What's the REAL Promise You're Making to Patients?
By the end of this module, you'll be able to:
Endpoints are not just numbers on a page; these are promises about what a drug will do for real people with real lives. Every clinical trial must be designed to answer ONE big question, which is formally defined as the primary endpoint. This single question serves as the "North Star" for the entire study, driving its design, sample size, and statistical analysis. Focusing on a single primary endpoint is crucial because introducing multiple primary endpoints significantly increases the risk of getting a "false positive" result, a statistical pitfall known as Type I error.
For example, in Oncology, the gold standard is often Overall Survival (OS); for Obesity, it’s percent body weight reduction, such as the -20.2% weight loss seen with Tirzepatide in SURMOUNT-5; and for HIV Prevention, the endpoint is HIV incidence, which saw ZERO infections in the PURPOSE 1 trial.
A major sign of potential trouble in a clinical trial is post-hoc changes to the primary endpoint. If a company alters the primary endpoint after the trial has begun, this often suggests the original, pre-specified measure was not met, indicating a potentially failed study.
Secondary endpoints represent the additional, "nice-to-have" benefits of a drug, showing effects beyond the main question posed by the primary endpoint. They assess valuable improvements like HbA1c reduction or better physical function. However, if a drug misses its primary endpoint, its secondary endpoints should be met with caution. In some rare diseases, drugs have been approved on successful secondary endpoint(s) even when primary endpoints had failed, although the sustainability of such approval remains risky.
| Drug (Generic) | Company | Indication | Original Approval | 2025 Status | Sources |
|---|---|---|---|---|---|
| Sohonos (palovarotene) | Ipsen | Fibrodysplasia ossificans progressiva (FOP) | Aug 2023 despite failed Phase III endpoints |
FDA-approved; label updated 2025; no generics |
FDA Label (2025) EMA Summary |
| Elevidys (delandistrogene moxeparvovec) | Sarepta Therapeutics | Duchenne muscular dystrophy (ages 4–5) | Jun 2024 accelerated; confirmatory trial missed endpoint |
Approved; 2 patient deaths (2025); sales flat; confirmatory trial ongoing |
Sarepta Q3 2025 Earnings FDA Safety Update |
| Qalsody (tofersen) | Biogen | SOD1-ALS (rare ALS subtype) | Apr 2023 accelerated; surrogate endpoint |
Approved; expanded to UK (Jul 2025) & Canada (Mar 2025) |
UK MHRA Approval Biogen Canada Press |
| Aduhelm (aducanumab) | Biogen / Eisai | Alzheimer’s disease | Jun 2021 controversial surrogate data |
DISCONTINUED – withdrawn Nov 2024 |
Biogen Official Discontinuation FDA Archive |
When communicating results, emphasize the success of the primary endpoint first: "Doctor, our primary endpoint was overall survival, and we extended life by a median of 14 months. Our secondaries showed quality of life improvements as well—would you like to see that data?"
If a rare disease drug had failed its primary endpoint but approved on secondary endpoint(s), don't hide the miss — own it transparently. Lead with clinical impact and regulatory validation, and ask questions that invite engagement with practice-relevant evidence: "Doctor, I know the Phase 3 primary endpoint wasn't met. But this drug was still FDA-approved and is now expanding in use because of strong signals in secondary endpoints and an unmet need. ~40% of patients had durable responses and patients' quality of life improved significantly. Would you like to see the real-world registry data or the updated prescribing trends?"
Composite endpoints combine multiple clinical measurements or events (X, Y, and Z) into ONE endpoint. These endpoints are frequently used when the individual events are rare, or when trials would otherwise take an impractically long time to complete, which is common in cardiovascular research. The major risk, however, is that if the components combined are NOT equally severe, the results can be misleading or lead to overestimation of benefit.
Regulatory bodies now mandate that companies must report EACH component separately. Sales representatives must be alert to trials where a less severe component (such as an emergency room visit) drives all the observed statistical benefit.
Surrogate endpoints function as substitute markers (like Blood pressure or HbA1c) for "true" clinical outcomes like survival or cure. These markers allow for faster trials (months instead of years) and result in lower cost. The critical risk is that the surrogate measure must reliably CORRELATE with the true, long-term clinical outcome.
