After decades of foot-dragging, the FDA has put drugmakers on notice that greater inclusion in clinical trials – balanced gender enrollment, more cultural diversity and wider age spans – is coming. Hand-wringing, it appears, won't halt the inevitable. Instead, the industry is facing the need to move proactively to design trials that more closely match the targeted populations for drug candidates.

The FDA issued its Guidance for Industry Collection of Race and Ethnicity Data in Clinical Trials in 2005, and greater inclusion became a mandate in section 907 of the FDA Safety and Innovation Act of 2012 (FDASIA), when the FDA required the inclusion of demographic subgroups in clinical trials.

The agency issued its guidance on including more elderly in drug trials all the way back in 1989, and that framework also gained new impetus with FDASIA. In December 2013, the FDA's Center for Drug Evaluation and Research (CDER) examined the inclusion of older patients in clinical trials in a 108-page memo titled Good Review Practice: Clinical Review of Investigational New Drug Applications. That analysis concluded that sponsors routinely deny enrollment to older subjects with multiple chronic conditions, including those with psychiatric disorders – including depression – heart disorders, atherosclerosis or diabetes.

In a conference call with reporters in February, Robert Temple, CDER's deputy director of clinical science, suggested sponsors must be prepared to answer questions about broader inclusion during discussions about protocol design and at end-of-phase II meetings. (See BioWorld Today, Feb. 4, 2014.)

In April, the FDA held a public meeting to gather feedback from industry representatives about mechanisms to improve the collection, analysis and availability of demographic subgroup data in new drug applications. Speakers from a variety of organizations gave the agency an earful, including the need to enforce current requirements for making trial populations representative and including subgroup analyses in those trials. (See BioWorld Today, April 2, 2014.)

The string of guidances, meetings and memos seems designed to put sponsors on notice that, this time, the federal government is serious about improving diversity in clinical trial populations.


Drugmakers might be excused for greeting the announcements with a jaundiced eye. Little progress has occurred on FDA initiatives, according to Kenneth Getz, director of sponsored programs and associate professor at the Tufts Center for the Study of Drug Development (CSDD) and chairman of the Center for Information and Study on Clinical Research. Although studies funded by the NIH generally recruit representative and diverse populations of volunteers, Getz said, Tufts CSDD research shows that disparities in minority enrollment remain in many industry-funded trials.

But industry is starting to take the message seriously. Andrew Womack, director of science and regulatory affairs for the Biotechnology Industry Organization (BIO) and the author of BIO's response to the FDA's proposed action plan for collecting and analyzing subgroup data, told BioWorld Today that greater demographic inclusion "is definitely a priority" in the biotech industry. Biotechs recognize the scientific validity of providing data that show how people with genetic differences based on gender, ethnicity or age might respond to a given drug.

That said, concrete efforts to address the agency's concerns vary by "the type of therapy as well as the company," Womack conceded. The same type of FDA-regulated label information that increased physician understanding of how to prescribe newly approved drugs for pediatric populations is needed for other subgroups, he said.

Jocelyn Ulrich, director of scientific and regulatory affairs for the Pharmaceutical Research and Manufacturers of America (PhRMA), agreed on the need to recruit more diverse patient populations, and she said drugmakers must go further.

"It's very clear that we have a lack of participation across the board that's impacting the efficiency of the clinical trials process and also impacting the participation of underrepresented populations," Ulrich told BioWorld Today. "Any efforts we can undertake to improve awareness, education and participation broadly must also be sensitive to underrepresented populations."

That mission, which should be led by culturally competent personnel, should include outreach to physicians in underserved communities and the use of culturally sensitive materials.

But the feasibility of enrolling representative subpopulations in numbers that are sufficiently powered to draw valid conclusions while balancing the urgency to develop drugs to serve the broader population remains problematic. It's the perennial problem of conducting a well-designed and controlled study in a selective patient group yet still generating sufficient data to convince regulators that findings can be generalized to a broader patient population, observed Hua Mu, senior vice president of operations at Wuxi Apptec, of Shanghai. But the challenges are growing as global populations age and become more culturally diverse.

"We're facing challenges in age groups, where the elderly population has traditionally been underrepresented," said Mu, who held clinical leadership positions at Roche AG and its Genentech Inc. unit, Abraxis Bioscience (now Celgene Corp.) and Biogen Idec Inc. before joining Wuxi. Now, advocacy organizations and regulators are seeking greater inclusion, "and that creates operational challenges," he acknowledged.

