By CAROLINE CHEN
AND RILEY WONG — PROPUBLICA
SEPTEMBER
19, 2018
It’s a
promising new drug for multiple myeloma, one of the most savage blood
cancers. Called Ninlaro, it can be taken as a pill, sparing patients painful
injections or cumbersome IV treatments. In a video sponsored by the
manufacturer, Takeda Pharmaceutical Co., one patient even hailed Ninlaro as “my
savior.”
The Food
and Drug Administration approved it in 2015 after
patients in a clinical trial gained an average of six months without their
cancer spreading. That trial, though, had a major shortcoming: its racial
composition. One out of five people diagnosed with multiple myeloma in the U.S.
is black, and African-Americans are more than twice as likely as white
Americans to be diagnosed with the cancer.
Yet of
the 722 participants in the trial, only 13 — or 1.8 percent — were black.
The
scarcity of black patients in Ninlaro’s testing left unanswered the vital
question of whether the drug would work equally well for them. “Meaningful
differences may exist” in how multiple myeloma affects black patients, what
symptoms they experience, and how they respond to medications, FDA scientists wrote in
a 2017 journal article.
The
racial disparity in the Ninlaro study isn’t unusual. Reflecting the reluctance
of the FDA to force drug makers to enroll more minority patients, and the
failure of most manufacturers to do so voluntarily, stark underrepresentation
of African-Americans is widespread in clinical trials for cancer drugs, even
when the type of cancer disproportionately affects them. A ProPublica analysis
of data recently made public by
the FDA found that in trials for 24 of the 31 cancer drugs approved since 2015,
fewer than 5 percent of the patients were black. African-Americans make up 13.4
percent of the U.S. population.
As a
result, desperately ill black patients who have exhausted other treatment
options aren’t getting early access to experimental drugs that could extend
their life spans or improve their quality of life. While unapproved treatments
also carry a risk of setbacks or side effects, new cancer drugs have
dramatically shifted outcomes for some patients.
Recently
approved lung cancer treatments are “revolutionary,” said Dr. Karen Kelly,
associate director for research at UC Davis Comprehensive Cancer Center. Even
in the first phase of clinical testing, which is aimed at making sure a drug is
safe, 20 percent of cancer patients now see their tumors shrink or disappear,
up from 5 percent in the early 1990s, Kelly said.
Dr.
Kashif Ali, research head at Maryland Oncology Hematology, has spent seven
years recruiting patients for about 30 cancer and blood disease trials a year.
He said he’s often seen minorities, including Africa- Americans, miss out on
trials because of financial hurdles, logistical challenges, and their lingering distrust of the medical community due
to a history of being victimized by medical experimentation.
“They’re
potentially losing out on life-extending opportunities because it’s one more
option they no longer have,” Ali said. “Especially when patients are in
advanced stages of cancer, treatments are like stepping stones: When one stops
working, you move on to the next.”
Not
joining a trial can mean “you’ve lost life expectancy,” he said.
Pat
Conley, a 72-year-old retired business analyst whose multiple myeloma relapsed
last year, has never participated in a clinical trial. She was interested
several times and didn’t meet the criteria. Now she’s eligible for one, but
worries about the burden of regular hourlong trips from her Fayetteville, Ga.,
home to the trial site in Atlanta, as well as the copays for medical tests.
“They’ll want a new biopsy, and, Lordy, biopsies are not cheap,” she said.
Still,
two drug regimens haven’t halted her cancer and she wants something positive to
come from her illness. “If they don’t have African-Americans to test it on, how
will they know it’s going to work?” she asked. “If it doesn’t help me, it’ll
help my children, it’ll help somebody else.”
Pharmaceutical
companies contacted by ProPublica all said diversity in clinical trials is
important to ensure that drugs meet patients’ needs. The issue “is not elevated
high enough in the discussion on clinical studies,” said John Maraganore, chair
of the industry group Biotechnology Innovation Organization. But he added that
enrolling minorities is challenging, often for reasons beyond the
manufacturer’s control, and that it would require a “public-private partnership,
working with the FDA and NIH [National Institutes of Health].”
