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The importance of representation in clinical trials

pharmafile | June 2, 2021 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing | Representation, clinical trials

Before any kind of new medicine can be made available to the market, it has to go through a strictly monitored development process. Only after passing strict safety and quality standards will a licence be granted.

In the UK, licences for new medicines are granted by the MHRA and the EMA, and will continue to be for two years post-Brexit.

The incredible progress of the coronavirus vaccinations − including the Moderna, Oxford-AstraZeneca, and Pfizer-BioNTech vaccines − allowed the life-changing medicine to gain approval and be distributed faster than most could have imagined possible.

Moderna, Oxford-AstraZeneca, and Pfizer-BioNTech developed their safe and effective COVID-19 vaccines in less than a quarter of the time it took to achieve the same for mumps − the previous record holder.

What this triumph demonstrates, in addition to the wonder of modern medicine, is the importance of swift and efficient clinical trials.

However, a lack of ethnic and gender representation in clinical trials in general can make the data unreliable.

Underrepresentation in clinical trials

Historically, women have been excluded from clinical trials for reasons such as hormone fluctuations due to menstruation, as well as fears that women included may fall pregnant during the trial, even when the drug in question is designed primarily for women.

It was this way of thinking in 1977 that led to a freak incident involving adverse reactions to the sedative Thalidomide. The FDA decided “women of childbearing potential” should be excluded from the vaccine trials because they were deemed to be too “complex” and “risky”.

It is now known that due to the difference in cell make up between men and women that reactions for drugs may differ.

When it comes to ethnic minorities in clinical trials, participation is much lower than compared with white people. For example, of 4,922 patients who participated in clinical trials that led to approvals for 18 new oncology drugs during 2020, 73% were white, 14% were Asian, 6% were Hispanic, and 5% were Black or African American, according to the FDA.

In fact, it was only in 1993 that the National Institutes of Health (NIH) Revitalization Act mandated that women and members of racial and ethnic minorities be recruited for all NIH-sponsored clinical trials.

A decade-long study, published in JAMA Network Open, found that among US-based vaccine clinical trials, people who are Black/African American, American Indian/Alaska Native, Hispanic/Latino, and aged 65 and older were the most underrepresented groups. Conversely, adult women were overrepresented.

The research team examined 230 US-based vaccine trials of all phases, with nearly 220,000 participants from July 2011 through June 2020, and found that 78% of all participants were White and 11% were African American, while American Indians/Alaska Natives accounted for 0.4%, Hispanics/Latinos accounted for 12%, and people 65 and older accounted for 12%. Asian and Native Hawaiian/Pacific Islander participants were equitably represented in vaccine trials compared to the US population.

Dr Steve Pergam, an Associate Professor in the Vaccine and Infectious Disease Division at Fred Hutchinson Cancer Research Center said: “The COVID-19 pandemic and its devastating impact, particularly on BIPOC (Black, Indigenous, and people of colour) communities and older adults, is a painful reminder of the health disparities in our country.

“This collaborative work highlights a problem that’s plagued the scientific community for too long − inadequate representation in clinical trials. The diversity seen in COVID-19 vaccine trials demonstrate we can do this, but we need to assure future studies focus not just on rapid enrolment but also on inclusion.”

Risks of underrepresentation

Representation in clinical trials is vital as a lack of it can lead to a lower vaccination uptake in underrepresented communities. If people feel as though they’re not being included in the trial, it can lead to them not trusting the end result.

Dr Michele Andrasik, a Senior Staff Scientist at Fred Hutchinson Cancer Research Center who also leads engagement efforts for the COVID-19 Prevention Network said: “Vaccine hesitancy and a lack of understanding about safety is a major challenge we’re facing with COVID-19.

“By improving enrolment diversity, we can better engage these underrepresented groups early in the trials stage and address the education and trust issues.”

The Association of the British Pharmaceutical Industry (ABPI) is calling for the research community to work with government, funders, and the public to tackle issues around diversity and inclusion in research. The ABPI President Haseeb Ahmad, said: “I speak a lot about how companies and society need to be more progressive in their approach to diversity – this is as true for clinical research as it is for everything else.

“From shaping the design of a clinical trial to recruiting the right patients – all members of the public from all backgrounds should have the opportunity to be involved and engaged with research. This not only ensures that new medicines and treatments are developed with the patient in mind, but that the research findings are representative of society.

“In particular, the COVID-19 pandemic has reinforced the need to address the underrepresentation of Black, Asian, and ethnic minority (BAME) groups in research, who have been disproportionately impacted by the disease.

“In a study investigating the differences in engagement with medical research across ethnic groups, BAME groups were less likely to participate, with occupation, education, health, attitudes to medical science, and belief all identified as contributing factors.

“To improve the participation of BAME groups in research, as well as their broader involvement and engagement, we urgently need to rethink how we conduct research. The National Institute for Health Research (NIHR) Clinical Research Network’s INCLUDE project developed new guidance to facilitate best practice in the design, funding, approval, and delivery of research for underserved groups.

“Pharmaceutical companies are also playing their part, with TransCelerate Biopharma, a group of global biopharmaceutical companies establishing a clinical trial diversification initiative to enhance the racial and ethnic diversity of clinical trial populations.

