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Many companies are working hard to ensure their clinical trial populations match the diversity of the intended patient population, and Medical has a central role to play.

By Hugh Gosling on Jan 24, 2018

In 2000, as the Human Genome Project was reaching its crescendo, US President Bill Clinton reported a conversation with a scientist in his State of the Union Speech. “We are all, regardless of race, genetically 99.9 percent the same.”

This figure may now be disputed, but the point remains – we human beings are far more alike than we are different. Yet, that difference is everything. It makes us good at mathematics while our neighbor a star in the arts, it makes us prefer the taste of black tea over a non-fat soy cinnamon latte. For good or ill, we celebrate the individual differences between us and our fellow men and women in every part of our lives.

However, when it comes to medicine and health, our individuality is rarely so visible. Populations are homogenized, averages calculated, thresholds established to delineate disease and non-disease states. Nowhere is this phenomenon placed under such a microscope as in the carefully controlled environment of the clinical trial, into which participants cannot enter until they have met a stringent list of criteria.

Yet, this search for patients that are most likely to give our scientists the cleanest data has led to a mismatch between the make-up of clinical trials populations and the patient population the drug is destined to treat. The full range of our differences has not been factored in.

Today, the situation is changing, says Pol Vandenbroucke, VP Medical Strategy in the Chief Medical Office at Pfizer, and many companies are actively seeking to ensure that those entering their clinical trials reflect the true diversity of the intended patients. “If a population is not involved in clinical trials, we simply do not know how our drugs behave in that population,” he says. “The goal here is not to match the diversity in the overall population but specifically to ensure our clinical trial populations resemble the makeup of the population that has the disease.”

Not doing so can have a significant knock-on effect. “Regulator and payer attention to the diversity in trials is growing; the FDA, for instance, has a website called Clinical Trial Snapshots that lists the demographic characteristics of the populations that drugs were studied in and whether there is sufficient information to establish potential differences in the way some segments of the patient population may respond.”

Moving beyond access, unrepresentative trials can negatively influence the commercial success of a drug. “With labelling, we are seeing statements appear that state if there is insufficient information available in a particular patient group. Clearly, this can have an impact when a drug is marketed. Also, some companies have had to carry out additional studies as part of post-approval commitments, and those studies can be time consuming and have an impact on the cost of development.”

Understandable reluctance
Considering the potential downsides, why has a drive towards better diversity in clinical trials not come sooner? “The industry has struggled to make clinical trial populations reflect the end user population because it is very difficult to do,” says Vandenbroucke.

Progress has been made in recruiting more women into clinical trials. “With gender, the male-female ratio is much better than 20 years ago and, while we need to remain vigilant, this is less of an issue today.” Yet, other factors remain a challenge. “In the US, in particular, it is difficult to enroll certain ethnic groups in clinical trials, notably African-Americans and Latinos.”

Some of this difficulty can be traced to mistrust related to a dark chapter in the history of medical science, he says. “With African Americans, there are historical issues, including around the Tuskegee Syphilis trials, and the memory of these linger, adding to the reluctance to participate in clinical trials.”

Beginning in the 1930s, the Tuskegee trial ran over four decades to observe the natural progression of untreated syphilis in rural African-American men in Alabama under the guise of receiving free healthcare from the United States government. The study continued even after curative treatment became available and study subjects were not informed.

While this reluctance has been acknowledged over many years, it does not fully explain the lower levels of patient involvement in trials among African Americans. “There is also the question of whether patients are exposed to the possibility of participating in clinical trials. We know that African Americans and Latinos are far less likely to be offered the chance to enroll in a clinical trial by their physicians, which is especially important in oncology and rare diseases where sometimes a trial may be the only treatment option.”

Low involvement in trials by members of the Latino population is also a serious issue, he says. “When we analyzed the data, the lack of inclusion was largest in the Latino population in the US, even lower than African Americans. This is a problem for several reasons; firstly, this population is the fastest growing in the US, already representing about 15% of the population, and secondly, because it is a population that suffers disproportionately from diseases like diabetes, obesity and hypertension.”

