Calculating the Costs of Clinical Trials

Patients eager to contribute to research may not be fully aware of the hidden costs of trial participation

Of the three potential risks of participating in a clinical trial listed on the National Institutes of Health (NIH) website, two are related to the potential costs, hidden and otherwise: People who participate in clinical trials may be required to make more frequent visits to the doctor and/or need to travel farther for those visits, and some of the costs of participating in a trial may not be covered by health insurance.¹

Clinical trials of novel hematology and cancer drugs are designed to improve upon existing treatments, yet only a small proportion of patients with those conditions are enrolled. Older patients and minorities are largely underrepresented in cancer clinical trials. Studies also have shown that lower-income patients are up to 30% less likely to participate in clinical trials than higher-income patients – suggesting that cost represents a barrier to research.^2,3

Even when insurance companies and trial sponsors help to cover the costs of participating in clinical trials, patients – who dedicate substantial amounts of time and take significant risks to advance science – may find themselves out of luck once the trial ends. ASH Clinical News recently spoke with several clinical trial and ethics experts about the hidden costs of clinical trial participation, the prices of post-trial access to investigational drugs, and some of the steps being taken to ease this burden.

What's Covered, Doc?

"People making decisions about clinical trial participation are thinking about their treatment options inside and outside of clinical trials, and the money they may or may not have to pay for them," said Joseph Millum, PhD, of the Department of Bioethics at the NIH Clinical Center. "Being able to support people so that they don't have to worry about costs could make a big difference."

At the NIH Clinical Center, a hospital devoted entirely to clinical research, the costs of participating in a clinical trial are completely covered, Dr. Millum explained. A patient's medical insurance is not billed. There are no co-pays or co-insurance charges.

This is likely not the situation for people who participate in clinical trials conducted at academic or community medical centers.

Insurance policies for covering trial participation costs "can vary quite a bit," Dr. Millum said. For example, research costs – providing the experimental drug, conducting tests related to the research – are typically covered by the trial sponsor, he explained. "Other care that the patient receives that is part of the clinical trial but considered to be routine care for the patient's condition is usually covered by medical insurance … assuming the patient has medical insurance."

Coverage of routine care for cancer clinical trials was mandated by the Patient Protection and Affordable Care Act (ACA), which states that payers "may not deny (or limit or impose additional conditions on) the coverage of routine patient costs for items and services furnished in connection with participation in the trial."⁴

Private insurance companies and Medicare must cover routine patient costs for qualifying clinical trials. (See SIDEBAR for the long list of requirements that clinical trials must meet to qualify.) Coverage through Medicaid varies on a state-by-state basis, however, and defining "routine care" can be a bit of a gray area.

"If you are enrolled in a trial and having your blood drawn every week as part of the trial protocol, maybe you would be having blood drawn every two weeks as part of routine care, but how can we determine which of those draws are part of the trial and which are part of routine care?" asked Dr. Millum.

The language describing coverage of clinical trial participation also contains loopholes, where costs could fall outside the label of a "trial cost" or "routine cost." For example, a coverage determination guideline on UnitedHealthcare's website states that coverage is limited or excluded for "a service that is clearly inconsistent with widely accepted and established standards of care for a particular diagnosis."⁵ Aetna's website stipulates that "all applicable plan limitations for coverage of out-of-network care will apply to routine care costs in clinical trials."⁶ Cigna's clinical trial fact sheet notes that routine patient services, such as transplant-related services or select outpatient services, are managed the same way whether they are part of or outside of an approved trial – and are subject to the same precertification requirements.⁷

"I've heard anecdotal accounts of participants who find that their insurance is billing them for things that they thought were routine care," Dr. Millum said. "We know that, as a patient in the U.S. medical system, it can be baffling what [services] will cost until you actually see the bill. This happens within clinical trials."

In addition to mandating coverage, the ACA also mandated that payers could not deny a patient participation in an approved clinical trial.⁴ Denials still occur, said Jennifer Holter-Chakrabarty, MD, of the University of Oklahoma's Stephenson Cancer Center and vice chair of ASH's Committee on Government Affairs.

