FDA may have dropped standards too far in hunt for chloroquine to fight coronavirus: Sources

On 21^st March, 2020, two days after the US President Donald Trump first touted chloroquine drugs as a “gamechanger” in the fight against COVID-19, administration officials privately described what they felt was a “win” in the president’s efforts to build an emergency stockpile of the drugs: a hefty donation of pills from Bayer AG.

In an exchange of enthusiastic emails among federal health officials reviewed by Reuters, Keagan Lenihan, Chief of Staff, US Food and Drug Administration (FDA), cautioned that “three to four days” of testing would be needed.

“Potentially serious issues with product so let’s be careful when we take that win,” she wrote.

Bayer has since donated three million tablets of the drug, called Resochin, to the US national stockpile for treatment of COVID-19. After a brief period of testing, its use in the US was approved on an emergency basis.

But three US government sources familiar with the matter told Reuters that there is reason to be concerned about the quality of Resochin and its makers, located in India and Pakistan.

Although some rules can be waived in an emergency, the FDA dropped its quality-control standards too far as it scoured the world for scarce supplies of chloroquine drugs, according to the sources, who spoke on condition of anonymity.

The plants that make Resochin ingredients and finished doses in India and Pakistan have never been registered with, or inspected, by the FDA, according to the three government sources, as well as FDA documents compiled in the private online database FDAzilla.com. Some chloroquine drugs were already approved by the FDA before the pandemic as anti-malarial medications, a process that required plant inspections. Resochin was not approved.

Pakistani regulators, who inspected Bayer’s Resochin plant in Karachi in 2015, found a “gross failure” in manufacturing processes there, according to documents from the Drugs Regulatory Authority of Pakistan, reviewed by Reuters. And though the FDA has never screened the Indore, India, plant that supplies ingredients for Resochin, the US agency has inspected other Indian plants run by the same Indian supplier and found serious deficiencies, including falsification of records, inspection documents spanning 2014 through 2019 show.

Responding to questions from Reuters about Resochin, Michael Felberbaum, spokesman, FDA said that the agency “sampled and tested the donated drugs to evaluate acceptability for importation” and they met appropriate standards.

Asked about Lenihan’s 21^st March email, , the FDA spokesman said the agency “does not comment on alleged, leaked emails.”

In a statement to Reuters, Bayer said that the FDA had tested Resochin “and found it to be of appropriate quality for release to the (stockpile) for emergency use. We are proud to make this donation to the US government in the fight against COVID-19.”

Resochin is part of a class of medications containing one of two active ingredients – chloroquine or hydroxychloroquine – that the Trump administration has praised as a potentially life-saving treatment. However, the effectiveness of chloroquine drugs against coronavirus has not been proven. Even though in use for years in the United States, as a treatment for malaria and autoimmune conditions like lupus, the medicines can have serious side effects, including heart arrhythmias.

The three US sources who spoke with Reuters, as well as an independent expert, said spot-testing is not always sufficient to ensure a drug’s safety and effectiveness, and plant inspections normally done by the FDA are crucial to ensuring overall quality.

“If you’re talking about millions of doses, you can’t test every product,” said Stephen Payne, who for years chaired a practice group specialising in the FDA and healthcare at a global law firm. “You have no idea what you don’t know.”

A photo opportunity

Trump first endorsed chloroquine drugs to treat COVID-19 from the White House podium on 19^th March, 2020, citing “very, very encouraging early results” and downplaying any risks. “If things don’t go as planned, it’s not going to kill anyone,” he said.

The statements came as the administration was being hammered for its slow response to the growing coronavirus crisis, which, to date has infected more than 637,000 people in the United States, killing almost 31,000. His comments set high public expectations for the drugs, which are now being snapped up all over the globe.

In emails two days later, federal health officials greeted the Bayer donation of chloroquine phosphate, or Resochin, with eagerness.

Cicely Waters, Director – External Affairs, the US Department of Health and Human Services (HHS), saw a media opportunity. A shipment of two million tablets was due to arrive at John F Kennedy International Airport in New York City.

“I would like to get photos of the product coming off of the FedEx plane so we can be prepared to support the story with visuals if this turns out the way we hope,” wrote Waters.

Lenihan of the FDA told the group of health officials that “if it is the product we think it is and it is not toxic, we will release it to ASPR” – the Assistant Secretary for Preparedness and Response, a division within HHS.

Reached by email, Lenihan referred Reuters back to the FDA press office. Waters did not respond to an email seeking comment.

One of the participants in the 21^st March email discussion appeared to raise the issue of which agency should get credit for the deal. Joseph Hamel, Manager ­– Strategic Innovation and Emerging Technology ASPR, asked in an email to the group: “How do you want to handle? FDA win? ASPR win? Happy either way, please let us know.”

Hamel did not return an email seeking comment.

Asked about the email exchanges, an HHS spokesman echoed the FDA’s statement, saying the agency would not comment on “alleged, leaked emails.”

Gross failure

The pills and ingredients welcomed by the administration had origins that should have raised red flags and prompted greater scrutiny, said the three sources who spoke to Reuters.

In 2015, Bayer’s plant in Pakistan, was cited by that country’s regulators for making Resochin that was lower in potency than labelled, according to inspection documents reviewed by Reuters.

A whistleblower complaint led to the discovery of more than 21 million Resochin tablets that were too weak, more than 12 per cent under the specified weight of 400 milligrams, according to the Pakistani regulatory records.

Officials blamed the problem on a “gross failure” of manufacturing operations, citing improperly calibrated machines, poorly trained workers and insufficient staffing. Weak medications can fail to treat the illness for which they are prescribed and harm patients.

The investigation was ultimately resolved with Bayer’s agreement to destroy the 21 million doses.

Regarding the 2015 incident, the company told Reuters, “All batches produced with lower content due to an error in production were never released, the corresponding batches destroyed.”

According to FDA records reviewed by Reuters, the active ingredients for the drug are made at a plant in Indore, India, run by Ipca Laboratories Ltd, an Indian drug manufacturer and ingredient supplier that exports its products globally.

In 2016, the FDA issued a warning letter to Ipca regarding three of its plants in India that make chloroquine ingredients and finished pills for companies other than Bayer. The plants did not include the one making the active ingredient for Bayer’s Resochin. Nonetheless, the US government sources said, Ipca’s troubled history calls into question its general practices.

The FDA found the company was deleting, manipulating and fabricating laboratory data, according to the agency’s records. The company vowed at the time to “resolve these issues at the earliest.”

In 2017, the agency restricted drugs and ingredients from those three plants from entering the US market, a regulatory sanction called an import alert. Then in August 2019, the FDA accused one of the Ipca plants of a “cascade of failure” for not properly maintaining its quality data, agency records show.

Ipca did not respond to questions from Reuters about its track record with the FDA.

On 20^th March 2020, a day after Trump praised the anti-malarial drug from the podium, the FDA lifted its import alert for Ipca’s chloroquine ingredients and completed tablets from the three restricted plants, according to a 21^st March statement filed by Ipca with the Indian stock exchange.

The company pledged in the statement to adhere to stringent manufacturing standards, “and thus help mankind in the best possible way in these testing times.”

Katherine Eban reported from New York; Editing by Elyse Tanouye and Julie Marquis