While the US Food & Drug Administration’s accelerated-approval process was designed to ease access to life-saving drugs, communication gaps could mean people are undergoing treatments known to be ineffective, with certain withdrawn drugs being sold by manufacturers in other countries.
In August 2021, Amol Akhade, an oncologist at Nair Medical Hospital in Mumbai received an e-mail from Swiss drug manufacturer Roche recommending a drug named atezolizumab for a specific kind of breast cancer.
Akhade was surprised, reports the journal Nature. That month, Roche had withdrawn the drug for this purpose in the United States (although it is still approved to treat other cancers).
For the type of breast cancer in question, known as triple-negative because it lacks three key protein markers, atezolizumab was made available in 2019 through the FDA’s Accelerated Approval Programme – a fast-track process designed to get desperately needed drugs to patients faster than is possible with conventional approval.
But a follow-up study found atezolizumab made little difference to tumour growth, that people taking it were less likely to survive up to two years after treatment than those not taking it.
When the FDA received these data in 2021, it indicated accelerated approval was no longer appropriate, and Roche withdrew the drug for this form of breast cancer. The same thing happened with the European Medicines Agency (EMA), based in Amsterdam, but not everywhere else.
In India, for example, where the drug was still approved for triple-negative breast cancer, Roche continued promoting the treatment until at least September, which Akhade says was “quite shocking”.
When asked about its responsibility to patients, Genentech, the Roche subsidiary in California that developed atezolizumab, said the drug was still approved in 100 countries for triple-negative breast cancer.
“All of our medicines strictly adhere to the regulatory and promotional requirements of all local healthcare authorities,” the company said.
Accelerated approvals in the US are granted on the basis of clinical studies that suggest a health benefit without necessarily demonstrating it fully.
The process prioritises speed over certainty, and requires companies to complete follow-up studies to confirm benefits.
“It’s a reasonable compromise”, says bioethicist Holly Fernandez Lynch at the University of Pennsylvania, “so long as we can get the confirmatory evidence quickly.”
But companies don’t always conduct studies timeously, and researchers say the FDA’s median time to withdrawal for a drug failing to hold up in confirmatory studies is four years; sometimes decades.
Some high-profile accelerated approvals have raised eyebrows.
Experts worry that the evidence used to support the approval of the Alzheimer’s disease drug aducanumab was insufficient; three FDA advisers resigned in protest.
Other specialists complain that the process allows companies to market expensive drugs for rare childhood diseases to desperate parents without sufficient evidence.
There are currently nearly 200 cancer treatments approved through this pathway. Follow-up studies have led to the withdrawal of 26, and 68 are still awaiting confirmatory evidence.
Numerous prescriptions can be made between a drug’s accelerated approval and the publication of follow-up results. If those results are negative, the drug can still be prescribed to many people before its eventual withdrawal, and even afterwards – particularly when professional medical bodies recommend its use.
And accelerated approvals have an effect beyond US borders, because many countries use FDA decisions to guide their own regulatory policies.
Central to the problem, says Lynch, is a failure of communication – both in the outcomes of follow-up studies and the nature of accelerated approval itself. “Clinicians and patients often view FDA approval as an on–off switch. A drug is approved or it’s not.” But it’s not that simple.
Communication gaps
The Accelerated Approval Programme was established in 1992, resulting from efforts from activists and advocates during the 1980s HIV epidemic. People facing a deadly disease were willing to swop some uncertainty for quicker access.
It allowed drug makers to use a “surrogate” endpoint to gauge a treatment’s purported benefits. For example, studies of most cancer drugs estimate whether a treatment can pause a tumour’s growth – progression-free survival – rather than looking at metrics like tumour regression or extended lifespan.
Nature reports that although this endpoint is thought to correlate to a longer life, evidence is mixed.
The distinction between surrogate endpoints and more direct ones isn’t always obvious, even to clinicians, says Reshma Ramachandran, a health-services researcher at Yale University.
“Manufacturers have made it seem accelerated approval is just like any other approval. It’s not, and that level of uncertainty is not really being translated to clinicians.”
Ravi Parikh, a medical oncologist at the University of Pennsylvania, often navigates the maze of evidence for the use of different drugs. He parses data from clinical trials as well as guidance from groups like the National Comprehensive Cancer Network (NCCN), a non-profit alliance of clinical cancer centres that helps to create guidelines for practitioners.
Parikh has seen accelerated-approval drugs help his patients to live longer. But he has sometimes felt unsure about the benefits of a newly available drug for a person in need. “There’s a temptation to use them even though they may not be as effective,” he says.
To understand how others deal with that inclination, Parikh and his colleagues reviewed how doctors responded to the accelerated approval of five cancer medications that were later withdrawn for lack of confirmatory evidence.
