April 16, 2020
By Mark Flatten

Figuring out whether readily available drugs can blunt COVID-19 can be done quickly. But getting any of those treatments approved by the U.S. Food and Drug Administration cannot be. The reason: The agency remains wedded to its decades-old model for assessing medications even in the midst of a global pandemic, said Dr. Joseph Gulfo, a longtime critic of the FDA’s drug approval process and author of the book Innovation Breakdown: How the FDA and Wall Street Cripple Medical Advances.

What is lacking is an appropriate sense of urgency, he said.

Proving a drug works to the satisfaction of the FDA takes time. It also requires statistical certainty.

In the midst of the global pandemic that has already killed more than 139,000 people worldwide, and roughly 31,000 in the United States, time and absolute certainty are two things we cannot afford, said Gulfo, who has more than 30 years of experience in the biopharmaceutical and medical device industries and was on President Trump’s original short list to be FDA commissioner.

What is needed are new approaches that will determine in days or weeks, rather than months or years, whether readily available drugs can be repurposed into effective treatments.

Some of those approaches are already allowed in federal law and regulations governing the FDA. Others have been used before to curb runaway pandemics. Still others are being used already outside the standard FDA drug approval process by frontline doctors, hospitals, and drug companies that are forging ahead to discover in real time what works, and what doesn’t, when it comes to treating patients.

A Decades-Old Drug Approval Process

As yet, there are no FDA-approved treatments or vaccines against COVID-19. There are many drugs developed to treat other conditions that do show promise. Some are already on the market. Others are undergoing testing or review by the FDA but have not received final approval for anything and therefore are not commercially available.

Yet those potentially lifesaving treatments are mired in the standard clinical trials regime that was developed in the 1960s. More than 100 trials have been launched in the United States to deal with COVID-19 (and more than 500 worldwide). Most are to determine whether some drug or combination of drugs developed to treat other illnesses will work against the virus. Others are exploring plasma therapies, diagnostic tests, how best to use medical devices, and even behavioral counseling techniques.

Results for many of the drug studies are not expected for a year or more. Still others are designed in a way that leaves some of the test patients untreated because they will be given a placebo, the equivalent of a sugar pill, to achieve a statistical endpoint.

Until those studies are complete, any potential cures will remain “unproven” and “unapproved” in the view of the FDA, regardless of whether they could be saving the lives of patients today.

“It’s disgusting. I can’t stand it,” Gulfo told the Goldwater Institute in a recent interview. “Even with COVID there is no urgency.”

The FDA’s standard for approving a new drug, or a new use for an existing drug, is that it must be shown safe for use in humans and effective in treating a targeted condition. Safety and effectiveness must be proven in clinical trials in which the medications are dispensed to carefully screened and monitored patients. Under the traditional design, only some of the test subjects receive the medication. Others are given a placebo. If over time the treated group does substantially better than the placebo group, based on a statistical equation called the P-value, then it can be deemed effective. Even then, the FDA must determine that the medicinal benefits of the new drug outweighs any risk. The whole process from development to final FDA approval normally takes more than a decade.

The testing for COVID-19 treatments is somewhat different in that some of the drugs under review have already been approved to treat other conditions. That means they have already been proven safe for use in humans. The only question is whether they will be effective in treating COVID-19.

Other potential treatments have passed the studies showing they are safe, but studies have yet to establish they are effective against whatever condition they target, and therefore, these possible treatments have not been approved by the FDA for anything.

The drug being studied the most is hydroxychloroquine, an offshoot of the drug chloroquine that has been around since before World War II to treat malaria.

Small, early studies of the chloroquine drugs, as well as widespread anecdotal reports, indicate they show some potential to treat COVID-19, either alone or in combination with an antibiotic, zinc, or other compounds. Since they are already approved to treat malaria, lupus, and rheumatoid arthritis, doctors can dispense the chloroquine drugs to patients in what’s called an off-label use. Thousands of patients with COVID-19 have already been receiving the chloroquine drugs. Some have gotten it off label from front-line doctors. Others have been treated under an emergency use authorization issued by the FDA in March allowing the release of hydroxychloroquine from the national stockpile for use on hospitalized patients who do not have access to clinical trials.

But any benefits achieved in those treatments are deemed anecdotal and are not a substitute for clinical trials when it comes to the FDA’s needed “proof” of safety and effectiveness.

There are currently about 26 clinical trials on the chloroquine drugs planned in the U.S. that are listed on clinicaltrials.gov, the most of any of the potential treatment. Some have started recruiting patients. Others are still in the planning stages. About half of those studies show completion dates within the next year. Some will not be finished until 2023.

About half of those studies include a placebo group.

Taking the standard clinical trials approach to researching potential therapies for COVID-19 is wrong and deadly, Gulfo said. He advocates leveraging information that is already available both from untreated patients and from those who have received therapies off label.

