The accelerated approval pathway brings drugs to market faster for diseases with unmet need, but high costs and uncertainty about efficacy and safety present challenges for payers, providers, and patients. Speakers reviewed the history of the pathway and several proposed reforms in a session at AMCP Nexus 2022.

Established in 1992, the accelerated approval program was established to provide therapies for patients with serious conditions and unmet need. Drugs approved through this pathway may provide a novel therapy where none exist or may have a meaningful advantage over available therapies, said Leslie Fish, RPh, PharmD, vice president of pharmacy, IPD Analytics.

“It was really in response to the AIDS epidemic,” Dr Fish said. “They had to get drugs to patients faster because patients were dying very quickly.”

The US Food and Drug Administration (FDA) has the same requirements for phase 1 and 2 studies for both accelerated approval and standard review processes. But in standard review, manufacturers are also required to provide data from two phase 3 trials confirming safety and dosing.

Additionally, accelerated approval is typically granted based on surrogate endpoints, which are endpoint substitutes that may be used when clinical outcomes take a long time to study or it is widely recognized that the surrogate endpoint predicts long-term benefit. In osteoporosis, for example, bone mineral density is a surrogate endpoint, Dr Fish said.

By requiring shorter, smaller, and fewer studies, the accelerated approval pathway allows products to be brought to market sooner, but not necessarily for a cheaper price.

“Pharmaceutical companies…felt that if they shortened the studies and could start using surrogate markers, drugs would not be as expensive because the trials would not be as expensive. That actually did not play itself out,” Dr Fish said.

Since the pathway’s establishment, 307 indications have been granted accelerated approval. Most drugs granted accelerated approval between 1992 and 2021 are not for novel drugs but rather for new indications for drugs already on the market, said Michelle Rogers, PharmD, BCPS, director of clinical pharmacy, IPD Analytics.

“In the last 2 decades, the pathway has really been used for oncology products,” Dr Rogers said. “If you look at the span of 30 years, one quarter of these [indications] were actually approved in just the last two years.”

In 2021, most indications approved through this pathway were first in class (42%) or designated orphans (72%), Dr Rogers said.

Five non-oncology drugs are in the accelerated approval pipeline, Dr Rogers said, including lecanemab and donanemab for Alzheimer disease; tofersen for amyotrophic lateral sclerosis; delandistrogene for Duchenne muscular dystrophy; and sparsentan for immunoglobulin A nephropathy.

Confirmatory Study and Withdrawal Delays

The accelerated approval program requires manufacturers to conduct post-marketing confirmatory studies to verify the drug results in a clinical benefit. If the confirmatory trial fails, Dr Fish said, an indication may be withdrawn.

Since 1992, 11% of indications granted accelerated approval have been withdrawn, while 51% have been converted, Dr Rogers said. The remainder (38%) have not yet been converted.

“One of the biggest challenges with accelerated approval is…there have been a lot of reports of delays in trials being completed,” Dr Rogers.

Confirmatory trials may be delayed due to the pandemic or the length of time it takes to recruit patients, or manufacturers may need more time to revise the study protocol or analyze data.

A 30-year analysis conducted by NPR revealed 50 (42%) currently outstanding confirmatory trials started at least 1 year after approval or had not begun at all. Nineteen trials had not started 3 years after accelerated approval, 33 (25%) trials were running at least 1 year behind on due dates, and over one-fourth (28%) of the trials had no data related to whether they had started.

An ICER report spanning 1992 to 2016 showed 13% of accelerated approval indications were on the market a median 9.5 years without confirmatory evidence, Dr Rogers said.

Indication withdrawals may also be delayed, although the time to withdrawal has shortened over the years. The median time from the date of initial approval to the date of withdrawal was 10.4 years between 1992 and 2001 but dropped to 3.5 years between 2012 to 2021.

