The hardest drugs to get through prior authorization share a few common characteristics: 

• high cost
  
  

• documentation-heavy criteria
  
  

• and coverage policies that vary widely by plan

Transaction-level data from 2024 shows that among branded prescriptions initially rejected by prior authorization, only 54% were ultimately approved, and only 35% of those rejections were resolved the same day.

In this article, you’ll explore the top 7 hardest drugs to get through prior authorization in 2026.

The 7 Hardest Drugs (and Classes)

1. Weight-Management GLP-1s

No drug class combines every access obstacle the way obesity-indication GLP-1s do. Coverage is the first issue. KFF found 82% of Marketplace plans covered Ozempic for diabetes while just 1% covered Wegovy (the identical semaglutide molecule) and Medicare Part D is barred by statute from covering drugs used for weight loss. Employer-sponsored plans add another layer. Weight-loss coverage is a benefit-design choice, and most employers opt out. A 2026 International Foundation of Employee Benefit Plans survey found that while more than 90% of employers cover GLP-1s for diabetes, only about 36% cover them for weight loss.

Where coverage exists, the criteria stack up: BMI thresholds with clinician-measured values inside a recent window, ICD-10-coded comorbidities, and documented lifestyle intervention. The result is that roughly 45% of initial requests are denied, with first-submission approval rates as low as 29-34% for Wegovy on some plans.

Why it's hard: Multi-part criteria brings multiple ways for an otherwise eligible patient to fail on paperwork alone. The most common denial reason is insufficient documentation of a structured 3-6 month lifestyle intervention.

2. Tirzepatide

In a 2026 JAMA Health Forum analysis of over 200,000 initially rejected branded prescriptions, tirzepatide had the lowest ultimate approval rate, at 49%, of the 10 most-dispensed molecules in the sample. That covers both Mounjaro (type 2 diabetes) and Zepbound (weight management). One of the reasons is that CVS Caremark removed Zepbound from its standard commercial formularies effective July 1, 2025, with Wegovy as the preferred weight-management GLP-1. Relief is scheduled, though, and CVS Caremark will add Zepbound back to its commercial formularies as an additional preferred option on October 1, 2026, a change that should meaningfully improve tirzepatide approval chances for plans that adopt it.

Why it's hard: Tirzepatide sits at the intersection of high list price, explosive demand, and dual indications that invite scrutiny of every request. Even the diabetes indication draws careful review because plans work to distinguish it from off-label weight-loss use.

3. Oral Oncology Drugs

An analysis found the share of covered brand-name cancer drugs subject to utilization management rose from 68% in 2016 to 85% in 2020, which is the largest increase among the five therapeutic areas examined.

A Journal of Clinical Oncology study cited in the same analysis found that when Part D plans imposed new PA requirements on oral anticancer drugs, patients already stable on therapy experienced an average 10-day fill delay with increased odds of discontinuation within 120 days.

Why it's hard: Renewal reviews hit patients mid-treatment, and documentation requirements (staging, biomarkers, prior lines of therapy) are extensive.

4. Non-Preferred Biologics

Within most biologic classes (TNF inhibitors, IL-17s, IL-23s) plans designate one or two preferred products. Prescribe a different biologic in the class and step therapy usually applies. The request is reviewed against whether the patient has first tried, and had an inadequate response to, the preferred agent. That's the core reason non-preferred biologics see lower approval rates. Many denials are step-therapy determinations redirecting the prescription to the preferred product, not judgments that the requested drug is inappropriate.

Research cited by Trilliant Health found step therapy applied in 38.9% of specialty drug coverage policies across 17 large commercial plans and 55.6% of those protocols were more stringent than the corresponding clinical guidelines, with only 34% consistent with them.

Why it's hard: Approval hinges on documenting a treatment history that satisfies the plan's preferred-agent sequence: drug, dose, duration, and reason for discontinuation of each step; which may exceed what the guidelines themselves ask for. Missing step-therapy documentation is also a major driver of extended timelines. It can add 5-10 business days to a specialty review. Before writing for a non-preferred agent, it's worth checking whether the preferred biosimilar or originator is clinically acceptable.

5. Newly Launched Specialty Drugs

New-to-market drugs face the heaviest scrutiny. Two-thirds of new drugs approved from 2013 to 2017 and covered in Medicare Part D required prior authorization from at least one large insurer and for 40% of those drugs, the PA criteria were more restrictive than the FDA label itself.

Why it's hard: Early in a launch, plans haven't yet built confidence in real-world value, criteria are still being written and rewritten, and electronic PA question sets may not even exist yet. This is often because the drug hasn't completed the plan's Pharmacy and Therapeutics (P&T) committee review, the formal process that establishes formulary placement and coverage criteria. Until then, requests route to manual review queues or sit behind outright new-to-market blocks, like the one CVS Caremark applied to the oral GLP-1 Foundayo until June 2026.