When this correlation breaks down, drugs can fail spectacularly. For instance, Relyvrio for ALS initially showed a slowing of functional decline based on the Phase 2 surrogate, but the subsequent Phase 3 trial showed NO benefit on survival or function (p=0.667), leading to the drug's withdrawal.
Always check if a surrogate endpoint has been validated to predict patient benefit. Surrogate endpoints are useful in clinical studies but carry significant risk. The FDA has provided a Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure on its website.
Patient-Reported Outcomes (PROs) are data collected directly by the patient about their symptoms, function, and quality of life, effectively answering the question: "How do YOU feel?". This encompasses measures like pain scales, fatigue assessments, and physical function surveys. In oncology, patients constantly weigh the benefit of survival against the burden a therapy places on their daily lives.
PROs are gaining importance in the modern clinical landscape. First, the FDA requires PROs for many drug approvals, demanding evidence that the treatment improves patients' qualities of life, not just physical longevity. Second, RWE initiatives often reveal a critical gap between adverse events reported by investigators and those reported by patients. For instance, real-world non-small cell lung cancer (NSCLC) patients reported fatigue at a rate of 78%, while the FLAURA clinical trial reported it at only 21%.
Real world patients often have different experiences with symptom severity and quality of life than closely monitored, clinical study patients. Insurance companies and payers now utilize PRO data to determine whether a high-cost treatment's expense is justified by a corresponding, demonstrable improvement in the patient's quality of life.
Make the PRO data CONCRETE in your clinical conversation: "Doctor, 78% of patients reported significant improvement in physical function—meaning they could walk further, climb stairs without shortness of breath, and had more energy for daily activities."
Time-to-event endpoints are used to capture the duration of an event, rather than a simple binary outcome. Survival, for example, may be the difference between "6 months vs. 6 years.". These endpoints are essential for measuring the longevity of a treatment's effect. Key examples include Overall Survival (OS), Progression-Free Survival (PFS), and Time-to-First-Exacerbation. These metrics are all meaningful for patients making informed decisions about their treatment plans within the context of personal lives.
The shift to remote monitoring has allowed moving beyond "clinic snapshots" of the past. FDA now accepts digital endpoints for drug approval collected from tools like Wearables or Continuous Glucose Monitors (CGMs). These technological advances provide a significant advantage of 24/7 data capture. CGMs, for example, provide up to 288 readings per day compared to a single clinic finger prick. This continuous data capture allows clinicians to detect clinically significant changes EARLIER than traditional measures. Automated data capture also reduces patient burdens of having to remember "reporting" significant health events, and even facilitates identification of "early warning" precursor events that the patient may not be aware of.
To be an effective and credible scientific resource, a sales representative must:
THE BIG PICTURE: Endpoints are fundamentally promises to patients about what a drug will deliver. Know what your drug promised. Know if it delivered. And know how to concisely explain BOTH to a physician on a busy Monday.
Oncology & Patient-Reported Outcomes (PROs):
1. Benbow JH, Rivera DR, Lund JL, Feldman JE, Kim ES. Increasing Inclusiveness of Patient-Centric Clinical Evidence Generation in Oncology: Real-World Data and Clinical Trials. ASCO Educational Book. 2022:42:116-126.
2. Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018:378:113-125.
Obesity/Metabolic Trials:
3. Aronne LJ, Horn DB, le Roux CW, et al; SURMOUNT-5 Trial Investigators. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med. 2025;393(1):26-36. doi:10.1056/NEJMoa2416394. PMID: 40353578.
HIV Prevention Trials (Lenacapavir):
4. Bekker LG, Das M, Abdool Karim Q, et al; PURPOSE 1 Study Team. Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women. N Engl J Med. 2024;391(13):1179-1192. doi:10.1056/NEJMoa2407001. PMID: 39046157.
Surrogate Endpoint Failures (ALS):
5. Paganoni S, Macklin EA, Hendrix S, et al. Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. 2020;383(10):919-930. doi:10.1056/NEJMoa1916945. PMID: 32877576.