Article: The importance of racial diversity in clinical trials

Contents

ARTICLE AT A GLANCE

This article is about:

How well different racial groups are represented in cancer drug clinical trials in the United States.

Clinical trials: eligibility and benefit

Clinical trials provide the information used by the FDA to determine whether or not a cancer drug is safe and effective and should be approved for public use. Even when early data is promising, it is always possible that a drug may be ineffective or have unintended serious side effects.

Clinical trials are experiments; they offer no promise of personal benefit to participants beyond helping society to understand if a particular treatment is useful. Clinical trial participants may have early access to experimental drugs, with the warning that the drugs may or may not work as hoped. Receiving the drug in question is not guaranteed; some participants receive the current standard of care or, in cases where there is not a standard of care, a placebo rather than the experimental drug.

Clinical trials typically test a cancer drug for a particular cancer type and have a list of criteria for participation that fits the target population of the research. This is called eligibility criteria. Some of the factors that may affect eligibility include:

•   cancer type and stage
•   presence or absence of specific tumor type or other test results
•   patient age or gender
•   general health or other health considerations

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Most racial groups are not well represented in clinical trials for cancer drugs

Ideally, participants in a research study should represent all people with the type of cancer being studied. This helps doctors predict how well or how poorly a drug will work for most people with this type of cancer. However, these trials often fall short of this goal.

To be more transparent, the FDA began providing "Drug Trial Snapshots" with demographic information about who participated in each approved drug trial.

Propublica, a nonprofit news outlet, looked at data about participation in clinical research trials in the United States for 31 cancer drug trials. The majority of clinical trials for cancer drugs had large racial disparities in enrollment. Although African Americans account for 13.4% of the U.S. population, 24 of the 31 trials had fewer than 5% African American participants.

For example, ProPublica looked at trials for a type of cancer called "multiple myeloma." Multiple myeloma affects African Americans twice as often as white Americans. Clinical trials representative of the population affected would have twice as many black participants as white participants. However, in the 4 clinical trials that led to FDA-approved drugs for multiple myeloma, only 2-10% of participants were African American.

Why are some groups underrepresented in clinical trials?

There are complex reasons that affect who participates in a clinical trial.

Patients must be made aware that the trial exists and that they might be eligible for participation. Sometimes researchers may not focus on recruitment in minority communities. There needs to be education about what participation in a clinical trial entails (time, cost, risks) and eligibility.

There are potentially financial hurdles to overcome. Because patients or their healthcare insurers may be responsible for a portion of the cost involved in participating the trial (e.g. for copays for non-experimental tests or travel to trial locations), lack of financial resources affect who is able to participate. A 2015 study indicated that patients with more limited means (household incomes below $50,000) were 32 percent less likely to participate in a clinical trial.

Health considerations affect eligibility. Clinical trials have become more selective about which patients fit eligibility criteria. On average, African Americans have more health concerns that might preclude participation (e.g. heart conditions or diabetes).

Additionally, there is a distrust of medical experimentation in minority communities due to abuses in historic trials such as the Tuskegee study from 1932-1972 in which minority men with syphilis were allowed to go untreated. While there is strong oversight of clinical trials today because of these past events, there is still understandable hesitation among some potential participants.

Why does underrepresentation in clinical trials matter?

• Early access, which can be beneficial (and in some cases may improve or extend life) is unavailable.
• Some drugs may be more or less effective in people of certain backgrounds. Some drugs may have different side effects and safety profiles for people of different racial or ethnic backgrounds.
• Minorities must make decisions about newly-approved cancer drug treatment with incomplete and possibly inaccurate information.

Clinical trials with skewed racial representation limit conclusions about effectiveness. Understanding whether or not trial findings apply similarly to different populations would greatly enhance the clinical utility of the study's outcomes.