BIO's position is that companies must work harder to minimize protocol exclusions by relying on scientific evidence rather than outright bans – for example, on patients older than 65 or with certain prevalent comorbidities. Exclusions "need to be scientifically rooted and thoughtfully administered to make trials more broadly accessible just from the enrollment criteria," Womack said.

"But saying that you can join and ensuring that you do join are two different things," he quickly added. Although exclusion criteria should have a scientific underpinning, the establishment of an enrollment target for a certain subgroup in a given trial may require sponsors to have boots on the ground, in one form or another.


An abstract by researchers at the Johns Hopkins University School of Medicine presented in June at the American Society of Clinical Oncology meeting in Chicago hinted at the impact of exclusion criteria and operational barriers on enrolling trials. Noting that, nationwide, only some 3 percent of patients participate in clinical trials, the researchers analyzed medical oncology records from a consecutive series of new breast, non-small-cell lung (NSCLC), pancreas and prostate cancer patients in trials conducted at Johns Hopkins.

They found that four reasons were most commonly cited for non-enrollment: No trial was available or the patient did not meet eligibility criteria (36 percent to 55 percent); standard treatment was recommended or preferred (6 percent to 23 percent); the patient lived too far from the cancer center to participate (1 percent to 22 percent); and the patient was lost to clinical follow-up or chose to receive care elsewhere (5 percent to 14 percent). Combined, those factors eliminated 64 percent of breast, 83 percent of pancreas, 84 percent of prostate and 89 percent of NSCLC patients from trial participation at Johns Hopkins. The paper was published in the Journal of Clinical Oncology.

To mitigate some of those issues, sponsors should consider "branding" their studies through outreach campaigns, perhaps in conjunction with local health professionals and community organizations, to increase familiarity in underrepresented populations, Womack suggested. Companies also should "thoughtfully address" some of the recognized barriers to participation, from primary care access to child care to transportation, and consider subsidizing or paying for those services, he said.

"One could make the argument that these steps could add cost, but if done thoughtfully and in a strategic manner, they could add a tremendous amount of value, too," Womack pointed out. "Whenever there's a cost, there's also an opportunity."


The National Cancer Institute's (NCI) comprehensive cancer center designation also carries significant prestige within a community and obligates health care organizations to develop networks that encompass patients and providers from outside their local catchment areas, observed Ellen Sigal, chairwoman and founder of Friends of Cancer Research, who helped to mobilize the lung cancer master protocol, or Lung-MAP, trial now under way.

"For cancer trials, that's part of their mission," Sigal said.

A trial like Lung-MAP, which has more than 335 sites open and aims to expand to 500 sites, attracts not only large academic medical centers but also smaller hospitals in far-flung locations, attracting considerable geographical distribution and commensurate diversity in underserved populations. The multidrug, biomarker-driven squamous cell lung cancer clinical trial is using state-of-the-art genomic profiling to match patients to multiple substudies testing investigational treatments targeting genomic mutations that drive the growth of their cancers. (See BioWorld Insight, July 28, 2014.)

Large networks are essential to enroll sufficient populations to study relatively rare cancers, which may affect only 5 percent of patients with a certain gene. Reaching patients in the communities in which they live is equally critical to improving cancer drug development, Sigal stressed, since approximately 85 percent of cancer treatment occurs in community settings. "Often these patients aren't even offered a clinical trial," she said.

Efforts like Lung-MAP help to improve both metrics.

"We're seeing a lot of patients being enrolled in areas we actually would not have expected," including rural centers, Sigal told BioWorld Today. "We need to get these patients treated in real-world situations. I'm hopeful these larger trials and these new networks that NCI established will accomplish those goals."


Drugmakers may wince at the thought of financing broader outreach efforts, but Paula Brown Stafford, president of clinical development for the contract research and development organization Quintiles Transnational Corp., maintained that cost isn't, or shouldn't be, a deterrent to incorporating greater diversity in trial populations.

"I don't see this as a cost issue," Stafford told BioWorld Today. "We're just being directed to find the right patients for the right trials." While recruitment has been a perennial challenge in drug development, "the promise of personalized medicine has driven more emphasis on recruiting ethnically diverse populations for that research."

That challenge is ramping up as patients become more savvy consumers and seek to use the best possible therapy to treat an illness.

