Nature: How a Controversial US Drug Policy Could Be Harming Cancer Patients Worldwide

From Nature: In August 2021, Amol Akhade, an oncologist at Nair Medical Hospital in Mumbai, India, received an e-mail from the Swiss drug manufacturer Roche recommending the use of a drug named atezolizumab to treat a specific kind of breast cancer. Akhade was surprised. That month, Roche had withdrawn the drug for this purpose in the United States (although it is still approved to treat other kinds of cancer). 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 US Food and Drug Administration’s (FDA’s) Accelerated Approval Program. Accelerated approval is a fast-track process designed to place desperately needed drugs in the hands of patients quicker than is possible with conventional drug approval. But a follow-up study found that atezolizumab made little difference to tumour growth, and that people who received it were less likely to survive up to two years after treatment than were those not taking it. When the FDA received these data in 2021, it indicated that 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 to promote the treatment until at least September, a fact that Akhade says he found “quite shocking”. “It’s not like patients with triple-negative breast cancer are different in the United States and outside,” he says. “We cannot have such differential treatment.” When asked about its responsibility to patients, Genentech, the Roche subsidiary in San Francisco, California, that developed atezolizumab, said that the drug is 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,” said an e-mail from the company. Accelerated approvals in the United States are granted on the basis of clinical studies that suggest a health benefit without necessarily demonstrating it fully. The process prioritizes speed over certainty, and it requires companies to complete follow-up studies to confirm a treatment’s benefits. This is a “very reasonable compromise”, says bioethicist Holly Fernandez Lynch at the University of Pennsylvania in Philadelphia, “so long as we can get the confirmatory evidence quickly and reliably”. But there are complications that have made the programme controversial. Companies don’t always conduct studies in a timely manner, and the FDA hasn’t always been great about enforcing them. Researchers have noted that the median time to withdrawal for a drug that fails to hold up in confirmatory studies is four years; sometimes it takes decades. And 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 have complained 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 (see ‘Cancer drugs on the go’). A lot of prescriptions can be made in the time 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, thanks to the fact that many countries use FDA decisions to guide their own regulatory policies. At the heart of 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 — either a drug is approved or it’s not,” she says. But it’s not that simple.

Communication gaps

The Accelerated Approval Program was established in 1992, as a result of efforts from activists and advocates during the HIV epidemic in the 1980s. At the time, people facing a deadly disease were willing to accept a little uncertainty in exchange 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 such as tumour regression or extended lifespan. Although this endpoint is thought to correlate to a longer life, evidence for this link 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 in New Haven, Connecticut. “Manufacturers have made it seem that accelerated approval is just like any other approval. It’s not, and that level of uncertainty is not really being translated to clinicians,” she says. 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 offered by groups such as the National Comprehensive Cancer Network (NCCN), a non-profit alliance of US clinical cancer centres that helps to create guidelines for practitioners, based in Plymouth Meeting, Pennsylvania. 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.

Read more at Nature.