Ethnicity will also become an increasingly important factor in European populations in the near future, says Vandenbroucke. “In most European countries, we are seeing a much larger part of the population coming from outside the continent. There is rarely up-to-date information available on the ethnic make-up of the population in a specific disease area; to know, for example, how many people of African descent in European cities have diabetes. But, we must have this information in order to guide our clinical research teams.”

Another layer of complexity is added when considering pediatric trials, he says. “Children tend to be at the forefront of demographic changes, and this is sometimes forgotten.”

Getting older
However, diversity goes far beyond gender and ethnicity, says Vandenbroucke. “Globally, many populations are ageing, and we need to recognize that our bodies – and how our bodies deal with drugs – change as we age. It is crucial that we understand how our drugs behave in older adults.”

Yet, ‘older adults’ are also far from a homogenous group, he says. “With older adults, we see huge variation and complexity. We see significant comorbidity as well as polypharmacy, all of which needs to be better understood. What’s more, an 85-year-old is fundamentally different from a 65-year-old across a huge range of factors, not least the number of other treatments they receive and their lifestyle.

“Even in the same age bracket, people are very different, and the concept of frailty is very important – you can have a very robust 75-year-old or a very ill 75-year-old. The inclusion criteria of trials need to take all of this into consideration.”

A new angle
Within companies, Medical is well-placed to take on the Herculean task of ensuring diversity in clinical trials, says Vandenbroucke.

“Drug developers are incentivized mainly by how quickly they can complete a development program, so speed is incredibly important, not least to ensure that breakthrough drugs reach the patients that need them as fast as possible. I believe that, if we are to evolve the model to ensure we pay much more attention to the diversity of the trials population, it needs to be driven from a different angle. This is best done by a group that is closest to the actual patient population and which has experience of treating a diverse patient population, so Medical is an ideal department or group to do that.”

At Pfizer, efforts have been pursued on two “very different” levels; the first is reaching out externally. “Historically, a lot of diversity efforts have been focused on reaching out to organizations such as the National Urban League or groups that represent Latino physicians or nursing associations, or even working through churches, and there is definitely a need for this.”

However, it is the second level that Vandenbroucke believes needs greater focus. “What has had less attention paid to it is reaching out internally to development teams and trials sites to help them to focus on a more diverse population. There are studies that show that African Americans in the US will participate in trials, but we need to raise awareness of this among investigators,” he says. “We need investigators to proactively reach out to a diverse population but a lot of the time they are never asked to.”

The team developed a series of videos for use with development teams and investigators to help them talk about the various barriers to diversity and ways to overcome them. For instance, with Latino patients, this might be the language barrier.

Tools are also important, he says. “We’ve developed a system for development teams to access information related to the diversity of the population in real time, to see how it compares to the diversity of the population that will eventually use the drug. We’ve seen great results in some of our pilot programs, with teams paying much more attention to diversity than before.”

Along with awareness and tools comes governance. “Ifthe governance of trial programs emphasizes the need for diversity, and has metrics, then it becomes a very powerful tool to focus teams on coming up with ways to increase the diversity of their population. This may include going to different sites where we can access more diverse populations – historically, development teams have gone to the sites they know – so there’s also an element of building capacity to ensure we have clinical sites that have greater access or willingness to access diverse populations.”

Vandenbroucke believes he is pushing against an open door. “Trial teams want the best possible data, and we’ve been surprised how quickly we reached a much more representative population in the pilot projects. How close are we to true diversity? There is still a lot to do and we are still very far from having achieved it, but we’ve made very good progress in some of our pilot programs and we’ve learned quite a bit that we will apply to the rest of the portfolio.”

Pol Vandenbroucke will be joining a line up of thought leaders at our Medical Affairs USA event in April