6. Off-Label Prescriptions

Any drug prescribed outside its FDA-approved indication lands in the hardest tier, regardless of the molecule. Coverage policies are anchored to labeled indications, so an off-label request typically requires individual medical review, supporting literature, and a detailed medical-necessity rationale rather than a standard question set.

There is, however, a defined evidentiary path, especially for Medicare. Under Medicare's coverage framework for label and off-label drug use (LCD L33394), an off-label use can qualify as a medically accepted indication when it's supported in a recognized drug compendium at a qualifying level:

• AHFS Drug Information (AHFS-DI): indication is supportive
  
  

• NCCN Drugs and Biologics Compendium: indication is Category 1 or 2A
  
  

• Micromedex DrugDex: indication is Class I, IIa, or IIb
  
  

• Clinical Pharmacology: indication is supportive
  
  

• Lexi-Drugs: indication is rated Evidence Level A

Commercial policies frequently reference the same compendia, so a qualifying listing is the strongest single piece of evidence an off-label submission can carry.

Why it's hard: There's no standard question set to satisfy. The strongest submissions lead with a qualifying compendium listing where one exists, add peer-reviewed evidence, and explain why labeled alternatives were inadequate for this specific patient.

7. Formulary-Excluded Brands: When There's No PA to Win

The standard formulary exclusion lists of the three largest PBMs, which together process nearly 80% of U.S. prescriptions, have each grown to more than 600 products, expanding from brands with generic equivalents to include biosimilars, specialty therapies, and oncology medications.

Why it's hard: An excluded drug requires a formulary exception request. This is a separate, less standardized process with its own evidentiary bar. Often the faster path for the patient is checking whether a covered on formulary equivalent exists before writing the script.

What the "Hard" Drugs Have in Common

The hardest drugs share three traits:

• Multi-part, documentation-heavy criteria: BMI windows and lifestyle records for weight management; staging, biomarkers, and prior lines of therapy in oncology; preferred-agent trial histories for biologics. Each requirement is an independent failure point per submission.
  
  

• Coverage variability: When formulary status differs plan to plan, or coverage is excluded, the same prescription can be routine for one patient.
   

• High cost plus high volume: The drugs drawing the most scrutiny are the ones reshaping pharmacy budgets, which is why review intensity has grown fastest exactly where prescribing has.

The encouraging part is that most of these denials are winnable. First-level appeals for GLP-1 medications are overturned roughly 35-45% of the time when submitted with adequate documentation, and in Medicare Advantage, 80.7% of appealed denials were overturned in 2024, yet only 11.5% of denials are ever appealed.

Let Develop Health Take On Your Hardest PAs

Our prescription AI extracts the evidence these submissions demand directly from your clinical notes, and pre-fills each payer's question set with citations so multi-part criteria are satisfied on the first pass. Most customers are able to reduce time spent filling out a prior authorization by 80%. 

If a denial comes back, the system analyzes the stated reason, drafts a clinically grounded appeal, and submits it if you elect to do so. 

Book a demo to see how it works.

Frequently Asked Questions

What is the hardest drug to get through prior authorization? 

By the numbers, tirzepatide (Mounjaro/Zepbound). It had the lowest ultimate approval rate, at 49%, among the 10 most-dispensed molecules in a 2026 JAMA Health Forum analysis. As a category, weight-management GLP-1s face the steepest overall odds.

Why do weight-loss GLP-1 prior authorizations get denied so often? 

Mostly documentation. The top denial reasons are missing lifestyle-intervention records, BMI documented outside the required window, and comorbidities without proper ICD-10 coding, which are administrative gaps.

Is it worth appealing a denial for these drugs? 

Yes. In Medicare Advantage, 80.7% of appealed denials were overturned in 2024 (a figure spanning all services and drug classes), yet only 11.5% of denials were appealed. For specialty drugs, peer-to-peer reviews overturn denials at rates up to 75%, and first-level GLP-1 appeals specifically succeed roughly 35-45% of the time with adequate documentation. Even simple persistence pays off: 54% of all branded prescriptions initially rejected by PA in 2024 were ultimately approved.

Do coverage odds differ by patient population? 

Yes. In the 2026 JAMA Health Forum analysis, ultimate approval rates for initially rejected branded prescriptions were lowest for Medicaid beneficiaries (48%) versus 60% in Medicare, and patients with multiple chronic conditions were most likely to face delays.

Can I avoid these hard PAs entirely? 

Sometimes. Checking real-time benefit data before prescribing reveals whether a covered, preferred alternative exists, and for excluded brands, that check can spare the patient another process.