Black
participation reached 10 percent in trials for only two of the 31 cancer drugs:
the multiple myeloma drug Darzalex, where the figure was exactly 10 percent,
and Yondelis, which treats two types of soft tissue cancer. Twelve percent of
patients in the Yondelis trial were black, the highest proportion in the
ProPublica study. Both drugs are made by Johnson & Johnson, which said it
has an internal working group on trial diversity. The working group trains site
leaders in best practices for diverse recruitment and seeks minority physicians
to help run trials, since some patients prefer being treated by doctors of
their own race.
Not
enrolling in clinical trials is just one of many ways that African-Americans
trail white Americans in the quality of their health care. From diagnosis to
death, they often experience inferior care and worse outcomes. Because some
black Americans can’t afford the health insurance mandated under the Affordable
Care Act, they remain less likely to have coverage than non-Hispanic white
Americans. African-Americans are 30 percent more likely than
white Americans to die from heart disease. Black mothers are three to four
times as likely as white mothers to die in pregnancy or childbirth,
and black children are diagnosed with autism later than white children.
While the
scarcity of African-Americans stands out in ProPublica’s analysis, there appear
to be gaps in participation of other minority groups as well. Asians were
well-represented in trials held in some foreign countries, but they made up
only 1.7 percent of patients for drugs for which at least 70 percent of trials
were conducted within the U.S. By comparison, about 6 percent of the U.S.
population identifies as Asian. Almost two-thirds of the trials didn’t report
any Native Americans or Alaska Natives, who together make up about 2 percent of
the U.S. population. ProPublica’s analysis excluded Hispanics, because the FDA
reports did not have a separate category for them until 2017 and do not
distinguish between white and non-white Hispanics.
The very
relationship of race to drug development is fraught with controversy. Race is
primarily seen as a social concept, rather than as a product of measurable
biological traits. Yet there’s growing evidence that, whether for environmental
or genetic reasons, drugs may have different effects on different populations.
In 2014,
the state of Hawaii sued Bristol-Myers Squibb Co. and Sanofi, the manufacturers
of the blood thinner Plavix, accusing them of deceptive marketing for failing
to disclose that the drug was less effective for some patients of East Asian or
Pacific Islander descent. The drug makers have denied allegations of misconduct
and argue that genetic traits have not been proven to affect how well Plavix
works. The case is pending. In the meantime, the FDA has added a warning to the
label saying that Chinese patients are more likely to have a gene variation
that renders the drug ineffective. Researchers at the University of California,
San Francisco, have found that a commonly used asthma medication, albuterol, doesn’t work as well for
African-American and Puerto Rican children as it does for European-American or
Mexican children.
Inadequate
minority representation in drug trials means that “we aren’t doing good
science,” said Dr. Jonathan Jackson, founding director of the Community Access,
Recruitment, and Engagement Research Center at Massachusetts General Hospital
in Boston. “If we aren’t doing good science and releasing these drugs out into
the public, then we are at best being inefficient, at worst being
irresponsible.”
The
National Black Church Initiative, a coalition of 34,000 U.S. churches, urged
the FDA in 2017 to mandate diversity in all clinical trials before approving a
drug or device. “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,” it wrote to Commissioner Scott Gottlieb.
The FDA
hasn’t done so. Although it noted in a 2013 report that a
lack of diversity betrays a key ethical principle of medical research — equal
justice for all — the agency has shied away from setting quotas or numerical
guidelines for participation by race.
Instead,
it has relied on persuasion. In its 2014 Action Plan, it
said it aims to “share best practices,” to “support” industry efforts at
improving diversity in clinical trials, and to “encourage” patients to
participate in trials via social media, emails, and blog posts.
“The FDA
believes that enrollment should reflect the patients most likely to use a
medical product,” spokeswoman Gloria Sanchez-Contreras said. The FDA “does not
have the regulatory authority to require specific levels of minority
representation in clinical trials,” although it may ask drug makers for
additional data, she said.
Dr.
Rachel Sherman, the FDA’s principal deputy commissioner, said that she’s “not
entirely satisfied” with minority enrollment but that clinical trials have
become more diverse in other ways. Two decades ago, women and children were
rarely included in drug studies. Now those groups are better represented and
the FDA is working on including more minorities, she said.
Sherman
added that the agency has to balance how much information it demands from drug
makers against the need to get a drug onto the market, where it will be broadly
available for all patients.