To evaluate how the ACA's mandate has affected clinical trial accrual rates, researchers surveyed more than 250 cancer research centers and community-based institutions in 2017 about the status of insurance denials, then examined patterns of delays and denials in a focused group of 77 participants.⁸ Most institutions (62.7%) had experienced at least one insurance denial in 2014, the year the ACA mandate went into effect, and academic centers were more likely to report trial denials than community sites. The most common reason provided for denial was the failure of insurance plans to cover trial participation. Other reasons included that the trial site was out of the provider network, or that the patient had a grandfathered plan that did not include coverage of clinical trials.

Dr. Holter-Chakrabarty said that recently she is seeing a disturbingly similar pattern in her practice.

"In the past year, there have been much more restrictive changes, with some insurance companies not allowing patients to go on clinical trials," Dr. Holter-Chakrabarty said. "One patient with testicular cancer was placed on a clinical trial where the standard-of-care arm received autologous transplant and he was told he could not participate. The treatment was considered ‘experimental' and the insurance wouldn't allow it."

Hidden Cost Figures

Even when participation in a clinical trial is approved by insurers, patients are still left with sizable out-of-pocket costs. For example, those with private insurance are responsible for co-pays, co-insurance, and deductible costs.

In addition to the medical costs, there are often ancillary costs associated with traveling to and from the treatment site. Many patients must drive to the trial site, paying for gasoline and tolls; once there, they may have to pay for parking, meals, and if necessary, overnight lodging.

"For more intensive trials, patients may have to give up full- or part-time jobs," said Joseph Mikhael, MD, MEd, from the Translational Genomics Research Institute (TGen), an affiliate of City of Hope Cancer Center. "We try to capture as many of these costs as possible when designing a trial, but whether they are covered will depend on the trial sponsor."

The personal costs of trial participation can reach hundreds and thousands of dollars, according to a recent survey by researchers at the University of Texas MD Anderson Cancer Center. Of 105 patients who had been participating in phase I clinical trials for at least one month, half lived more than 300 miles from the clinic, and about one-third required air travel to get to the clinic.⁹ The median monthly out-of-pocket cost for nonmedical expenses was $985 and for medical expenses was $475.

"If a patient is at the point of looking at a phase I trial, it is likely that someone is traveling with the patient," Dr. Millum said. "The costs for that caregiver might also include the cost of child care or lost wages, among other expenses."

For certain treatments, like chimeric antigen receptor T-cell therapies, a caregiver is required to accompany the participant because the patient is not allowed to drive. In addition, the caregiver and patient might need long-term lodging because the patient is required to be at the clinic for almost a month.

Financial access is a huge concern, according to Dr. Mikhael, who studies myeloma in under-served populations. "The African American population may account for roughly 20% of myeloma patients, but only 6% of the population enrolled on clinical trials," he said. "That participation rate is related not only to financial issues, but it is definitely one part of it."

The Trial Is Over. Now What?

In addition to costs of participating in a clinical trial, access to investigational drugs after a study ends and a drug becomes commercially available can be cost-prohibitive for patients. This became a major issue in the context of treatment for people with HIV, according to Dr. Millum.

"In the 1990s and 2000s, when many trials took place in low- or middle-income countries in sub-Saharan Africa, there was much debate about access to drugs," Dr. Millum said. "People questioned what happened to these patients after drugs were approved and participants were likely to not have access."

Now, many years later, studies sponsored by the NIH will often include information about drug access after the study ends, Dr. Millum noted. "As far as studies sponsored by private companies, there is quite a lot of variation in policies on post-trial access," he added.

The period between a clinical trial ending and a drug receiving marketing approval from the U.S. Food and Drug Administration (FDA) is a vulnerable time for patients. "Sometimes that bridging, that doughnut hole, is a huge gap for my patients, and we need to find a way to avoid that," said Dr. Holter-Chakrabarty.

Some clinical trial sponsors are pledging to provide access to drugs to fill that gap – but with considerable limitations. For example, Novartis has stated that it will include a post-trial access provision in all of its clinical trial protocols. And, when trial results show superiority of the investigational product to a comparator, patients who participated in and completed the trial will have free, post-trial access "until the product is commercially available and accessible locally."¹⁰

However, commercial availability does not equal access. A novel anticancer drug routinely costs more than $100,000 per year without insurance, with some more recent launches having a price tag of more than $400,000 for a year of treatment.^11,12 Even participants with Medicare Part D coverage without low-income subsidies may be stuck paying thousands of dollars out of pocket for a specialty tier drug.