Kill the Placebo

The first thing to do is get rid of the placebo control group in clinical trials, Gulfo said. It is unnecessary and may condemn those taking the placebo to pointless suffering or death if the drug turns out to be effective.

About 2 million people worldwide have been identified as having COVID-19 since the outbreak began several months ago. There is already ample information as to how the disease progresses when left untreated. So there is no need for a placebo group, Gulfo said.

The FDA already allows for the use of this “historical control” data in its regulations. This approach lends itself particularly well to dealing with an epidemic since it allows vast amounts of data on the normal course of the disease to be gathered quickly, Gulfo said.

Besides, in this time of crisis what is needed is not some small, incremental change in outcomes that can only be teased out through rigorous statistical analysis of treated versus untreated patients, Gulfo said.

“We’re in an emergency right now,” Gulfo said. “We’re looking for things that can give us a quantum edge. You don’t need a placebo control to see a quantum change. It just jumps out at you.”

Leverage Existing Drugs

The best approach in a crisis is to repurpose existing drugs, dispense them widely, and monitor their effects in the real world, Gulfo said. There is no time to gather data in traditional clinical trials that will take years to complete. The chloroquine drugs are especially well-suited to this approach. Since they have been widely used to treat other conditions for decades, their risks are already well-known. Thousands of COVID-19 patients have been treated either off-label or in the limited studies that are underway. In either case, results as to how the patients are responding are being generated in real time. That data should be collected and used to assess the drugs’ effectiveness in lieu of a formal clinical trial. That will tell us within weeks whether a given treatment works.

“You’ll use them for three or four weeks,” Gulfo said. “At most you get better or unfortunately you succumb, but at max four weeks.

“Here we are talking about acute short-term use of two approved drugs. I’m beside myself with the debate.”

Studying drugs that are not already approved by the FDA is more complicated. For one thing, they cannot be prescribed off-label.

However, drugs that have already proved their safety and show potential for fighting COVID-19 could be widely dispensed in a more controlled setting, such as a research hospital, but without the rigid confines of a clinical trial, Gulfo said.

Rely on Real-World Evidence

Using all available information from COVID-19 patients, both treated and untreated, will give a faster and more accurate assessment of what works in the battle against the virus than the traditional clinical trials being planned, Gulfo said.

By collecting real-world data rather than relying on statistical studies of carefully screened patients, researchers can assess immediately how well the drug works generally, how it works on subgroups of the population, and whether particular groups are more at risk of adverse side effects.

The FDA has been under pressure from Congress to make better use of real-world data in its assessments of new drugs and medical devices. The pharmaceutical company Oracle has already established a way to collect data from the off-label treatment of patients. On April 1, Oracle announced it had built and donated to the U.S. government a massive data collection system to track the effectiveness of promising COVID-19 therapies, including hydroxychloroquine. The system allows patients and the doctors treating them off-label to feed information into the database as to a particular drug’s success, failure, problems, and dosage. It is available to every physician in the U.S. and was developed in collaboration with federal health agencies including the FDA.

According to the Oracle press release:

“By collecting this real-world patient data throughout the United States now, and throughout the world soon thereafter, we will quickly discover which of the new drugs are most effective against COVID-19, their optimal dosages, and how early in the disease progression the drugs need to be administered. In this way, each patient will participate in the fight against this deadly virus.”

Old Approaches to New Virus

When an Ebola outbreak hit several West African nations in 2014, the FDA scrapped its traditional approach to clinical trials and allowed simultaneous research into multiple potential treatments outside the standard model. Because of concerns it would be unethical to leave some patients untreated, or leave them being treated with drugs that proved to be less effective, the trials were designed so that patients could be switched to whichever drug was showing the best results. If one drug showed itself to be superior, that treatment became the minimum standard of care as the research continued. There was no placebo control group.

The FDA still brags about its flexibility in rapidly designing an adaptive trial model that allowed it to deal with the Ebola crisis in Africa rapidly, ethically, and in a manner that did not sacrifice scientific integrity.

“A randomized trial is essential for collecting conclusive evidence about the relative benefits of treatments, but it is difficult to conduct trials in the context of an epidemic, in part because it would be unethical to withhold potentially effective treatments from patients,” the agency says in an article posted on its website.

Gulfo says he’s not optimistic the FDA will show that same sense of urgency when it comes to dealing with COVID-19 in the U.S. Nor does he anticipate the agency will relax its reliance on traditional clinical trials to “prove” hydroxychloroquine or any other drug is effective.

“They’ve always been immune to the realities of the world,” Gulfo said of FDA regulators. “They are immune to the realities of patient care. And it’s wrong.”

Mark Flatten is the National Investigative Journalist at the Goldwater Institute.

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