“When it
comes to clinical research in this country, there’s a credit card, and there’s
a limit on the credit card,” she said. “If we spend on one thing, it won’t get
spent on another. We have to be judicious in what we require and what we demand
and what we encourage.”
Diversity
has its trade-offs. Clinical trials already cost hundreds of millions of
dollars, and drug makers say that requiring participants to be racially
representative would likely add more time and expense.
“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,” said Maraganore, who is also CEO of drug maker Alnylam
Pharmaceuticals Inc.
To offset
costs caused by these delays, manufacturers might reduce the number of drugs in
development, depriving some patients of experimental treatments, or raise
prices, which would translate into higher insurance premiums and make new drugs
even less affordable for the uninsured. Maraganore favors improving diversity
through patient education — “a carrot-based approach” — rather than government
regulation.
Despite
these short-term expenses, eliminating racial disparities in clinical trials
would ultimately save costs through disease prevention and improved treatment,
according to a 2015 analysis by
researchers at the University of California, San Francisco. Without FDA
pressure, though, manufacturers may be unlikely to increase efforts to recruit
African-Americans, especially if their sights are set on a worldwide market.
They can use the same clinical trial data to gain approval in the European
Union, or Japan.
Takeda,
which is based in Tokyo, Japan, tested Ninlaro in the U.S., Japan and 24 other
countries, including Australia, Austria, Denmark, New Zealand, Sweden, and
others with small black populations. “Clinical trials are reflective of the
ethnicity distribution in the population where the study takes place,” Phil
Rowlands, head of Takeda’s oncology unit, said in an email. “While we cannot
control enrollment eligibility based on the strict clinical criteria, our
recruitment efforts extend to diverse patient populations, including
minorities.”
Asked why
Takeda didn’t pick sites with higher black populations, Rowlands said that
Takeda does not “select sites with ethnicity as an eligibility criteria unless
specific risk factors require that.”
Income is
another reason for sparse African-American representation. Clinical trials are
largely a middle-class option. A 2015 study found that patients with an annual
household income below $50,000 had 32 percent lower odds of
participating in a trial than patients with income above that threshold. The
median household income of African-Americans in 2016 was $39,490, compared to
$65,041 for non-Hispanic white Americans.
Patients
who can’t afford to travel long distances to a trial, take time off work, or
find child care are at a disadvantage. They are usually reimbursed for travel
and food costs, but drug makers are careful not to pay too much because they do
not want to appear to be enticing patients to join when it isn’t in their
medical interests, said Laurie Halloran, founder and CEO of a consulting firm
for the drug industry.
While the
experimental drug used in a study is free, any approved treatments that are
part of the trial typically need to be covered by a patient’s own insurance,
according to Ali, the research director at Maryland Hematology Oncology.
He
recalled one black patient who was eligible for a study that entailed taking an
already approved drug in combination with a new treatment. The approved drug
cost $10,000 a month and the patient’s insurance charged 20 percent as his
copayment, Ali recalled. The patient decided that joining the trial would be
too expensive. He instead underwent chemotherapy, which was cheaper, but he
didn’t tolerate it well. The patient is now considering hospice, Ali said.
Criteria
for admission to clinical trials have become more stringent over
the years, Mass. General’s Jackson said, and patients of color are increasingly
excluded. They are more likely than white people to have
other conditions such as stroke, hypertension, and diabetes, which could
complicate research results. Trials often want to enroll “the healthiest sick
people they can find” and preclude patients with other conditions. “The wall
basically gets taller and taller,” he said.
Aredia
Taylor didn’t qualify on other grounds. A former U.S. Department of Agriculture
supervisor for food safety inspections, she was diagnosed with multiple myeloma
in 2014 and has undergone a gamut of treatment, including various chemotherapy
drugs and a stem cell transplant.
While the
transplant drove her cancer into remission, there is no cure for multiple
myeloma, and she needs to take Revlimid — a standard treatment — daily to keep
the cancer at bay. The drug has given her side effects that she describes as
devastating to her daily life, including diarrhea, muscle spasms, and an
inability to concentrate. She said she wants to stop taking Revlimid and would
be willing to try an experimental treatment.