“There is no doubt that a key pillar of ethical research is delivering maximum benefit for all. By opening up research and being more inclusive, we can truly improve how we research and develop medicines and vaccines so that they better meet the needs of patients worldwide.”

Though women on the whole are more fairly represented in clinical trials now, the same still cannot always be said for pregnant woman. Due to the risks involved, they are often told they cannot take part in clinical trials, meaning they have to make the decision for themselves when it comes to vaccinations.

This was the case when the global vaccine rollout first began in December and pregnant women were given the choice to take a drug that hasn’t been tested on pregnant people or risk getting COVID-19. This was an especially difficult decision when pregnant women are also extremely vulnerable to adverse COVID-19 complications.

Despite health experts across the world – including WHO, FDA, and CDC, the NHS and the Federation of Obstetric and Gynaecological Societies of India (FOGSI) – almost unanimously asserting that it is safe for pregnant and lactating women to take the COVID-19 vaccines, the Ministry of Health and Family Welfare in India continues to list pregnant women and “women who are not sure of their pregnancy” as contraindications to the vaccine.

In February, Pfizer became the first company to announce it was conducting clinical trials on pregnant women with the Pfizer-BioNTech COVID-19 vaccine. The UK is also set to launch its first Pfizer-BioNTech vaccine study for pregnant women. Though this is a great step, unless all the other vaccines do the same, pregnant women won’t feel assured that they’re safe.

Dr Hrishikesh Pai, gynaecologist and infertility specialist, said: “It would be appropriate if the Ministry of Health, Government of India modifies its advisory so that the pregnant and breastfeeding women can be vaccinated.”

It’s important to generate this data so that everyone can make informed decisions. More data, whether for pregnant women or ethnic minorities, would allow vaccine regulators and health authorities to tackle the problem of vaccine hesitancy with statistics and proven fact, rather than rumour and hearsay.

Other factors

Although lack of data and representation from clinical trials plays a big part in vaccine hesitancy, confusion, and low take-up in groups such as ethnic minorities and pregnant women, there are a number of other factors that come into it.

A recent US poll by the Kaiser Family Foundation found that people of colour still lack the resources they need to make informed decisions about getting vaccinated against COVID-19. It found that the Black and Hispanic adults surveyed worry more than white respondents about missing work due to side effects, paying out-of-pocket for the free vaccine, or finding a reputable clinic to obtain the shot.

The survey’s interesting findings was that 45% of Hispanic adults said they did not have enough information about when they could get vaccinated, and 42% said they were unsure about their eligibility, even though all adults are now eligible.

Kaiser Family Foundation’s Associate Director for Public Opinion and Survey Research Ashley Kirzinger said: “Clearly more outreach efforts need to be done in these communities.”

Kirzinger highlighted that Black and Hispanic adults were not the most vaccine-hesitant. It was found that white Republicans have been more hesitant than any other demographic group, although this dropped from 29% in March to 20% in April.

In other words, people of colour with reservations about getting the vaccine were often seeking more information about the shot’s safety and efficacy. They had legitimate questions they wanted answered. In Hispanic communities, a language barrier may be keeping that information inaccessible.

This means that people without a certain level of English language proficiency are being left behind when it comes to information on medicine and vaccines. This would in turn lead to a lack of involvement from these people in clinical trials.

In fact, there has been a federal civil rights complaint made alleging people with limited English language proficiency do not have “meaningful access” to COVID-19 resources.

GlobalData has also found that the Indian variant of COVID-19 may impact minority and deprived communities hardest in the UK.

Emily Martyn, Infectious Disease Analyst at GlobalData, said: “Outside of India, the UK has reported the highest number of Indian-variant COVID-19 cases. In just one week, cases tripled from 520 to 1,723, the majority appearing in localised areas such as Bolton and Luton and mainly associated with people connected to travellers to and from India.

“However, scientists’ main concern is vaccine hesitancy among ethnic groups and deprived communities, who are more likely to die from COVID-19 than their White counterparts. Vaccine hesitancy for these groups stems from experiencing a greater number of negative encounters with the healthcare system.

“A recent UK poll conducted by the Royal Society for Public Health has shown that 57% of respondents from Black, Asian, and minority ethnic backgrounds would accept the vaccine compared to 79% of white respondents.

“The reasons behind vaccine hesitancy for ethnic minority groups point to factors such as low confidence in the vaccine, distrust, access barriers, inconvenience, socio-demographics, and a lack of communication from trusted providers.”

Martyn continued: “The UK needs to not only prioritise vaccine access to vulnerable communities, but also actively engage to build up trust and confidence in health systems. Public Health England and the BMA Council Chair Chaand Nagpaul demanded the government address the effect of COVID-19 on BAME communities back in June 2020. Now is the time for the UK Government and health services to step up and provide the help and support they desperately needed over a year ago, to prevent yet another wave of illness and death that has already hit these communities the hardest.”

Final thoughts

Representation in clinical trials has shown to be extremely important, as without it, there is a lack of data for certain parts of the population. This lack of data has an impact on advice given by regulators, trust in health authorities, and uptake in vaccinations.

Lack of representation in ethnic minorities for clinical trials also points to wider issues such as general distrust, negative encounters with the healthcare system, lack of access to facilities and information, and a lack of communication. Diversity and inclusivity are needed in all aspects of pharmaceutical healthcare to tackle these problems head on.

Lilly Subbotin