In The Hill, Mikkael Sekeres, MD, MS, editor-in-chief of ASH Clinical News and director of the Leukemia Program at the Cleveland Clinic, recalled the devastating moment experienced by many patients when, "after devoting themselves to the trial requirements and jeopardizing their own health for the benefit of others, they are faced with the realization that access to their life-saving solution is being taken away."¹³

All too often, patients' reward for selfless participation is having to pay out-of-pocket for the drug they helped to bring to market or, if they have insurance, hoping that their plan helps covers the costs.

"In Ohio, where I live, the number of patients with health insurance has decreased dramatically in the past couple years," said Eric Kodish, MD, a bioethicist and professor of pediatrics at Cleveland Clinic's Lerner College of Medicine. Nationally, the rate of uninsured Americans is increasing as well, for the first time since the ACA went into effect in 2014.¹⁴

"In a situation where we have a declining number of people with health insurance, it would be ethically admirable for sponsors to commit to provide ongoing support for getting participants medication if they don't have insurance," Dr. Kodish said, "especially because patients who volunteer for clinical trials are fundamentally doing something to try to help others as well as themselves."

When asked for comment on the issue of post-trial access to investigational drugs, Andrew Powaleny, a Pharmaceutical Research and Manufacturers of America (PhRMA) representative, told ASH Clinical News that "with nearly 7,000 medicines around the globe in development, the biopharmaceutical industry is committed to making participation in a clinical trial a less onerous process for the participant."

While it is tempting to hold the trial sponsor completely responsible for providing these treatments, Dr. Millum noted, the lack of post-trial access to investigational drugs also should make people question the larger system of medical care in the U.S. In countries with state-run medical systems, for example, patients have greater access to treatment after clinical trials.

Pay for Play?

The problem of low rates of clinical trial participation is due to many factors, with costs being just one of them. Still, financial assistance could make a big difference in whether individual patients enroll in trials, the experts who spoke with ASH Clinical News agreed.

In 2018, the FDA updated its guidance to institutional review boards and clinical investigators on payment and reimbursement for clinical trial participants.¹⁵ Although it acknowledged that paying research subjects in exchange for their participation is a common practice, the FDA "does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence."

In contrast, institutional review boards "should be sensitive to whether other aspects of proposed payment for participation could present an undue influence, thus interfering with the potential subjects' ability to give voluntary informed consent."

According to Dr. Kodish, attaching financial incentives to clinical trial participation can muddy the waters, ethically speaking, when obtaining informed consent.

"Patients in research are sometimes confused and think of research as a treatment, a concept known as ‘therapeutic misconception,'" Dr. Kodish said. "Attaching a financial commitment to participation might remove a barrier to participation and help to mitigate therapeutic misconception, but payment beyond reasonable expenses could be coercive, and could pressure people into participating in trials."

Lifting the Burden

If coverage of these "hidden" costs is not included in the clinical trial protocol, there are other resources that patients can turn to for financial assistance.

The Leukemia & Lymphoma Society's Susan Lang Pay-It-Forward Patient Travel Assistance program offers qualifying patients $500 in financial assistance for approved expenses, such as ground transportation, tolls, gas, parking, and more. A co-pay assistance program also offers financial support toward the cost of insurance co-payments or premiums for prescription drugs. Its Urgent Need Program provides support to patients with blood cancers in acute financial need who are enrolled in clinical trials.

The American Cancer Society's (ACS') Hope Lodge offers patients and their caregivers a free place to stay when their best hope for treatment is in another city. The ACS' Road to Recovery program provides rides to and from cancer-related medical appointments for patients who otherwise might not be able to make their visits.

National programs like the Cancer Foundation Assistance Coalition, the HealthWell Foundation, and the National Foundation for Transplants can provide financial or fundraising assistance to patients in need. Locally, organizations like Catholic Charities, Jewish Social Services, Lions Club International, Lutheran Social Services, and the Salvation Army may also offer financial assistance.

Many pharmaceutical companies or specialty pharmacies have established financial assistance programs or foundations to provide patients in financial hardship with free access to medications.

Dr. Holter-Chakrabarty encouraged anyone interested in increasing trial participation to help their patients take advantage of these resources. At Stephenson Cancer Center, she recounted, staff realized that without making financial resources more readily available, they were never going to be able to help some of the underserved population of Oklahoma.

