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How badly has the FDA been lagging?

As a Johns Hopkins scientist who has conducted more than 100 clinical studies and reviewed thousands more from the scientific community at large, I can assure you that the agency’s review can be done within 24 to 48 hours without cutting any corners. They just need to work harder.

Contrary to popular belief, the FDA process is not hands-on—it does not interview vaccine trial patients or look under a microscope at the immune cells. It’s doing a statistical analysis and looking at data. For the vaccine trial, the data set is small and straightforward. If my research team, normally tasked with analyzing data on millions of patients, was asked to review the smaller Pfizer vaccine study of 43,000 patients, it would take about one hour.

The FDA also reviews manufacturing data from Pfizer on how they made the drug. But not only can that data be reviewed in a few hours, it should have been done months ago when it was available. While the FDA was waiting for Pfizer’s long-term vaccine results to come in, the agency should have anticipated this step and done it early.

The final step of the FDA review is to look at the outcomes of the study volunteers, including rates and severity of infection and side effects in the vaccine and placebo groups. Again, there is no plausible reason why this basic analysis cannot be done in 24 hours. The FDA and external scientists have a simple task: confirm or reject  the review already conducted by the trial’s independent data safety monitoring board before FDA submission.

That is from Marty Makary, who also details an ongoing history of FDA delays during the pandemic, starting with the very first Covid testing attempts from the University of Washington, which the FDA tried to nix, but continuing throughout.  And:

FDA insiders say the agency and its approximately 17,000 employees were dark for the four-day Thanksgiving holiday, including those working on the vaccine approval.

For those of us who lived through the 2008 financial crisis (agencies other than the Fed were not on the ball in response), or who have studied (and indeed practiced) the economics of bureaucracy for forty years, or who know the extensive literature on how the FDA operates, will not be surprised by a lack of urgency.  Or from the NYT:

Dr. Fauci said the politicization of the pandemic in his own country had led regulators to move a little more cautiously than the British, to avoid losing public support.

Sorry people, but I read that as “for political reasons we did not go more quickly.”

Here from Statnews journalists Matthew Herper and Nicholas Florko defend the FDA, going into considerable detail, do read it.  Here is one excerpt, in direct contradiction to some of the above:

The agency’s staff “were eating turkey sandwiches on Thanksgiving while reviewing documents,” Peter Marks, who heads the FDA center conducting the vaccine reviews, said on a Thursday webcast run by the Journal of the American Medical Association.

Additionally, members of an FDA advisory committee that will convene Thursday to review the data and issue its recommendations, have expressed no desire to meet sooner. STAT spoke to four members of the panel and all said the agency should not try to move any faster.

My view is this: if your agency is saying “usually we move five to ten times more slowly,” it is highly unlikely their current procedures are optimized for speed.  It is fast organizations that are good at moving fast, right Usain Bolt?

We’re now at the point where Covid-19 is the single leading cause of death in this nation.

The FDA Burns

If you think the FDA has been slow at approving new coronavirus tests just look at their process for approving sunscreen products.

EWG: The FDA first began working to update sunscreen regulations more than 40 years ago. In February 2019, the agency at long last issued a proposed set of final rules, but they were never adopted.

According to EWG, the Environmental Working Group, the FDA has been too slow to test old ingredients for safety and too slow to allow new ingredients on the market thus leaving us with sunscreen products which are neither as safe nor as effective as they should be. In particular, Europe has better sunscreen protection than the United States. Here’s EWG:

Americans have fewer choices and notably poorer protection than Europeans do from ultraviolet A rays in their sunscreen options. Although most U.S. sunscreens prevent sunburn effectively when used correctly, they aren’t as good as European sunscreens at preventing the more subtle skin damage produced by lower-energy UVA radiation. UVA rays have less energy and don’t burn the skin, but they can cause the skin to age, suppress the immune system and contribute to the development of melanoma.

…Between 2003 and 2010, sunscreen makers applied for FDA permission to use eight sun-filtering chemicals developed by European companies. Four of these – Tinosorb S, Tinosorb M, Mexoryl SX and Mexoryl XL – appear to be more effective than avobenzone, the most common UVA filter permitted by the FDA. The FDA’s failure to respond to these applications prompted Congress to pass the Sunscreen Innovation Act of 2014 (FDA 2014). This act requires the FDA to review new applications for sunscreen active ingredients within 300 days, but it doesn’t relax the standards companies must meet to prove new ingredients are both safe and effective.

