Clinical trials and the diversity principle

For years, maybe decades, a few minutes in PubMed or Google has provided all the evidence the interested observer needs to learn that there’s a problem with the equitable representation of diverse people in clinical trials. It reaches across various aspects of demography – including age, gender, sexual orientation, socioeconomic status and geography – and is particularly visible when it comes to minority populations. For those people, the lesson has been rather more tangible – in the absence both of clinical trials themselves as a care option, and medicines proven to be effective for them.

Examples abound, but systemic lupus erythematosus (SLE) – a disease for which there has only been one new drug approval since 1955 – is a notable case in point: while Black people account for 43% of all cases, between 1997 and 2017 they made up just 14% of patients enrolled in SLE studies.

Given the pharmaceutical industry depends on an effective clinical trial paradigm to bring new, commercially viable medicines to market, and these issues have been so well described, for so long, you might think the situation is improving. Well, according to Drug Trials Snapshots, published by the FDA since 2015, between 2018 and 2019 they got marginally worse. Things are not any better anecdotally.

“Just last week I spoke to a Black woman who has had cancer for a decade and has never been offered a clinical trial, even as options failed her,” says Jen Horonjeff, co-founder and CEO of Savvy Cooperative, a patient-owned organisation that works to get patients’ voices heard by pharma and the healthcare industry.

"I spoke to a Black woman who has had cancer for a decade and has never been offered a clinical trial, even as options failed her" - Jen Horonjeff

The inevitable question is: Why? Respected organisations with cross-industry support, like CISCrP (Center for Information and Study on Clinical Research Participation), work tirelessly to promote awareness among the underserved populations themselves. Meanwhile, the FDA itself says its guidance has evolved ‘over the past few decades’ to encourage trial sponsors to recruit trial populations that reflect the population for whom the medicine will be prescribed, if approved. This remains a recommendation, rather than a rule, but the threat of a drug with an unrepresentative trial population having a warning placed on its label – or the sponsor being asked to run a whole new study – is real. And yet.

The tyranny of the timeline

There is no doubt the reasons people from minority groups continue to be under-represented in trials are complex. They extend from protocol design, to the feasibility and site selection process, to implicit and explicit bias among HCPs and patients, to health literacy, awareness, access, and historical abuses – among other considerations. Clinical trials are tough to coordinate and complete at the best of times, and these are big, knotty, overlapping problems. Expensive-sounding problems.

Let’s take feasibility as a case in point. According to Liz Beatty, Chief Strategy Officer at Inato, a technology start-up with a marketplace approach to site selection, it takes around 8.5 weeks for a sponsor to start working again with a site they’ve worked with in the past. If it’s a site they’ve never worked with before, it takes about 14.5 weeks.

“I think it became easy to justify that ‘we should stick with the sites we know',” says Beatty. “'We know how to get them started and then we won't have a negative impact on our timeline’. Just from a simple timeline and speed perspective, it became not worth the extra time, extra energy, extra training. All that extra operational work had a negative impact on getting your study started. And that is such a big time period for a pharma company, that whole study start-up period.”

"It became not worth the extra time, extra energy, extra training" - Liz Beatty

What this has inexorably led to is, in Beatty’s words, a hyper-concentration of clinical trials at the same centres, with the same investigators. Inato has data that shows over the last ten years 70% of all clinical trials have been run at 5% of the available sites. This has obvious implications for various aspects of diversity and inclusion.

Is a change gonna come?

In January, there was nothing to suggest the saga of how minority groups inevitably end up on the wrong side of that bottleneck would break out of industry commentaries, or the peer-reviewed pages of PubMed. But then COVID happened, and a broader narrative about the inter-relationship of race, socioeconomic status and healthcare outcomes began making international headlines. Clinical trial diversity suddenly seemed to have a whole new status.

In August, Bristol Myers Squibb announced it was committing $300m to tackle diversity in clinical trials, saying ‘COVID-19 has exposed the severity of social and health disparities in the US that increase the risk for infection and poorer health outcomes for Black/African American and Hispanic/Latino communities'. The company said its five-year investment would ‘extend the reach of clinical trials into underserved patient communities in urban and rural US geographies’, including training and developing 250 new racially- and ethnically-diverse clinical investigators’.

The following month, it happened again. Cambridge, Massachusetts-based Moderna said it had slowed enrolment in its phase 3 COVID-19 vaccine trial to ensure they were getting a representative population. With a dozen competitive vaccine trials in phase 2 or 3, and other protocols with demonstrably more aggressive schedules than their own, Moderna’s CEO Stephane Bancel was quoted as telling CNBC he would rather take an extra week – if it meant having a more diverse trial population.

The principle of the thing

The Moderna story showed two important truths. The first was that, even in the face of a novel virus that disproportionately affects minority groups, it remains very difficult to recruit a diverse trial population. The second was that it’s unacceptable not to. Whereas Black people make up around 14% of the US population, reports suggested their representation in the Moderna study was only 7%, and that just wasn’t good enough.

“I would say there’s a big move happening, across quite a few sponsors,” says Liz Beatty. “But not everyone is publishing a commitment like BMS,” she said. “So I think that’s where they really are standing out – they’re doing it at a corporate commitment level. And that’s always very positive to see, because that means they’ll get the support they need to really push the envelope around diversity in clinical trials.”

Bill Bernach, the legendary ad man and co-founder of DDB, one of the world’s most lauded creative agencies, once said a principle isn’t a principle until it costs you money. He was referring to DDB’s refusal to work on lucrative cigarette accounts during the 1960s, but there is something about his aphorism that cuts through when it comes to the diversity and representation problem. What stands out with both Moderna and BMS is the dollar commitment. Moderna effectively sacrificed potential sales, while in the detail and scale of its investment, BMS appears to be going to the heart of those apparently intractable, expensive-sounding problems.

“I see this as a tangible commitment to shift the tide,” says Jen Horonjeff. “We know the pharma industry in particular prides themselves on being patient-centred, but unless resources are allotted and action is taken, then it is nothing more than a self-proclaimed title. The same goes for diversity, equity, and inclusion efforts. The theme that emerges from each of these examples is money. To me, this is the real shift, and why it increases the probability that there will finally be substantial change.”

“COVID has been like a magnifying glass" - Angela Rochelle

At Langland, we work every day with healthcare clients looking for ways to understand and improve representation in their clinical trials. In September, we welcomed Angela Rochelle to our US team, in a new role as Head of Diversity Initiatives in Clinical Trials. Angela has more than two decades of experience in advertising and communications, inside and outside healthcare, and particular expertise when it comes to engaging minority populations.

“COVID has been like a magnifying glass, revealing systemic healthcare issues that have a negative effect on communities of colour,” she says. “Healthcare, and more pointedly clinical trial research, will have to put in more efforts to connect and engage with communities where they are, sharing information while also looking to truly understand real life barriers to clinical trial participation.”

Note the emphasis on efforts. This is a plural problem, and it needs plural solutions.