"They're looking for more data and information" to support treatment decisions, Stafford said. With patients asking more questions of their physicians than ever before and assessing how well physicians understand the role of each medication in their treatment regimen, "there's going to be more importance in labeling for the prescribing of products to match patient groups more distinctly," she added, noting that the process is being driven by the use of biomarkers.

According to Cortellis Clinical Trials Intelligence (CTI), the use of biomarkers in trials has increased more than fourfold since 2000, with 6,620 clinical trials using biomarkers conducted between Jan. 1, 2000, and Dec. 31, 2004; 17,803 trials using biomarkers conducted between Jan. 1, 2005, and Dec. 31, 2009; and 28,821 trials incorporating biomarkers conducted between Jan. 1, 2010, and Nov. 15, 2014.

Not surprisingly, many of those biomarkers haven't changed, with glucose and blood pressure two of the top three in all time periods. (See Figures 1, 2 and 3, below.)

But the growing use of markers such as tumor necrosis factor and cytokines, which have emerged among the top 20 biomarkers, combined with better tools to detect them, could lead even the biggest pharmas to become more specialized rather than developing drugs for all-comers – a trend that's already apparent in the race to develop medicines for rare diseases.

"I think we'll still see some blockbuster drugs," Stafford said, "but now we're looking at the right biomarkers for specific populations – including ethnicity and culture – and becoming more focused in our clinical research."

Stafford was among a panel of experts who testified earlier this year before the Committee on Energy and Commerce Subcommittee on Health Hearing on 21st Century Cures: Modernizing Clinical Trials. In her written testimony, she cited the use of newer trial designs, such as master protocols and adaptive designs, as one technique to enable more tailored and customized drug development without increasing the cost of clinical trials.

Stafford said Quintiles "strongly supports" the adoption of alternative development pathways to speed the introduction of new therapies that would address unmet medical needs for patients with serious or life-threatening conditions, such as the EMA's adaptive licensing approach now in a pilot program. (See BioWorld Today, March 21, 2014.)

In 2013, she pointed out, the FDA examined a similar alternative pathway, seeking to study the safety and effectiveness of a drug in a subpopulation of patients with more serious manifestations of a condition.

"Such a pathway could involve smaller, and more focused clinical trials than would occur if the drug were studied in a broader group of patients with a wide range of clinical manifestations," including the use of biologically and clinically meaningful surrogates as nonmortality endpoints, Stafford pointed out. "The labeling of drugs approved using this pathway would make clear that the drug is narrowly indicated for use in limited, well-defined subpopulations in which the drug's benefits have been shown to outweigh its risks."

Allowance of such designs and endpoints should obligate sponsors to conduct evaluations of longer-term, post-approval safety and outcomes, she added.


Indeed, as the clinical development process evolves, a drugmaker's knowledge of and creativity in selecting appropriate trial designs is part of the due diligence that investors perform, according to Jim Healy, general partner at Sofinnova Venture Partners in Menlo Park. The use of tools such as biomarkers, big data, master protocols and adaptive designs represents "different ways of coming at the same theme," he said.

"If you can identify a patient population that will have the highest response rate, highest treatment effect and best safety margin, those are the patients for which the drug should be the safest and most effective," Healy said. "The question is: Do you want to do the stratification using biomarkers? And how will those biomarkers be used across different ages, races and genders to identify relevant subgroups of patients?"

When looking at older populations, for instance, biopharmas should examine the impact of declining mobility and metabolism on a drug candidate's efficacy. Geriatric patients have different levels of drug absorption, distribution, metabolism and excretion and typically use many more drugs than younger populations. "It's important to understand that whole process," Healy said. "They're much more complicated patients."

For active trials in its portfolio companies, Sofinnova wants to see appropriate distribution across geography, gender, disease severity, race and age. Addressing such concerns requires sponsors and CROs to rigorously monitor patient distribution, sometimes initiating additional sites or shutting down existing ones to attain the right balance.

"It takes a lot more time and effort, and more money, as well," Healy admitted.


But broader outreach also could improve trial outcomes. An analysis of data from Cortellis CTI conducted this year by Alvaro Arjona, editorial director for drug development in the IP & Science Division of Thomson Reuters, found that inadequate subject enrollment was cited in 60 percent of the 5,900 terminated trial records in the database.

