In one of the opening sessions of AMCP 2023, Yuqian Liu PharmD, senior director, specialty clinical solutions, and Simone Ndujiuba PharmD, BCOP, director, clinical strategy and innovation, oncology, both from MagellanRx Management, discussed accelerated approval pathways, how they differ from traditional approval pathways, and the impact the process has on organizations and patients.

Dr Liu spoke first, outlining some of the major differences between traditional and accelerated approval pathways. She began by asking attendees if accelerated approval poses challenges to their organization. The majority of attendees who answered the digital poll agreed it does. 

Implemented in 1992, the FDA’s Accelerated approval program was designed to allow for earlier approval of therapies for serious or life-threatening conditions. 

“The number one key difference is the use of the surrogate endpoint. Traditional pathway approval requires minimum of 2 phase 3 clinical trials before approval vs the accelerated pathway where a confirmatory or phase 4 trial is completed after approval,” said Dr Liu, noting the latter is a conditional approval. 

There is solid data demonstrating accelerated approval has benefited multiple patient populations. 

“However, as managed care professionals, we do also need to think of the flip side,” said Dr Liu. “For accelerated approvals, our biggest challenge, when it comes to evaluating these products is the limited amount of clinical data available at the time of approval. We have smaller, lower quality studies that we’re looking at—a huge lack of long-term data. The surrogate markers only serve as predictor and are not exemplifying a true clinical outcome of the product or the true clinical benefit. 

Accelerated Approval Management Considerations

Some of the primary challenges associated with accelerated approval formulary decision making includes the following:

• Limited safety/efficacy data: some products come to market with very early phase 1 or 2 trial data. In oncology, some drugs are approved with only a single arm trial which limits information on value and long-term benefit of the drug. 
• Use of surrogate endpoints: Dr Liu notes this is a highly debated point in accelerated approval and will remain ongoing. Surrogate endpoints create difficulties in assessing real-world applicability and clinical benefit. Without long-term benefit, cost is almost impossible to factor into the decision making.
• Costs: Accelerated approval products tend to be costly
• Confirmatory trials: “Thirteen percent of accelerated approvals have been on the market for a median of 9.5 years without confirmatory evidence,” Dr Liu emphasized, “This is what keeps me up at night. We have been giving some of our patients some of these products for 10 years without fully understanding the long-term benefits.”  
• Dealing with the aftermath of market withdrawal: Sometimes these products have approval withdrawn after new data comes to light. Withdrawals overall are slowly trending downward though which Dr Liu notes still creates a substantial cost burden to payers because of the concept of “covering with caution.” Payers may be spending money to cover products only for the product to be withdrawn. 

The US Centers for Medicare & Medicaid Services (CMS) approved coverage with evidence development, either a CMS-approved study or an NIH-supported trial. 

Dr Liu closed her portion of the session asking attendees to enter one challenge in managing an accelerated approval which created the following word cloud, which highlighted “lack” as one of the top challenges, which Dr Liu attributed to lack of evidence or clinical support. Other highly submitted words included “clinical,” “cost,” and “efficacy.”

Impact on Rare Diseases and Oncology

Dr Ndujiuba began the second half of the session defining the parameters for rare disease designation, the Orphan Drug Act of 1983, and the financial impact of caring for these patient populations.
“Direct and mortality costs are the biggest drivers of cost,” said Dr Ndujiuba, with the total cost estimate of $125 billion dollars for 24 rare diseases. When extrapolated for 227 rare diseases, she said the total cost was similar for top priority diseases. 

Rare diseased incur an estimated “$2.2 trillion annual cost for 8.4 million people in the United States” which Dr Ndujiuba explained would be enough money to treat 133 million people with standard, mass market diseases. 

Primary challenges in the rare disease populations are similar to challenges for the overall accelerated approval pathways, including an increasing number of improved gene therapies, challenges for payers assessing clinical value, designing coverage criteria, competition, and determining real-world outcomes and value. 

In terms of clinical value/approval, one of the most commonly used surrogate endpoints for accelerated approval pathways for oncology treatments, specifically, is objective response rate followed by progression free survival, disease free survival, time to tumor progression, invasive disease-free survival, and pathological complete response rate. 

Withdrawn drug or indications for oncology therapies after accelerated approval are especially costly to the health care system. For example, intravenous olaratumab, which received accelerated approval in late 2016, was withdrawn after a confirmatory trial did not demonstrate survival benefit. For 6 months of therapy under accelerated approval, olaratumab cost $106,100 and in 2018 generated more than $300 million in sales. 

Another example was atezeolizumbab, granted accelerated approval as second-line treatment of malignant urothelial carcinoma. More than 14,000 outpatient Medicare fee-for-service claims were processed before the drug was withdrawn. The average Medicare payment/claim was $6854. The full Medicare fee-for-service population estimate included 6200 paid claims, amounting to $46 million in Medicare expenditure for an indication with no confirmed evidence or clinical benefit.

Alzheimer Disease

Accelerated approvals grated to aducanumab-avwa or Aduhelm, for mild cognitive impairment or mild dementia in June 2021. The annual cost for a patient weighing 75kg is $28,500. 

This approval was based on decreased biomarkers which has been discussed extensively since and found to be not entirely predictive of an Alzheimer diagnosis, prompting some controversy. 

The total cost of care for patients with Alzheimer disease and dementia is expected to increase from $321 billion in 2022 to more than $1 trillion by 2050. 

Another recent accelerated approval for mild cognitive impairment or mild dementia was granted to lecanemab-irmb or Leqembi in January 2023. Its estimated to cost $26,500 annual. Its approval was also based on decreased biomarker, and clinical benefit from a phase 3 trial.

Both therapies are priced higher than the suggested cost-effectiveness annual list price range from ICER. 

CMS has implemented a number of policies particularly related to future FDA-approved monoclonal anti-amyloid antibodies, restricting coverage to patients who are enrolled in CMS-approved or NIH-supported trials. 

Overall, speakers concluded there are still challenges to overcome in this area, especially related to clinical trial endpoints to demonstrate value and collaboration between manufacturers and payers.