In 2015, the FDA responded that the companies involved had not submitted enough information to prove their chemicals were, in fact, safe and effective for use (FDA 2015). The agency asked for more data, including complete study results, measurements of ingredient levels in people’s blood, and long-term studies on systemic toxicity and potential endocrine system disruption. The FDA has also proposed that all sunscreen ingredients, including those already in use, need to have adequate safety testing data.

Some information the FDA wants, such as complete copies of studies, might be easy for sunscreen makers to produce. But in other cases, the companies could take years to satisfy FDA requests. In the meantime, Americans are being shortchanged.

I first wrote about this issue in 2013 and seven years later, despite Congress passing a law in 2014, the FDA still has not acted.

My rule is very simple. I don’t think the FDA is better than the EMA so if any drug or device is approved in Europe it ought to be available for purchase in the United States with a label saying “Approved by the EMA. Not approved by the FDA.” (By the way, we do have reciprocity type agreements with Canada and New Zealand for food so this would not be unprecedented.)

Hat tip: John Thacker.

Addendum: You should actually get more sun to avoid vitamin D deficiency which is bad for a variety of reasons including, in my estimation, greater susceptibility to COVID.

FDA Allows Pooled Tests and a Call for Prizes

The FDA has announced they will no longer forbid pooled testing:

In order to preserve testing resources, many developers are interested in performing their testing using a technique of “pooling” samples. This technique allows a lab to mix several samples together in a “batch” or pooled sample and then test the pooled sample with a diagnostic test. For example, four samples may be tested together, using only the resources needed for a single test. If the pooled sample is negative, it can be deduced that all patients were negative. If the pooled sample comes back positive, then each sample needs to be tested individually to find out which was positive.

…Today, the FDA is taking another step forward by updating templates for test developers that outline the validation expectations for these testing options to help facilitate the preparation, submission, and authorization under an Emergency Use Authorization (EUA).

This is good and will increase the effective number of tests by at least a factor of 2-3 and perhaps more.

In other news, Representative Beyer (D-VA), Representative Gonzalez (R-OH) and Paul Romer have an op-ed calling for more prizes for testing:

Offering a federal prize solves a critical part of that problem: laboratories lack the incentive and the funds for research and development of a rapid diagnostic test that will, in the best-case scenario, be rendered virtually unnecessary in a year.

…We believe in the ability of the American scientific community and economy to respond to the challenge presented by the coronavirus. Congress just has to give them the incentive.

The National Institutes of Health (NIH) have already begun a similar strategy with their $1.4 billion “shark tank,” awarding speedy regulatory approval to five companies that can produce these tests. Expanding the concept to academic labs through a National Institute of Science and Technology (NIST)-sponsored competition has the added benefit ultimately funding more groundbreaking research once the prize money has been awarded.

This is all good but frustrating. I made the case for prizes in Grand Innovation Prizes for Pandemics in March and Tyler and I have been pushing for pooled testing since late March. We were by no means the first to promote these ideas. I am grateful things are happening and relative to normal procedure I know this is fast but in pandemic time it is molasses slow.

Why the FDA is banning the Gates-connected testing kits

Now we know:

An F.D.A. spokesperson said home collection kits raised additional concerns about safety and accuracy that required the agency’s review. The issue in the Seattle case appears to be that the test results are being used not only by researchers for surveillance of the virus in the community but that the results are also being returned to patients to inform them.

The two kinds of testing — surveillance and diagnostic — fall under different F.D.A. standards. In a pure surveillance study, the researchers may keep the results just for themselves. But coronavirus testing has largely revolved around getting results returned to doctors who can share the results with patients.

Here is the full NYT story, via Paul Novosad.  Just stunning.  Here is Alex’s earlier post on the episode.

What is the FDA Doing Now??!

My long-running skepticism about the safety and efficacy of the FDA is fast becoming conventional wisdom. Even normal people can’t believe what they are doing. This piece on the FDA in the New York Times reads like something I might have written for CATO.

An innovative coronavirus testing program in the Seattle area — promoted by the billionaire Bill Gates and local public health officials as a way of conducting wider surveillance on the invisible spread of the virus — has been ordered by the federal government to stop its work pending additional reviews.