Dr. Johnathan Jackson, founder of Community Access, Recruitment and Engagement Center at Massachusetts General Hospital in Boston, MA stated:   

"[...inadequate minority representation in drug trials means that] we aren't doing good science....If we aren't doing good science and releasing drugs out into the public, then we are at best being inefficient, at worse being irresponsible."

Disproportionate or unequal access to clinical trials by different racial groups means that some populations do not receive early treatment or interventions available to white participants. Why does that matter? Early intervention sometimes saves lives.

"So if you're part of a group where just getting access to medical care is a problem, odds are that you’re not going to have the opportunity to even be asked to participate in a clinical trial. Studies show that when minorities and nonminority members are asked to participate in a clinical trial, the participation rate is roughly equivalent." —excerpted from an interview with John J. Whyte, M.D., MPH, Director, Professional Affairs and Stakeholder Engagement, Center for Drug Evaluation and Research, FDA.

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How well do clinical trials for breast and ovarian cancer drugs represent minorities?

Not particularly well. FORCE looked specifically at clinical trials for breast or ovarian cancer that have been reported by Drug Trial Snapshots since the program began in January 2015. According to the FDA website, in 8 clinical trials involving the 5 drugs approved for breast and 2 drugs approved for ovarian cancer, none included sufficient nonwhite participants to conclude if there were differences in drug response between racial groups. These 8 breast and ovarian cancer drug trials included 5,563 participants, 5,247 of whom self-reported their race:

                          # of trial             % of trial         % of US population from
                        participants      participants        2017 US Census estimates

White                      4,345                   78.0                    76.6%

Black                          137                     2.5                     13.4%

Asian                          735                   13.2                       5.8%

Native American         28                     0.5                       1.3%

Multiracial                     2                   <0.1                        2.7%

Not reported/other  316                     5.7         

While white patients were fully represented in these 8 trials, black and Native American participants were notably underrepresented; 5 times fewer black participants were included than are represented in the U.S. population. The vast majority of Native American participants (26 women or 4% of participants) were in the Verzenio clinical trial for progress-free survival; the 7 other trials had 1 or no Native American participants.

Asian participants were better represented in some trials than in the U.S. population. This may warrant re-examination of whether drug responses among these participants are statistically similar or different from white participants. For example, in the trials of Nerlynx for early breast cancer and Talzenna for metastatic breast cancer in women with BRCA mutations, 13.6% and 11% of participants respectively were of Asian descent. The large number of Asian participants reflects that these trials were conducted both in the U.S. and in foreign countries, facilitating a greater recruitment of Asian participants.

The FDA did not collect data until 2017 on individuals who are ethnically Hispanic versus non-Hispanic participants, so Hispanic enrollment in trials before that date is unknown. The 2017 FDA report of the Drug Trial Snapshot program indicates that Hispanic participants were underrepresented in all of the breast and ovarian cancer drug trials:

Trial                             % Hispanic participants  Indication 

Kisqali                                    10%                         HR+, HER2- breast cancer

Nerlynx                                    2%                         HER2+ breast cancer

Verzenio                                 12%                        HR+, HER2- breast cancer

Zejula                                      3%                        Ovarian cancer    

US population    (2017 est.)   18%                       The percentage that would be                                                                               represented in clinical trials ideally

Clinical trials for prostate cancer have also underrepresented the most affected populations

In the U.S., 178 of every 100,000 African American men are affected by prostate cancer, compared to 106 of every 100,000 white American men: African American men are more likely to have prostate cancer than white men. If clinical trials were representative of the population affected, they would include more black participants than white.  If clinical trials were representative of the U.S. population in general, at least 13% black participants would be included.

In 7 trials involving 5 drugs between 2009 and 2015, only 3% of participants were black. Johnson & Johnson's Erleada trial for prostate cancer treatment had 66% white participants compared to 6% African American participants: 11 times more white than black participants, despite the cancer being more common among black participants. And this is one of the more representative trials.

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Voluntary or regulatory approaches to better demographic representation?