Stephenson's resources include five social workers and four patient navigators who work with the under- and uninsured populations to help them gain access to the necessary support to participate in clinical trials. The center also set up programs to support the state's Native American population, which accounts for about one-third of the center's trial participants.

"We have one of the highest recruitment rates in the nation, but we do it knowing that we can't have these individuals lose their houses because they are having to pay all these costs from the trial," Dr. Holter-Chakrabarty said.

Trial participation at the center also includes meeting with financial counselors, and patients are screened so that they are aware of costs at the onset.

"This can be very scary for them," she said. "So, once they have gone through financial screening, we do a secondary screen with our social workers and navigators to make sure we identify any other resources they are going to need."

The intention is to give people a full picture of clinical trial participation, not to scare them off from enrolling, Dr. Holter-Chakrabarty said. "If we do that, science will never move forward or bring cures to our patients. But we do need to do a good, honest job of educating patients about what costs are associated with clinical trials. We have to maintain that balance." —By Leah Lawrence

References

1. National Institutes of Health. Clinical Trials. Accessed September 16, 2019, from https://www.nih.gov/research-training/clinical-trials.
2. Unger JM, Hershman DL, Albain KS, et al. Patient income level and cancer clinical trial participation. J Clin Oncol. 2013;31:536-42.
3. Unger JM, Gralow JR, Albain KS, et al. Patient income level and clinical trial participation. A prospective survey study. JAMA Oncol. 2016;2:137-9.
4. Centers for Medicare & Medicaid Services. The Center for Consumer Information & Insurance Oversight. Affordable Care Act Implementation GAQs – Set 15. Accessed September 16, 2019, from https://www.cms.gov/CCIIO/Resources/Fact-Sheets-and-FAQs/aca_implementation_faqs15.html.
5. United Healthcare. Clinical trials Coverage Determination Guideline. Accessed September 16, 2019, from https://www.uhcprovider.com/content/dam/provider/docs/public/policies/comm-medical-drug/clinical-trials.pdf.
6. Aetna. Clinical trials, coverage of routine patient care costs. Accessed September 16, 2019, from http://www.aetna.com/cpb/medical/data/400_499/0466.html.
7. Cigna. Clinical trials fact sheet. Accessed September 16, 2019, from https://www.cigna.com/assets/docs/about-cigna/informed-on-reform/clinical-trials-fact-sheet-revised.pdf.
8. Mackay CB, Antonelli KR, Bruinooge SS, et al. Insurance denials for cancer clinical trial participation after the Affordable Care Act mandate. Cancer. 2017;123:2893-900.
9. Huey R, George G, Phillips P, et al. Out of pocket costs and financial toxicity experienced by patients in early phase clinical trials. J Clin Oncol. 2019;37(suppl 15):e18383.
   Novartis. Novartis Position on Post-Trial Access.
10. Novartis. Novartis Position on Post-Trial Access. Accessed September 17, 2019, from novartis.com/sites/www.novartis.com/files/novartis-position-on-post-trial-access.pdf.
11. Prasad V, De Jesús K, Mailankody S. The high price of anticancer drugs: origins, implications, barriers, solutions. Nat Rev Clin Oncol. 2017;14:381-90.
12. Rimer BK. National Cancer Institute. The Imperative of Addressing Cancer Drug Costs and Value. Accessed September 17, 2019, from https://www.cancer.gov/news-events/cancer-currents-blog/2018/presidents-cancer-panel-drug-prices.
13. The Hill. Cancer patients left in the lurch when some drugmakers stop clinical trials. Accessed September 16, 2019, from https://thehill.com/opinion/healthcare/449681-when-clinical-trials-end-many-cancer-patients-are-left-without-continuing.
14. United States Census Bureau. Health Insurance Coverage in the United States: 2018. Accessed September 17, 2019, from https://census.gov/library/publications/2019/demo/p60-267.html.
15. Food & Drug Administration. Payment and reimbursement to research subjects. Guidance for Institutional Review Boards and Clinical Investigators. Accessed September 17, 2019, from https://www.fda.gov/regulatory-information/search-fda-guidance-documents/payment-and-reimbursement-research-subjects.