…the program, a partnership between research groups and the Seattle and King County public health department that had been operating under authorization from the state, was notified this week that it now needs approval directly from the federal government. Officials with the Food and Drug Administration told the partnership to cease its testing and reporting until the agency grants further approval.

…the Seattle program …has wide backing, including from public health leaders, the Fred Hutchinson Cancer Research Center and Mr. Gates, whose foundation has been deeply involved in fighting the pandemic. The Centers for Disease Control and Prevention also provided an in-person technical adviser to the project.

Dr. Eric Topol, the director of the Scripps Research Translational Institute, who is not involved in the Seattle group, said it had “emerged as leading lights in this whole Covid-19 crisis.” He said it was “bizarre” that the F.D.A. would halt such a project.

By the way, Dr. Helen Chu, one of the leaders of the Seattle project, was one of the first Emergent Ventures prize winners for her work fighting the coronavirus (excellent pick, Tyler!). As you may recall, Chu started testing for coronavirus in an already running flu study without permission. Until she was shut down.

To repurpose the tests for monitoring the coronavirus, they would need the support of state and federal officials. But nearly everywhere Dr. Chu turned, officials repeatedly rejected the idea, interviews and emails show, even as weeks crawled by and outbreaks emerged in countries outside of China, where the infection began.

By Feb. 25, Dr. Chu and her colleagues could not bear to wait any longer. They began performing coronavirus tests, without government approval.

Federal and state officials said the flu study could not be repurposed because it did not have explicit permission from research subjects; the labs were also not certified for clinical work. While acknowledging the ethical questions, Dr. Chu and others argued there should be more flexibility in an emergency during which so many lives could be lost. On Monday night, state regulators told them to stop testing altogether.

The failure to tap into the flu study, detailed here for the first time, was just one in a series of missed chances by the federal government to ensure more widespread testing during the early days of the outbreak, when containment would have been easier. Instead, local officials across the country were left to work in the dark as the crisis grew undetected and exponentially.

History repeats itself, first as tragedy then as farce.

Addendum: I see now that Tyler covered this a bit earlier in the post below. I’ll leave this post up, however, as I have more details including Tyler’s connection.

FDA Prevents Import of Masks

The KN95 mask is China’s version of the N95 mask. 3M, America’s largest manufacturer of N95 masks, said in January that the masks are equivalent. But the FDA is not allowing KN95s into the country.

Buzzfeed: The KN95 mask is a Chinese alternative to the scarce N95 mask, but the FDA refuses to allow it into the country.

…By law, masks, along with most medical devices, can’t be imported or sold in the United States without the Food and Drug Administration’s say-so. Last week, to ease the national shortfall of protective gear, the FDA issued an emergency authorization for non-N95 respirators that had been certified by five foreign countries as well as the European Union. It conspicuously left the KN95 masks out of the emergency authorization.

The omission was all the more startling because in late February the Centers for Disease Control and Prevention said that KN95 masks were one of numerous “suitable alternatives” to N95 masks “when supplies are short.”

…Allowing the importation and use of KN95 could help to greatly alleviate the scarcity.

“The KN95 masks are far more readily available,” said Bob Tilton, who owns a New Jersey–based cosmetics packaging importer and earlier this month decided to use his familiarity with Chinese supply chains to bring in masks and other personal protective equipment to sell to hospitals. “The N95s are much harder to grab.”

Yet without the FDA’s seal of approval, importers are hesitant to order KN95 masks because they worry they’ll get held up at customs.

It’s not just the FDA that is to blame, however. America’s legal system is also to blame:

Many hospitals are refusing to accept them, even as free donations, because they fear legal liability should a health care worker get ill while using a nonpermitted device…Although some hospitals flat-out reject KN95 masks at any price on advice of their lawyers, people rounding up masks to give to hospitals have found that individual doctors or nurses will often accept the donations, given the dire need.

Consider that last bit of insanity. The ethical and common-law type rule is very simple: Do everything reasonable to protect your hospital workers. But what some feckless hospital administrators are actually doing is following “the law” even if it conflicts with the ethical rule.

