OIG raises concerns about accelerated approval pathway

Regulatory NewsRegulatory News | 30 September 2022 |  By 

More than one-third of accelerated approval applications do not meet their original confirmatory trial dates, and four drug applications were more than 5 years past their confirmatory trial deadlines, according to a recent report released by the US Department of Health and Human Services Office of Inspector General (OIG).
“The accelerated approval pathway holds promise for patients who face serious illnesses where adequate treatments are lacking. In the best-case scenarios, sponsors complete confirmatory trials promptly and provide evidence to verify the drugs’ clinical benefits. In those cases, FDA enables patients to access drugs that can help them and Medicare and Medicaid to pay for effective treatments,” the authors of the OIG report wrote.
But not all accelerated approval applications follow this path, and some sponsors do not promptly complete confirmatory trials, the report stated. “[S]ponsors may have little incentive to complete trials promptly once they can market a drug under accelerated approval. Likewise, patients may have little incentive to enroll in a confirmatory trial when the therapeutic treatment is already available,” the authors wrote. (RELATED: Study: 'Little incentive’ for drugmakers to complete confirmatory trials for accelerated approvals, Regulatory Focus 29 August 2022)
The report, the result of an OIG evaluation of the accelerated approval pathway, was spurred by the approval of aducanumab as an Alzheimer’s disease treatment based on surrogate endpoints without evidence of clinical benefit and over the concerns of an advisory committee of independent experts questioning evidence of effectiveness in aducanumab’s clinical trial program. (RELATED: FDA approves aducanumab for use in Alzheimer’s disease, Regulatory Focus 7 June 2021; Adcomm gives big thumbs down to aducanumab, Regulatory Focus 6 November 2020)
In August 2021, the OIG said aducanumab’s approval “raised concerns due to alleged scientific disputes within the FDA, the advisory committee's vote against approval, allegations of an inappropriately close relationship between the FDA and the industry, and the FDA's use of the accelerated approval pathway” when announcing its intent to evaluate the accelerated approval pathway. (RELATED: HHS OIG to review FDA’s use of accelerated approval pathway, Regulatory Focus 4 August 2021)
OIG’s report examined 278 drugs approved by the FDA Center for Drug Evaluation and Research (CDER) between 1992 and December 2021 to estimate the number of drug applications that completed confirmatory trials. The authors of the report also evaluated Medicare and Medicaid claims data between 2018 and 2021 for drug applications that received accelerated approval but had not yet completed confirmatory trials.
The authors of the report found 104 drug applications (37.8%) have not completed confirmatory trials, 35 drug applications (33.6%) had one or more trials that missed a completion date, and 4 drug applications had significantly passed the originally-planned clinical trial completion date by between 5–12 years. For the 139 drug applications (50.0%) where confirmatory trials were completed, the average time to completion was 48 months.
The report also found a lot of activity within the accelerated approval pathway had occurred within the last few years. Of all accelerated approvals granted since 1992, 70 of 278 (25.1%) occurred between 2020 and 2021. The authors of the report noted 35 drug applications (12.5%) were withdrawn since 1992, but 18 of 35 drug application withdrawals (51.4%) had occurred since January 2021. (RELATED: FDA approved more first-in-class drugs, gave more accelerated approvals in 2021, Regulatory Focus 7 January 2022)
OIG examined Medicare and Medicaid spending for the 35 drug applications with pending confirmatory trials and discovered that more than $18 billion was spent between 2018 and 2021, with Medicare Part B and Part D making up $14 billion, Medicare Part C comprising approximately $6 billion, and Medicaid spending totaling $3.6 billion.
“These estimates demonstrate that Medicare and Medicaid are spending billions of dollars on drugs that have yet to verify a clinical benefit,” the authors of the report said.
For its part, the US Food and Drug Administration (FDA) told OIG it is addressing the drugs with lapsed confirmatory trial completion deadlines but explained the process to withdraw a drug from accelerated approval is “lengthy and contentious.”   
“These challenges can result in drugs staying on the market—and being administered to patients—for years without the predicted clinical benefit being verified,” the OIG report stated.
“Ensuring that FDA has the tools to effectively administer the accelerated approval pathway is crucial to FDA’s mission to protect the public health by ensuring the safety, efficacy, and security of human drugs and biologics,” the authors said.
Previous defenses, criticisms of accelerated approval
The data in the report are similar to a recent paper published in Therapeutic Innovation & Regulatory Science in August 2022 where a group of authors from Amgen reached similar findings but drew different conclusions, arguing that the program is working as intended and that about half of accelerated approval drugs get converted to traditional approvals. (RELATED: Study: Accelerated approval pathway working as intended in most cases, Regulatory Focus 10 August 2022)
“Concerns voiced recently about the program are based on a small number of examples, and do not reflect overall management of the accelerated approval program over its 30-year history, particularly improvements seen in the last decade in the time from accelerated approval to conversion,” the authors wrote in their paper.
FDA have also defended their rationale for approving aducanumab in the past, noting the agency approved the drug because the benefits outweighed the risks for patients and there was an unmet need for Alzheimer’s disease treatments in the market. (RELATED: FDA defends Aduhelm's accelerated approval, while others call for reform, Regulatory Focus 14 July 2021)
Others have criticized the agency’s timeliness in pulling drugs from the market after missing confirmatory trial deadlines. FDA’s advisory committees have also shown reluctance to pull accelerated approval status from some drugs after they fail to show evidence of clinical benefit in pre-agreed confirmatory trials. (RELATED: ODAC recommends pulling 2 of 6 accelerated approvals, Regulatory Focus 30 April 2021)
Regarding the impact of drugs granted accelerated approval have on Medicare and Medicaid spending, some researchers have argued these drugs exclusive to accelerated approval compromise a small overall percentage of Medicare spending, but should still be priced low while confirmatory trials are being conducted. Benjamin N. Rome, of the Program on Regulation, Therapeutics, And Law (PORTAL) research group, told Regulatory Focus in an interview in December 2021 that “it’s a reasonable idea for policy makers to target lower prices for accelerated approval drugs until the clinical benefit has been confirmed using clinical endpoints that matter to patients.” (RELATED: Exclusive accelerated approval drugs comprise ‘relatively small share’ of Medicare spending, Regulatory Focus 6 December 2021)
Proponents for reform of the accelerated approval pathway have suggested several changes to the program, such as requiring FDA to hold advisory committee meetings for drugs granted approval under the program and giving FDA authority over endpoints set in confirmatory trials. (RELATED: Expert proposes changes to accelerated approval reforms in user fee bills, Regulatory Focus 8 June 2022)
OIG report


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