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How to Make Experimental Treatment Less of a Gamble How to Make Experimental Treatment Less of a Gamble
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When faced with an incurable disease, many people are willing to try anything that may help. This is especially true when the person’s disease profoundly changes their way of life, such as with paralysis or memory loss, or if it could lead to early death. When faced with an incurable disease, many people are willing to try anything that may help. This is especially true when a disease profoundly changes their way of life, such as with paralysis or memory loss, or if it could lead to early death.
People with such prognoses may be more willing than others to try experimental treatments, even without robust data showing that they are safe or likely to work. Patients and advocacy groups have pushed for faster access in recent years. In response, the Food and Drug Administration has created programs that speed up access to new medical products for serious conditions that lack effective treatments.People with such prognoses may be more willing than others to try experimental treatments, even without robust data showing that they are safe or likely to work. Patients and advocacy groups have pushed for faster access in recent years. In response, the Food and Drug Administration has created programs that speed up access to new medical products for serious conditions that lack effective treatments.
The agency recently approved a treatment for A.L.S., a fatal neurological disorder, despite questions about whether the drug, called Relyvrio, will extend patients’ lives or slow the progression of their disease. Because the drug appears safe, the agency reasoned that “given the serious and life-threatening nature of A.L.S. and the substantial unmet need, this level of uncertainty is acceptable in this instance.” The F.D.A. could withdraw the drug’s approval if ongoing confirmatory trials showed poor results.The agency recently approved a treatment for A.L.S., a fatal neurological disorder, despite questions about whether the drug, called Relyvrio, will extend patients’ lives or slow the progression of their disease. Because the drug appears safe, the agency reasoned that “given the serious and life-threatening nature of A.L.S. and the substantial unmet need, this level of uncertainty is acceptable in this instance.” The F.D.A. could withdraw the drug’s approval if ongoing confirmatory trials showed poor results.
This was reminiscent of the F.D.A.’s controversial 2021 approval of the Alzheimer’s drug Aduhelm through one of its programs to speed access to new treatments, called accelerated approval. An advisory committee for the agency determined that there wasn’t strong evidence that the drug worked, but the F.D.A. gave the green light anyway, to the delight of some patients and advocacy groups.This was reminiscent of the F.D.A.’s controversial 2021 approval of the Alzheimer’s drug Aduhelm through one of its programs to speed access to new treatments, called accelerated approval. An advisory committee for the agency determined that there wasn’t strong evidence that the drug worked, but the F.D.A. gave the green light anyway, to the delight of some patients and advocacy groups.
As a bioethicist who consults with patient advocacy groups and drug companies (unpaid) about access to experimental treatments outside of clinical trials — including Amylyx and Biogen, the makers of the two drugs mentioned — I understand the pressure companies and regulators like the F.D.A. are under, as well as the anguish felt by patients in need of treatment. Still, I’m deeply concerned about what I see as a trend toward prioritizing access to unproven medical products over gathering evidence that they safely work.As a bioethicist who consults with patient advocacy groups and drug companies (unpaid) about access to experimental treatments outside of clinical trials — including Amylyx and Biogen, the makers of the two drugs mentioned — I understand the pressure companies and regulators like the F.D.A. are under, as well as the anguish felt by patients in need of treatment. Still, I’m deeply concerned about what I see as a trend toward prioritizing access to unproven medical products over gathering evidence that they safely work.
If this trend continues, it could result in people increasingly using and paying for ineffective and possibly unsafe medical products. In the worst case, it could mark a return to an era when drug-related harms occurred under insufficient regulation.If this trend continues, it could result in people increasingly using and paying for ineffective and possibly unsafe medical products. In the worst case, it could mark a return to an era when drug-related harms occurred under insufficient regulation.
Determining if a medical product is safe and effective entails both scientific and value judgments. Data collected from clinical testing provides insight into a product’s impact on the human body and the condition it is meant to treat, but judgment and discernment are needed to decide if the medication is safe enough or effective enough to make it worthwhile, given possible side effects.Determining if a medical product is safe and effective entails both scientific and value judgments. Data collected from clinical testing provides insight into a product’s impact on the human body and the condition it is meant to treat, but judgment and discernment are needed to decide if the medication is safe enough or effective enough to make it worthwhile, given possible side effects.
There is no one indicator that a new medical product merits F.D.A. approval. Stakeholders have different views on what evidence is sufficient. Some may see statistically significant results from randomized clinical trials as critical, while others may put more value on patient testimonials. The F.D.A. has the challenge of making a decision for the entire country, amid these differing views.There is no one indicator that a new medical product merits F.D.A. approval. Stakeholders have different views on what evidence is sufficient. Some may see statistically significant results from randomized clinical trials as critical, while others may put more value on patient testimonials. The F.D.A. has the challenge of making a decision for the entire country, amid these differing views.
The F.D.A.’s approvals for Relyvrio and Aduhelm hinged on factors specific to those drugs and their uses. But both cases revealed that a lack of clear effectiveness data did not deter some patients from wanting the opportunity to try the drugs.The F.D.A.’s approvals for Relyvrio and Aduhelm hinged on factors specific to those drugs and their uses. But both cases revealed that a lack of clear effectiveness data did not deter some patients from wanting the opportunity to try the drugs.