FDA Stops At-Home Tests

TechCrunch…the U.S. Food and Drug Administration (FDA) has updated its Emergency Use Authorization guidelines to private labs that specifically bar the use of at-home sample collection. This means startups, including Everlywell, Carbon Health and Nurx, will have to immediately discontinue their testing programs in light of the clarified rules.

The FDA issued the updated guidance on March 21, and though some of the companies had already begun to ship their sample collection kits to people, and even begun to receive samples back to their diagnostic laboratory partners, even any samples in-hand will not be tested, and will instead be destroyed in order to comply with the FDA’s request

The tests are collected at home but the tests themselves are done in certified labs under quality-control standards (CLIA). It is of course possible, even likely, that tests collected at home are not as accurate as those collected by a trained nurse. But we don’t want trained nurses to be testing everyone–they have other things to do right now. Furthermore, some of these errors will be detected at the lab and can be fixed with a retest. False negatives are possible but going to a hospital or standing in line to get a test also comes with risk. False negatives will also become apparent to the extent that symptoms worsen at which time patients can seek medical assistance. Yes, of course, delay and false reassurance are also not without risk. Welcome to the world of tradeoffs. But at this point in time we need to unleash American ingenuity and enterprise and evolve our way to the frontier as conditions improve.

We need to learn now, regulate later.

FDA senior scientists

“The White House considered issuing an executive order greatly expanding the use of investigational drugs against the new coronavirus, but met with objections from Food and Drug Administration scientists who warned it could pose unneeded risks to patients, according to a senior government official.

The idea to expand testing of drugs and other medical therapies was strongly opposed by the FDA’s senior scientists this week, the official said, and represented the most notable conflict between the FDA and the White House in recent memory.”

Ahem.  Here is the full WSJ piece.

The FDA and Coronavirus

The failure of the FDA/CDC to adequately prepare for coronavirus, despite weeks of advance notice from China is one of the most shocking and serious examples of government failure that I have seen in my lifetime. After being prevented from doing so, private laboratories are now allowed to offer coronavirus tests and Bill and Melinda Gates’s Foundation is working on an at home swab and test.

But what happens when people get sick? What drugs will patients be allowed to try given that there is no standard treatment available? One experimental antiviral, Remdesivir, was given to the first US patient who was on a downward spiral but seemed to recover after receiving the drug. Gilead, the manufacturer says:

Remdesivir is not yet licensed or approved anywhere globally and has not been demonstrated to be safe or effective for any use. At the request of treating physicians, and with the support of local regulatory agencies, who have weighed the risks and benefits of providing an experimental drug with no data in 2019-nCoV, Gilead has provided remdesivir for use in a small number of patients with 2019-nCoV for emergency treatment in the absence of any approved treatment options.

If Gilead is willing to supply, should patients have a right to try? This seems like a good case for the dual tracking approach proposed by Bartley Madden–let patients try unapproved drugs but collect all information in a public database for analysis. Clinical trials for Remdesivir and other potential drugs are currently underway in China.

Chloroquine, might also be useful against Covid-19. Chloroquine was approved long ago to treat malaria and physicians are allowed to prescribe old drugs for new uses. New uses for old drugs are discovered all the time and they do not have to go through long and costly FDA approval procedures before being prescribed for the new uses. Since chloroquine has never been tested for efficacy against coronovirus, allowing physicians to prescribe it is similar to allowing physicians to prescribe an unapproved drug like Remdesivir. The difference in how new drugs and old drugs for new uses are treated is something of a regulatory anomaly but a fortunate one as I argue in my paper on off-label prescribing.

I suspect that my arguments for less FDA regulation will be relatively well received during the current climate of fear. Bear in mind, however, that for the patient who is dying it’s always an emergency.

Hat tip: Balaji Srinivasan, who really would make a great FDA commissioner.

Why are we letting FDA regulations limit our number of coronavirus tests?

Since CDC and FDA haven’t authorized public health or hospital labs to run the [coronavirus] tests, right now #CDC is the only place that can. So, screening has to be rationed. Our ability to detect secondary spread among people not directly tied to China travel is greatly limited.