They found clinicians quickly reached for the treatments when they became available. About one-quarter of eligible people received an accelerated-approval drug, most within the first year of approval. When further evidence failed to confirm a drug’s effectiveness, usage slowed but did not stop.
Clinicians continued to prescribe accelerated-approval drugs to 10% of eligible people, even after the drugs were withdrawn.
For some bladder cancers, immunotherapy drugs that received accelerated approval were later found to be less effective than older chemotherapies.
“In many cases, the previous standard of care is better,” Parikh says.
And if they’re on par with existing options, Parikh says clinicians must consider both the cost, which is often higher for newer drugs, and the differences in side effects. “For that reason, there’re still maybe some downsides of using it, even if it’s not substantially worse.”
Only recently have clinicians grown more aware that accelerated-approval drugs might rely on murky evidence, and that’s through efforts from advocacy groups like Doctors for America, Ramachandran says.
Global impact
The effects of accelerated approval can spread beyond US borders. Regulatory agencies in low- and middle-income countries sometimes rely on decisions from the FDA and EMA. Some lack their own regulatory framework, so follow the FDA’s decisions directly, under the guidance of the WHO.
For India, which has its own regulatory body, the Central Drugs Standard Control Organisation (CDSCO), and others, the FDA’s position on a drug can be very influential.
“The FDA is still seen as the gold standard in terms of regulatory review and approval,” Ramachandran says, “playing a huge role in the international space regarding setting the bar for what sorts of evidence should be accepted.”
But nuances of precisely which FDA approval pathway was used or what surrogate endpoints were measured are often lost in the process, with the concept of accelerated approval being poorly known outside the US.
An FDA spokesperson said it did not regulate drug products “intended for markets outside the US, but encourages global regulatory co-operation and harmonisation to improve efficiency of development and post-marketing safety surveillance”.
In the case of atezolizumab for triple-negative breast cancer, the CDSCO permitted its use after the FDA granted accelerated approval in March 2019, but did not mirror the FDA’s subsequent actions.
In February 2022, Akhade and his colleagues reported on how this happened for atezolizumab and nine other accelerated-approval drugs withdrawn in the US the previous year.
Although manufacturers used the accelerated approvals to promote the medicines in low- and middle-income countries, they did not withdraw them there when the data failed to support their continued use.
After discussions between the drugmaker and the CDSCO in June 2022, atezolizumab remained approved for triple-negative breast cancer
Medical oncologist Bishal Gyawali at Queen’s University in Kingston, Canada, who co-authored the commentary with Akhade, says it’s time for international drug regulators to look beyond the FDA and EMA for guidance.
Different countries experience different rates of certain cancers, and low- and middle-income countries should prioritise drugs that are most relevant to their populations instead of relying on the FDA “as a surrogate”.
But Matthew Herder, a pharmaceutical-law researcher at Dalhousie University in Halifax, Canada, says the FDA remains an international standard, because global regulators don’t have equivalent resources.
Thus, the responsibility to protect people with cancer globally needs to be shared, he says. “The WHO needs to take more seriously the problems with established systems like the FDA.”
Looking ahead
Reforms are possible, at least in the US. In late 2022, the government enacted the Food and Drug Omnibus Reform Act (FDORA), to make the accelerated-approval process more transparent and giving the FDA greater authority to ensure drug makers complete confirmatory studies.
Companies must now begin a clinical trial to gather the data needed for a conventional approval before applying for accelerated approval. It has also begun re-evaluating previous accelerated approvals – leading to high-profile withdrawals.
Other safeguards give the FDA more authority to ensure companies withdraw drugs when required to do so.
Parikh says the Accelerated Approval Programme could be strengthened further by gathering more data during preliminary studies, for instance investigators could track whether the treatment helps people survive longer than is typically observed with standard clinical treatments.
Comparisons of a drug in a clinical study with real-world data are imperfect, Parikh says, but could still help to guide decision-making.
And, Ramachandran says, professional guidelines that more accurately reflect the FDA’s decisions could reduce potential harms.
“It’s very low-hanging fruit for the guidelines to explicitly state when a drug has been through the accelerated-approval pathway.”
The NCCN said details of the evidence backing the use of a drug are not in the guidelines, but are included in other NCCN resources for clinicians.
Spreading that message internationally could also help regulatory authorities in low- and middle-income countries to weigh up the pros and cons of accelerated-approval drugs when making decisions. Herder says the uncertainty accompanying accelerated-approval drugs makes them “by far the riskiest drugs available”.
Until that message spreads, he adds, regulators in low- and middle-income countries relying on the FDA’s accelerated-approval decisions might do “more harm than good”.
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