Taylor,
58, said she saw pamphlets at her doctor’s office encouraging patients to ask
about clinical trials, so she asked her oncologist, Dr. Larry Anderson at the
University of Texas Southwestern Medical Center in Dallas, whether she should
join a study. He told her that she “wasn’t a fit,” she said. Anderson told
ProPublica that most trials are seeking patients with either newly diagnosed or
relapsed multiple myeloma, and since Taylor is currently in remission, she
wouldn’t be accepted.
Taylor
was disappointed. Knowing that African-Americans like herself are especially
susceptible to multiple myeloma, she’d like to be a part of developing more
effective treatments.
“I want
to pay it forward and be a blessing to somebody else,” she said. “I want to be
one of the people that they try to do a clinical trial for, so they find a way to
a cure.”
Spurred by Congress, the FDA
began in January 2015 to regularly publish a “Drug Trials Snapshot” for every
new drug approved, delineating the demographic breakdown for clinical trial
participants by sex, race, and age subgroups. ProPublica’s analysis focused on
participants in trials for the 31 cancer drugs approved since then, comparing
their demographics with data from the National Cancer Institute on
the incidence of various cancers by race.
Eighteen
of those drugs targeted cancers that are at least as likely to afflict black
Americans as white Americans. On average, only 4.1 percent of patients in those
trials were black. Trials for four multiple myeloma drugs, including Ninlaro,
averaged 5 percent black participation.
An FDA
study over a longer time period corroborated ProPublica’s findings. In a 2017
article in the journal Blood co-authored by Dr. Richard Pazdur, the FDA’s
cancer chief, the agency reported that black patients on average made up 4.5 percent of participants in
trials for multiple myeloma drugs since 2003. Higher enrollment of minorities
in myeloma trials would have “multiple benefits,” the FDA scientists noted. Not
only would “underserved populations” gain access to new therapies, but
additional data could help researchers identify subtypes of the blood cancer
and develop targeted treatments.
A similar
pattern emerges for treatments of non-small cell lung cancer. It occurs in 56
out of 100,000 black Americans, versus 49 out of 100,000 white Americans. Yet
ProPublica found that in trials for two recently approved drugs for a type of
non-small cell lung cancer driven by a mutation in what is known as the ALK
gene, less than 2 percent of participants were black.
Those
drugs, Takeda’s Alunbrig and Genentech’s Alecensa, are approved for patients
whose lung cancer has spread to other parts of the body. In trials, both drugs
were able to shrink tumors, including lesions in the brain. Patients taking
Alecensa lived without the disease progressing for an average of 25.7 months,
more than double the 10.4 months for patients on another treatment.
“We
believe that we must consider differences across all populations to deliver on
the promise of personalized health care,” said Meghan Cox, a Genentech
spokeswoman, adding that the drug maker is “continuing to study patient
response to Alecensa across populations in the post-marketing setting.”
Similarly,
prostate cancer affects 178 out of every 100,000 African-Americans, more than
for any other race in the U.S., compared to 106 out of every 100,000 white
Americans. Black Americans are twice as likely as white Americans to die from
prostate cancer.
Yet from
2009 to 2015, in seven trials conducted for five new prostate cancer therapies,
only 3 percent of participants were black, according to a study conducted by Dr. Daniel Spratt, vice
chair of research for the department of radiation oncology at the University of
Michigan. More recently, 11 times as many white as black participants — or 66
percent compared to 6 percent — joined trials for Johnson & Johnson’s new
prostate cancer treatment, Erleada.
The FDA
approved Erleada in February after trials showed patients on the drug lived an
average of two years longer without their cancer spreading into other organs
than if they were taking a placebo. In a J&J press release, physicians
hailed Erleada’s “impressive clinical benefits” for prostate cancer patients.
J&J
is “confident in the efficacy and safety data that have supported the approval”
of Erleada, J&J spokeswoman Satu Glawe said.
Like
Genentech, J&J and Takeda said they track drugs after approval to see if
any racial differences emerge. For example, after another J&J drug for
prostate cancer, Zytiga, went on the market in 2011, the company ran a new
study of 100 patients, 50 black and 50 white.
“We were
aware of the low number of African-American men” in the pre-approval drug
studies of Zytiga, Glawe said. The post-marketing study was intended “to ensure
the medication was also providing clinical benefit to these patients.” In fact,
it showed that black men responded better than
white men to the drug.