That is from Scott Gottlieb, former commissioner of the FDA, and also from Scott:

#FDA and #CDC can allow more labs to run the RT-PCR tests starting with public health agencies. Big medical centers can also be authorized to run tests under EUA. For now they’re not permitted to run the tests, even though many labs can do so reliably 9/9 cdc.gov/coronavirus/20

Here is further information about the obstacles facing the rollout of testing.  And read here from a Harvard professor of epidemiology, and here.  Clicking around and reading I have found this a difficult matter to get to the bottom of.  Nonetheless no one disputes that America is not conducting many tests, and is not in a good position to scale up those tests rapidly, and some of those obstacles are regulatory.  Why oh why are we messing around with this one?

For the pointer I thank Ada.

FDA Dual Track Legislation Advances

S&P Global: Four Republican lawmakers have authored new legislation to permit drugs for critically ill patients to enter the market before completing late-stage trials, saying the bill was necessary because the U.S. Food and Drug Administration’s regulatory process was too slow and burdensome.

The bill would create a time-limited conditional approval pathway in the U.S. similar to a system that has long been used by European regulators.

…The conditional approval would be valid for one year and could be renewed annually for up to five years….Companies would be required to meet certain obligations, like completing clinical investigations to provide full demonstration of safety and effectiveness and other studies.

…Companies could seek full U.S. approval at any time. The FDA would be required to let manufacturers include in their applications the real-world evidence they collected during the conditional approval period.

The lawmakers want the FDA to be able to grant the limited marketing authorization to new drugs that have successfully completed phase 1 and 2 trials, with the idea that companies could generate revenue to help fund their phase 3 studies.

They emphasized their legislation is targeted especially at small biopharmaceutical companies that may struggle to cover the costs of late-stage trials.

Under the dual-track approval system, companies would be able to sell pharmaceuticals earlier but would be required to track outcomes so greater real world information would be developed in the FDA process. The result is a more dynamic approval process better suited to modern medicine. The idea is due to the excellent Bartley J. Madden (note my bias).

Madden and Nobel-prize winner Vernon Smith explained the dual-track idea, noting:

Today’s world of accelerating medical advancements is ushering in an age of personalized medicine in which patients’ unique genetic makeup and biomarkers will increasingly lead to customized therapies in which samples are inherently small. This calls for a fast-learning, adaptable FTCM environment for generating new data. In sharp contrast, the status quo FDA environment provides a yes/no approval decision based on statistical tests for an average patient, i.e., a one-size-fits-all drug approval process.

A similar process has been adopted in Japan for regenerative medicine.

FDA Tiered Approval

have an interesting op-ed on a tiered approval regime for the FDA:

Instituting a codified approval paradigm based on four tiered levels of clinical effectiveness (biomarkers, clinical signs and symptoms, disease modification and clinical outcomes) — with evidence regarding clinical utility progressively increasing — would greatly reduce the regulatory uncertainty and subjectivity, as well as the time to approval of innovative medicines.

Moreover, the four tiers, coupled with a commitment to apply state-of-the-art technologies (Apple Watch, telemetry and other health monitoring systems) to obtain clinical evidence would allow for additional learnings from use of drugs by practicing doctors treating real world patients. This knowledge would unearth additional uses, information that can be added to the product label to allow safer and more effective use of drugs and the identification of drug combinations that lead to even greater health benefits.

See also Bartley Madden’s work on Free to Choose Medicine which would similarly create dual tracks, one the standard FDA process and a second observational track that would bring drugs to market more quickly with the tradeoff being fewer clinical trials. As clinical trials rise in expense and more treatments are targeted towards smaller patients groups (i.e. personalized medicine) and as statistical techniques improve, we will need and can benefit from reforms to the FDA process along these lines.

Bring Back the FDA’s Parallel Track

In 1992, the AIDS/HIV “parallel track” was approved as a regulatory change for FDA to allow patients exclusive access to AIDS/HIV drugs that had passed safety tests but had not yet passed all efficacy tests. Other drugs did not have access to this approval option. As a result of parallel track, the highly effective anti-viral drug stavudine was approved, saving thousands of lives.

…In the years that followed, FDA and Congress created several paths to speed approval and open access to promising medications, including accelerated approval, priority review, fast track, breakthrough therapy, right to try, and expanded access, or “compassionate use.” Unfortunately, these approaches are often confusing, and it is difficult for drug developers to determine which approach to pursue. None of these reforms have matched the openness and simplicity of the parallel track…

Ed Hudgins in How Extending the AIDS Drug Access Model to Other Diseases Would Save Lives.