Comparing a Clinical Trial to Standard Treatment

Standard treatment is the therapy that experts currently accept for your cancer. Its results are already known, published, and counted. A clinical trial treatment does not have that record yet. If it did, there would be nothing left to study.

That asymmetry is the honest starting point. You are not choosing between two measured options. You are choosing between a measured option and a question.

That does not settle it. A measured option with poor numbers may be worse than a promising question.

Phase 3 trials, the ones that compare a new treatment against current standard therapy, assign people to groups by chance. That is randomization. A computer usually does it, and as the National Cancer Institute (NCI) puts it, "neither you nor your doctor can choose which group you will be assigned to."

People reasonably ask how a doctor can leave that to chance. The answer has a name: clinical equipoise. The idea, set out by Benjamin Freedman in the New England Journal of Medicine in 1987, is that randomizing is ethical when there is genuine "uncertainty within the medical community as a whole" about which option is better. Not certainty in your doctor's head, but disagreement across the field.

An NIH Clinical Center bioethics lecture puts the test in everyday terms. Your doctor may lean toward treatment A, but "if your appointment had been with my colleague down the hall, she would have recommended B."

So ask your oncologist: is the field genuinely split on this, or do you personally think one arm is better?

The fear that stops many people is the placebo, an inactive look-alike treatment. NCI is clear that "placebos are rarely used in cancer treatment clinical trials."

When they do appear, it is in one of two situations. Either no standard treatment exists for that cancer, or the trial uses an add-on design: everyone gets the standard treatment, and one group also gets the new drug while the other also gets a placebo. The comparison is standard care versus standard care plus something. Nobody is left untreated.

You must be told in advance if a placebo is part of the design.

• Phase 1 enrolls around 15 to 30 people. It asks whether the treatment is safe, what side effects it causes, and how high a dose people can tolerate. There is usually no standard-treatment arm. You are not comparing anything; you are the first data.
• Phase 2 enrolls roughly 50 to 100 people and asks whether the treatment appears to work against the cancer.
• Phase 3 enrolls 100 to several thousand and is the true head-to-head against standard therapy.
• Phase 4 happens after FDA approval and tracks long-term safety in large, diverse populations.

So "should I take the trial or the standard treatment?" is a different question in phase 1 than in phase 3. In phase 3 you are choosing between two credible options and letting chance decide. In phase 1 you are testing something largely unknown, usually because standard options have run short.

Costs split into two buckets. Mixing them up causes most of the billing panic.

Patient care costs, also called routine costs, are what NCI describes as "costs that you would pay even if you weren't in a trial": visits, hospital stays, standard drugs, scans, labs. These are "often covered by health insurance."

Research costs are the trial-specific ones: the investigational drug, extra scans done only for the study, research-only lab work. NCI notes that "often these costs are not covered by health insurance. But they may be covered by the trial's sponsor."

Federal law backs up the first bucket. Under section 2709 of the Public Health Service Act, added by the Affordable Care Act, non-grandfathered health plans may not deny a qualified person participation in an approved clinical trial for cancer or another life-threatening condition. They may not "deny (or limit or impose additional conditions on) the coverage of routine patient costs" for services provided in that trial, and they may not discriminate against someone for taking part. This applies to plan years beginning on or after January 1, 2014. Grandfathered plans, meaning older plans that predate the law, are outside this requirement.

Medicare has its own rule, national coverage determination 310.1, which covers routine costs defined as "items and services that are otherwise generally available to Medicare beneficiaries" in a qualifying trial. It specifically does not cover the investigational item itself, "items and services provided solely to satisfy data collection and analysis needs," or anything "customarily provided by the research sponsors free-of-charge." NCI states that Medicaid "covers all routine patient care costs in a clinical trial."

Ask your insurer three things in writing: is this an approved clinical trial under your rules, is prior authorization needed, and is the treating site in network.

Trial schedules are usually heavier than standard treatment schedules. More visits, more blood draws, more imaging, and often a site that is farther from home.

Mileage, parking, hotel nights, meals, lost work time, and childcare or elder care are real and are not routine patient costs. Some sponsors reimburse travel. Ask whether reimbursement comes upfront or after the fact, because that matters if money is tight.

Ask both, and compare the answers:

If the cancer grows on the trial treatment, what do I do next? If it grows on standard treatment, what do I do next?

Sometimes the trial preserves your options and sometimes it uses one up. A trial that requires you to have had no prior treatment for a stage may close off a standard drug you could still take later. A trial that accepts heavily pretreated patients may cost you nothing in future options. This ordering question is often more important than the trial's headline results.

• What is the standard treatment here, and what does it typically achieve for someone in my situation?
• What phase is this trial, and is there a standard-treatment arm?
• If it is randomized, what are my chances of each arm, and is a placebo involved?
• Which parts will my insurance be billed for, and which parts does the sponsor pay?
• How many extra visits, scans, and blood draws does the trial add?
• What would take me off the trial, and what would I do then?
• Does joining this trial close off any treatment I could otherwise have later?

• National Cancer Institute — How Do Clinical Trials Work?.
• National Institutes of Health Clinical Center — Randomized Clinical Trials: Clinical Equipoise.
• National Cancer Institute — Insurance Coverage and Clinical Trials.
• Centers for Medicare & Medicaid Services — Affordable Care Act Implementation FAQs, Set 15.
• Centers for Medicare & Medicaid Services — NCD 310.1, Routine Costs in Clinical Trials.
• National Cancer Institute — What Are Cancer Clinical Trials?.

Helpful next pages include Clinical Trial vs. Standard Treatment, What Is 'Standard of Care' in a Trial?, What Is Randomization in a Clinical Trial?, Questions to Ask About a Clinical Trial, Questions Before Signing Clinical Trial Consent, Clinical Trial Visit Schedule: What to Check.