congress or the American people and say, This year we approved 50 percent fewer drugs than last year, Gellad said.

There are proposals for encouraging the FDA to pursue cost-effective therapies, just as there are proposals for encouraging reductions in carbon emissions. For example, health-policy researchers havesuggestedallowing the agency to shrink the window in which pharmaceutical companies can exclusively profit from their compounds, if those companies charge too much money for negligible benefits. Carpenter hasrecommendedincreasing the fees that companies pay to the FDA, and then having the agency use those resources to fund more-rigorous clinical studies. Medicare already has theauthorityto withhold payment for questionable treatments (and is now considering thatoptionfor aducanumab). But as with cap-and-trade policies for carbon emissions, aggressive approaches have failed in the face of powerful stakeholders. Its not just the profit-driven pharmaceutical industry fighting these policies; patient groups are also effective advocates for quicker, easier access to new treatments.

[Read: An age-old battle: the FDA versus the shill]

In the absence of meaningful political progress or collective action, efforts to address the spread of bad or useless therapieslike efforts to address climate changeare left to individuals. The FDA may keep approving marginal treatments, but doctors dont have to prescribe them. In theory, we could take a stand, and just say no to aducanumab. Theres an assumption that physicians are good stewards and theyre going to take care of everybody and theyre not going to prescribe something thats not effective, Joseph Ross, a physician and health-policy expert at Yale, told me. But you and I know how it really works in the real world. Indeed, I do. For doctors, the allure of slowing the progression of a debilitating condition, satisfying patient requests, and evenprofitingfrom every prescription will make aducanumab hard to resist. Many of the passionate academic physicians I talk with seem willing to take up this fight in their own clinic, and recommend against the drugs use, but theyre just idealists at the fringe, not the rank and file of the profession91 percent of whom recentlyrespondedthat they generally trust that the benefits of an FDA-approved therapy will outweigh its risks.

This is the tragedy of the concerned citizen: We are personally destined to fail. Just as switching to an electric car or turning your lights off wont cool a warming planet, a minority of idealistic doctors wont stop the flood of ineffective treatments. But its not impossible that the aducanumab fiasco will yield some systemic change. Vinay Prasad, an oncologist and drug-policy expert at UC San Francisco, suspects that the total cost of this or some future drug could end up being high enough to cause a fiscal crisis, prompting action at long last. The American economy can handle a great deal of wasteful health-care spending, he told me. But it cant tolerate an infinite number. The FDA might have finally acknowledged these financial considerations when it rapidlyreversed courseto recommend that only a subset of patients with early Alzheimers disease receive aducanumab. That change could save insurers billions of dollars, and it makes them more likely to place explicit limits on which patients will have their expenses covered.

An interminable health-care-cost crisis will eventually spill over into other political issues, Prasad said. For example, the average worker experiences rising health-insurance premiums asstagnating wages. Its profoundly destabilizing in a society in ways we dont see, he told me. But whether politicians will do more than pursue empty hearings remains unclear. Before aducanumab, the exorbitant cost of new hepatitis C treatments, initially as much as $1,000 a pill, generated similarhand-wringingbut no real policy change.

If an independent investigation leads to a reversal of the aducanumab decision, then perhaps such an unprecedented turn of events will prompt a real public reckoning. The most likely outcome, though, is that the bad headlines will recede and a new, lower bar for evidence will be set. With each alarming declaration of the hottest day on record, after all, it gets harder to remember what cooler temperatures felt like in the first place.

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Analysis: The FDA Is a Melting Iceberg - GovExec.com