Seeking to use adaptive trial designs and to enroll more inclusive populations aren't mutually exclusive goals, according to Wuxi's Mu. Instead, the use of adaptive design can enable sponsors to conduct more efficient trials of potentially promising drugs in subpopulations without wasting precious resources.

He offered some hypothetical scenarios.

"Let's say you have patients from different ethnic groups represented in a trial, and you find a certain ethnic group responded to the drug therapy particularly well," Mu suggested. "At that point, you may want to modify your study design to target that study subpopulation and accumulate more data so you can show that the new medicine really benefits that group of people. On the other hand, if a specific subgroup does not benefit from the medicine at all, you can make a quick decision and maybe drop that group."


Cancer is probably the biggest indication in which regulators and patient advocates are troubled by the lack of diversity in clinical trials, but others, such as Alzheimer's disease, loom large as the population ages and individuals older than 65 – the most common enrollment cutoff – represent increasingly large proportions of treated patients. If drugmakers expect to meet the challenges of expanding trial enrollment while holding the line on costs, they need a business case designed to accomplish that goal.

Getz suggested developing a plan that starts at the point of access.

"The literature shows very high willingness among minority patients to participate in clinical trials, but many patients from diverse communities don't know of, and can't gain access to, clinical trials because so few minority physicians participate in them," he said.

Tufts CSDD research also shows that the incidence of minority and female principal investigators is very low, yet patients most prefer to see a physician who shares their gender and ethnicity. Sponsors and CROs can invest resources and time to identify and nurture relationships with individual female and minority physicians and sites or networks that encompass more diverse physician panels, Getz suggested.

"It's hard to make the numbers work long term, however," he admitted. "Often, after an initial investment of time and resources and engagement on a study or two, sponsors move on to their next project, and female and minority investigators are unable to attract enough clinical study grant volume to stay in business. Our research shows the highest levels of turnover among minority investigators."

Movement toward conducting trials in actual use settings and the advent of electronic health records supporting trial enrollment may facilitate more effective identification and recruitment of minority study volunteers, Getz added, but drugmakers still need to make those steps priorities.


Drugmakers often are wary of working with physicians who are not experienced in running clinical trials, PhRMA's Ulrich admitted, and she agreed that sponsors and CROs must "change the conversation." They should educate physicians in underserved communities about the mechanisms of operating clinical trials and provide them with sufficient resources to join trial networks, she suggested. Drugmakers and CROs also should partner with organizations outside the health care arena that reach underserved populations.

"There's an educational piece as well as a cultural competency piece," she said. "But first there needs to be a change within the industry to reach outside traditional academic medical centers by going to local hospitals and other places in underserved areas."

The impetus to hold those conversations may be accelerated by major policy shifts by the Department of Health and Human Services (HHS) and the NIH. Last month, HHS issued a Notice of Proposed Rulemaking requiring researchers to submit results from trials of investigational compounds that fail to meet clinical or safety endpoints. Simultaneously, the NIH released a draft policy that would apply the HHS data reporting requirements to interventional trials that it funds. The proposed changes will subject nearly all clinical trials to mandatory reporting under Title VIII of the Food and Drug Administration Amendments Act of 2007, requiring researchers to register trials, including early stage and expanded access studies, and submit summary results to in a standardized format, no matter what the outcomes. (See BioWorld Today, Nov. 21, 2014.)

Biopharmas have an opportunity to work collaboratively with regulators now to develop workable strategies for enrolling underrepresented populations in a way that doesn't hinder overall drug development. The alternative to proactive cooperation could be an even more onerous regulatory environment with enrollment targets that could be hard to meet.

"We don't want to see a punitive system in place that could restrict access to a broader patient population," Womack said. Similarly, while assessments of demographic subsets may be carried out as part of a pre-specified or sensitivity analysis in assessing the effect of a drug in a clinical trial, subset analyses should not trump findings across the entire study population, according to BIO's response to the FDA.

PhRMA's Ulrich agreed.

"There may be some initial hurdles and investment in order to make sure physicians are adequately trained or we've invested in sites that will recruit an appropriate patient mix," Ulrich said. "At the same time, there will be a benefit. The more we understand about how well medicines work in the patients who will actually be taking them, the better off the entire industry will be. From a patient and public health perspective, it's important that we do the right thing."

Editor's note: See Tuesday's issue for the next part of BioWorld's series on the lack of diversity in clinical trials, with a focus on gender diversity.

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