The FDA
is able to look for signs that an approved drug isn’t helping a specific
population through a surveillance system launched
in 2016, called Sentinel, which provides access to medical claims and other
data on 200 million Americans obtained from insurers and other health
providers, Sherman, the FDA’s principal deputy commissioner, said.
Still,
post-marketing surveillance doesn’t compensate for lack of diversity in
clinical trials. Minorities still miss out on experimental treatments — and, if
they take a drug once it’s approved, may suffer unanticipated side effects.
Leaving
analysis of a drug’s effect on minorities until it’s already on the market is
“a hubristic assumption, unnecessarily arrogant,” Jackson said. Drugs should
“work for the individuals who are the most vulnerable,” he said. “That
necessarily includes racial and ethnic minorities.”
Like
African-Americans, Native Americans rarely enroll in clinical trials. Among the
drug trials analyzed by ProPublica, 64.5 percent did not report any Native
American participants, even for types of cancer that Native Americans get at
similar rates as other races. (It’s possible that some Native Americans were
enrolled but lumped into a generic “other” category.)
Native
Americans are at higher risk of colorectal cancer than white or
Asian-Americans. Yet the drug maker Taiho Oncology didn’t report a single Native
American among the 800 participants in its trials for the colorectal cancer
treatment Lonsurf. Taiho didn’t respond to requests for comment.
To
understand how a small minority group responds to a drug, researchers might
have to enroll more patients than what would be a nationally representative
sample. In a trial of 100 people, two Native American or Alaska Native patients
would reflect those groups’ proportion of the U.S. population, but wouldn’t
give doctors enough information about race-related impacts.
Dr. Linda
Burhansstipanov, founder of the Native American Cancer Research Corporation,
estimated that 85 percent of Native Americans want to participate in clinical
trials when informed of the opportunity. She knows several Native American
patients who drove three hours each way to participate in a trial, despite
losing an entire day of work.
Still,
trial protocols are rarely designed with minority communities in mind,
Burhansstipanov said. It has long been rumored among Native Americans, she
said, that a clinical trial in the 1990s required patients to take a medication
upon rising in the morning. In many Native American tribes, the first thing
people do when they wake up is greet the sun with morning prayers. For some
tribes, prayers can take more than half an hour. Because of the delay, the tale
goes, Native American patients were kicked out of the clinical trial for
violating the protocol. “The story spread and became a barrier for people to
take part in clinical trials,” she said.
In
addition, the history of unscrupulous medical experimentation on minorities
feeds wariness of clinical trials. Angela Marshall, an internal medicine doctor
and board member of Black Women’s Health Imperative, said she sees
a “lack of excitement among minority communities for clinical trials, coming
from a mistrust of the medical community.”
Her black
patients often cite the infamous Tuskegee study, conducted from 1932 to 1972 by
the U.S. Public Health Service, in which researchers knowingly withheld
treatment from African-American sharecroppers with syphilis in order to study
the progression of the disease. Some Native Americans are similarly suspicious
of the medical community, Burhansstipanov said, because the Indian Health
Service (a unit of the Department of Health and Human Services) sterilized thousands of Native American women in
the 1970s without their consent.
“The medical community has to engage in some
serious trust-building initiatives,” Marshall said.
That
trust is what has helped to keep Thomas Goode alive. An African-American
diagnosed with multiple myeloma in 2005 when he was 34, Goode has endured three
stem cell transplants. In between each transplant, he participated in clinical
trials, where he gained access to drug cocktails that helped bridge him to the
next procedure. He counted himself lucky that he lived close to Durham, N.C.,
which is a research hub, so he was able to see specialists and take part in
trials.
“I never
knew anything about clinical trials, but a lot of my trust and faith was in the
doctor,” he said. “I said, ‘I trust you, doctor, whatever you say.’”
Now,
Goode has gone six years without a relapse. “I’m in a good place right now,” he
said, “But if I didn’t try a trial, who’s to say I would still be here?”
More about the story
This
story was co-published with ProPublica, a
nonprofit newsroom based in New York City. Sign up for ProPublica’s Big Story newsletter to
receive stories like this one in your inbox as soon as they are published.
Caroline Chen can be reached at caroline.chen@propublica.org.
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