In 2017, the National Black Church Initiative urged the FDA to mandate diversity in all clinical trials before approving a drug or device, writing:

"Simply put the pharmaceutical community is not going to improve minority participation in clinical trials until the FDA compels them to do so via regulations."

To date, the FDA has encouraged but not required drug applicants to include diverse participants.

Dr. John Whyte, Director, Professional Affairs and Stakeholder Engagement, Center for Drug Evaluation and Research, FDA, stated that:

"Many stakeholder groups want FDA to require drug companies to include certain percentages of demographic subgroups in clinical trials and analyze subgroup data by sex, race and age before a drug is approved. While the FDA has many regulations and policies in place regarding clinical trials, these studies are the responsibility of the manufacturer that is developing the drug."

All of the drug manufacturers contacted by the Propublica authors indicated that diversity in trials was important to meet patient needs. However, some argued that requiring racially representative trials would add time and cost to an already expensive and time-consuming process.

Dr. John Maraganore, the CEO of Alnylam Pharmaceuticals and chair of Biotechnology Innovation Organization noted in the Propublica article that:

"If you have a significant delay in enrollment, that would delay the medication advancing to the whole patient population, hurting everybody, including the black population."

This conflict between increasing cost in time and money of trials and having trials be more representative and generalizable remains. Some U.S. companies are trying to address this issue by established internal working groups on diversity, trained site leaders for clinical trials about diverse recruitment and reached out to minority physicians to help recruitment efforts. These efforts have led to increased minority enrollment in some cancer drug trials.

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What happens after drug approval?

Clinical trials are expensive and important subsequent trials sometimes never occur. Concerns about how generalizable results are may be left unknown for a long time. To address these concerns, in 2008, the FDA’s Sentinel program began examining medical claims and data from insurers and health care providers to identify adverse events and drugs that do not help specific populations.

Some pharmaceutical companies voluntarily track drugs after approval to determine whether racial differences are observed. When Johnson & Johnson's drug Zytiga was approved in 2011 for metastatic prostate cancer, the company recognized that few African American men participated in the original clinical trial. To determine if results were similar or different between black and white men, Johnson & Johnson conducted a small post-market study trial of 50 black and 50 white patients. This study showed that black men respond better than white men to Zytiga.

Similarly, Megan Cox, a spokeswoman from Genentech, the company that markets the non-small cell lung cancer drug Alecensa, remarked:

"We believe that we must consider differences across all populations to deliver on the promise of personalized health care...[we] are continuing to study patient response to Alecensa across populations in the post-marketing setting."

However, waiting until post-market studies are conducted to determine if treatment is comparable means that many minority patients will face decisions about taking a drug with less information than other consumers. It may also mean that they will miss out on the early access that trial participation may provide.

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What does this mean for me?

Because of individual differences between people, research results may not guarantee your personal response to a drug. If you are a minority or otherwise underrepresented in clinical trials, be aware that research based on predominantly white participants may or may not predict your response to a cancer drug. While experimental drugs or procedures are provided without cost, the costs of standard tests or treatments are typically paid by participants or their health care insurers. There are organizations that provide resources to defray these costs of participation.

Consider participating in current trials that fit your current circumstances. Be aware that clinical trials are actively looking for participants who fit their research criteria. Spread the word about enrolling in clinical trials to others who may be potential participants in your community.

FORCE maintains a list of clinical trials enrolling participants that are relevant to the hereditary cancer community on our Featured Research page, as well as a user-friendly search tool for clinical trials. Check it out!

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Posted 11/6/18
 

References

Jointly published by ProPublica and STAT Plus: Caroline Chen and Riley Wong. "Black Patients Miss Out On Promising Cancer Drugs" ProPublica. Sept. 19, 2018.

Caroline Chen and Riley Wong. "Denied ‘life-extending opportunities’: Black patients are being left out of clinical trials amid wave of new cancer therapies." STAT+. Sept 19, 2018.
 

Disclosure

FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.