Dr Fish also emphasized that incentives are misaligned between the FDA and pharmaceutical manufacturers. Manufacturers have no incentive to complete confirmatory trials if data suggests the drug is not effective, because this will likely result in an indication withdrawal.

“If you are the manufacturer, there is really no incentive for you to hurry that along because the drug is being used and generating revenue for you. The FDA has had very little teeth in trying to get companies to [complete] the studies,” Dr Fish said.

Evidence and Reimbursement Challenges

The accelerated approval pathway presents other challenges and limitations, such as a lack of clinical efficacy and safety data and unclear labeling, especially regarding unknown side effects. Additionally, surrogate endpoints may not always be an accurate predictor of clinical efficacy.

Patients and physicians also may lack knowledge about the accelerated approval process, which can interfere with informed decision making in the clinical setting.

“Health care personnel—physicians, prescribers—do not understand how much they don’t know. Likewise, it’s really not conveyed that well to patients,” Dr Fish said.

Cost is also a concern, as stakeholders may be overpaying for products that have unknown value, and many medications granted accelerated approval are extremely expensive, Dr Fish said.

A GoodRx pricing analysis showed drugs with accelerated approval have 26% more price increases over 10 years compared to other medications. Dr Fish emphasized the impact this has on Medicaid plans, since they are required to pay for all FDA-approved medications and cannot limit coverage due to efficacy concerns.

On top of high costs, payers must also navigate challenges related to guideline recommendations, Dr Rogers said.

“Sometimes, even if confirmatory trials have not shown clinical benefit, even sometimes despite the withdrawal of approval, clinical guidelines continue to highly endorse these therapies,” Dr Rogers said, citing a retrospective, observational study published in BMJ in 2021.

“That has important implications. We use guidelines for policy development; in some cases, they could be used for Medicare reimbursement,” she said.

Proposals for Reform

Dr Fish and Dr Rogers reviewed some proposed reforms intended to improve the pathway but noted each reform comes with pros and cons.   

Suggestions include strengthening the selection of surrogate endpoints, which could improve certainty about efficacy and safety but may require prespecified thresholds for change that are too high, Dr Rogers said.

Label alerts and enhanced patient materials can foster transparency and discussion about uncertainty of the evidence, but it is unknown whether patients may find this information helpful or change their expectations and approach to treatment.

To speed up approval conversion and bolster accountability, some stakeholders have suggested more frequent updates, real-world evidence requirements, and other solutions for improving post-approval studies.

“[Current] House of Representative and Senate bills both address this expedited withdrawal issue, and one of the bills actually goes on to say, could we have an automatic withdrawal of the application if the manufacturer doesn’t meet the timeline for the confirmatory study?” Dr Rogers said. “But there are always going to be issues with studies, so would that require extensions to the study timelines?”

Patient recruitment can be difficult for confirmatory studies since they are conducted with drugs that are already approved, and these proposals also would require more staffing and resources from the FDA, Dr Rogers said.

Additionally, stakeholders have proposed reimbursement reforms such as increasing federal rebate levels, discounting drugs for Medicare, and limiting pricing until full approval. Some have suggested using outcomes-based contracts to pay for the drugs, but Dr Rogers said this may complicate the drug development process.

“There could be less incentives for manufacturers to use the accelerated approval pathway, particularly for companies that may only have one or two products for rare diseases on the market. Furthermore, could this have a negative impact on drug innovation altogether? With outcomes-based contracts, there are complexities and an unclear impact,” Dr Rogers said.

Some states hope to exclude Medicaid coverage of low-value drugs, such as Massachusetts, which in 2017 requested the Centers for Medicare & Medicaid Services (CMS) waive the obligation of dispensing accelerated approval medications. However, CMS did not grant the waiver. 

Stricter utilization management in the oncology and rare disease spaces may limit costs, Dr Fish said, but it remains unclear what solutions will work best.  

“None of these are the magic bullet. These are relatively simple fixes, but some of these might require big changes to the pathway altogether,” Dr Rogers said.