I can understand the argument, on an emotional level, that when it comes to your body and life, you should be able to assume whatever risk you want. There’s also the compelling argument that in certain situations, whether it’s a pandemic affecting millions or a rare, devastating disease, there should be a lower bar for evidence and a greater willingness to allow people to assume risk. The idea that absolute certainty about a product’s safety or efficacy is not always needed was on display in the F.D.A.’s emergency use authorization for Covid-19 vaccines and therapeutics (which had strong early evidence that they worked well and were safe). Such regulatory flexibility can provide relief in a crisis, but its use should be exceptional.I can understand the argument, on an emotional level, that when it comes to your body and life, you should be able to assume whatever risk you want. There’s also the compelling argument that in certain situations, whether it’s a pandemic affecting millions or a rare, devastating disease, there should be a lower bar for evidence and a greater willingness to allow people to assume risk. The idea that absolute certainty about a product’s safety or efficacy is not always needed was on display in the F.D.A.’s emergency use authorization for Covid-19 vaccines and therapeutics (which had strong early evidence that they worked well and were safe). Such regulatory flexibility can provide relief in a crisis, but its use should be exceptional.
Evidence-based medicine requires a rigorous system of medical product evaluation. Even in crises like the pandemic, when access is hastened, every effort must be taken to ensure the continued study of products quickly pushed to market.Evidence-based medicine requires a rigorous system of medical product evaluation. Even in crises like the pandemic, when access is hastened, every effort must be taken to ensure the continued study of products quickly pushed to market.
Once a drug receives accelerated approval from the F.D.A., the manufacturer is supposed to continue to collect data about its safety and effectiveness. If the confirmatory data is not convincing, the product may lose its approval. But this isn’t always happening. A 2022 report by the Department of Health and Human Services’ Office of the Inspector General found that accelerated approvals, which were introduced in 1992, have increased significantly in the last few years, and more than one-third of these drug applications have incomplete confirmatory trials.Once a drug receives accelerated approval from the F.D.A., the manufacturer is supposed to continue to collect data about its safety and effectiveness. If the confirmatory data is not convincing, the product may lose its approval. But this isn’t always happening. A 2022 report by the Department of Health and Human Services’ Office of the Inspector General found that accelerated approvals, which were introduced in 1992, have increased significantly in the last few years, and more than one-third of these drug applications have incomplete confirmatory trials.
Even if the data shows a product is not safe or effective, the F.D.A. can’t quickly remove it from the market. For example, the preterm birth prevention drug Makena received accelerated approval in 2011. In October 2020, the F.D.A. proposed that it be withdrawn because the follow-up study failed to verify it worked. Nevertheless, the drug continues to be sold in the United States, and the agency is meeting soon to discuss it.Even if the data shows a product is not safe or effective, the F.D.A. can’t quickly remove it from the market. For example, the preterm birth prevention drug Makena received accelerated approval in 2011. In October 2020, the F.D.A. proposed that it be withdrawn because the follow-up study failed to verify it worked. Nevertheless, the drug continues to be sold in the United States, and the agency is meeting soon to discuss it.
It’s clear that a better process is needed.It’s clear that a better process is needed.
A solid step toward addressing these deficiencies while preserving the benefits of accelerated approval is found in a bill introduced in the House in March, the Accelerated Approval Integrity Act. The bill would require drug companies to enter into an agreement with the F.D.A. on how the follow-up studies will be conducted before accelerated approval is granted. It would mandate more frequent updates from follow-up studies, automatically expire accelerated approval one year after the agreed-upon deadline for further study and streamline the process for taking ineffective products off the market.A solid step toward addressing these deficiencies while preserving the benefits of accelerated approval is found in a bill introduced in the House in March, the Accelerated Approval Integrity Act. The bill would require drug companies to enter into an agreement with the F.D.A. on how the follow-up studies will be conducted before accelerated approval is granted. It would mandate more frequent updates from follow-up studies, automatically expire accelerated approval one year after the agreed-upon deadline for further study and streamline the process for taking ineffective products off the market.
More reforms may be needed, but adding this kind of rigor will go a long way toward making it possible for clinicians, patients and insurers to have more confidence in the system and in the treatments it approves.More reforms may be needed, but adding this kind of rigor will go a long way toward making it possible for clinicians, patients and insurers to have more confidence in the system and in the treatments it approves.
The desire of patients to use unproven medical treatments amid harrowing illness is unlikely to abate. However, access at the expense of collecting essential data is not a win for patients. Accelerated approval provides a reasonable model, but the guardrails have so far been largely theoretical. Only with changes can the promise of this program be truly met.The desire of patients to use unproven medical treatments amid harrowing illness is unlikely to abate. However, access at the expense of collecting essential data is not a win for patients. Accelerated approval provides a reasonable model, but the guardrails have so far been largely theoretical. Only with changes can the promise of this program be truly met.
Alison Bateman-House is an assistant professor in the division of medical ethics in the department of population health at N.Y.U. Grossman School of Medicine. She researches ethics and policy issues concerning access to investigational medical products, and advises pharmaceutical companies on access and clinical trial design.Alison Bateman-House is an assistant professor in the division of medical ethics in the department of population health at N.Y.U. Grossman School of Medicine. She researches ethics and policy issues concerning access to investigational medical products, and advises pharmaceutical companies on access and clinical trial design.
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