Millions of adults around the world are diagnosed with ADHD every year, and there is a great need for research in the field. Yet much clinical research on adult ADHD suffers from serious methodological shortcomings that make it difficult to use the results in practice, researchers from the University of Copenhagen and the University of Sao Paulo show in a new study.
Originally developed for children, the diagnosis of ADHD is often difficult to make in adults. This is partly because the diagnostic criteria are based on behaviour in children. When diagnosing adults, however, these criteria are often based on adults’ subjective experiences, eg, of having difficulty concentrating or being very impulsive.
“The rising number of adults diagnosed with ADHD raises important questions about diagnostic validity – especially since many were never identified in childhood and are now seeking help, sometimes prompted by ADHD content on social media. That made us curious: how have randomised controlled trials on ADHD dealt with this diagnostic challenge?” explains Dr Igor Studart, who is first author of the study published in European Psychiatry.
Moreover, ADHD shares its symptoms with a number of other mental disorders such as depression, schizophrenia, and bipolar disorder, making it crucial to exclude these disorders when diagnosing ADHD. This requires a thorough diagnostic assessment by an experienced psychologist or psychiatrist.
But it is not always the case that such a thorough assessment is made. The study now shows that even psychiatric research into ADHD often neglects this fundamental work.
“We have examined how 292 of the most credible studies in evidence-based medicine – the so-called randomised controlled trials – diagnosed their adult subjects,” says Professor of Psychiatry and Consultant Psychiatrist Julie Nordgaard, who conducted the study together with Associate Professor and Senior Researcher Mads Gram Henriksen and Dr Igor Studart.
She continues:
“We conclude that half of the studies did not ensure a broad and thorough diagnostic assessment of the patients before the trial to rule out other disorders. This means that they can’t actually know, if their subjects have other mental disorders such as depression or schizophrenia. And that’s not all. More than half of the studies included subjects, who have also been diagnosed with other mental disorders, making the diagnosis even more difficult to allocate”, Julie Nordgaard explains.
According to the researchers, these methodological shortcomings are problematic, because they imply that it is impossible to know which disorders and symptoms the treatment investigated in these trials potentially had an effect on.
“This makes the research results from many of these clinical trials difficult to utilise. Yet, the results of randomised controlled trials are considered particularly trustworthy, and they may inform the guidelines we use to treat adult ADHD patients, even though the results from many of these trials should be assessed very carefully,” says Mads Gram Henriksen.
A need for consistent and robust diagnoses
According to the researchers, one of the problems with the diagnostic assessment in many of the clinical trials is that it seems to have been carried out by people who are not trained to do so. And often with methods that are not thorough enough.
“In 61% of the studies, they do not state who diagnosed the subjects. In only 35% of the studies, it is stated that a psychiatrist or psychologist made the diagnosis. But diagnostic assessment should always be performed by an experienced professional with the necessary training to ensure that the diagnosis is made correctly, and this should be stated in the studies’ method section,” explains Mads Gram Henriksen.
In some cases, the assessment and thus the diagnosis was made by the subject themselves, and in one particularly egregious case, it was done with the help of a computer, the researchers explain.
“In psychiatry, we really need that all diagnoses, not just ADHD, are made with the same uniform criteria and by trained professionals. Otherwise, we cannot rely on the results or compare them across studies,” says Julie Nordgaard and concludes:
“Especially in a situation where a diagnosis such as ADHD in adults is increasing, we need to be very thorough and have a solid foundation. Otherwise, we risk too many people getting a wrong diagnosis and not being able to give them the most effective treatment. Or they risk receiving unnecessary treatment that causes side-effects.”
Investigation finds evidence of serious misreporting, raising fresh doubts over the approval and decade long use of ticagrelor
Photo by National Cancer Institute on Unsplash
In a follow up investigation into the multibillion dollar drug ticagrelor, The BMJ has uncovered fresh concerns, this time in key platelet studies used in its FDA approval.
For more than a decade, ticagrelor (Brilinta in the US and Brilique in Europe) has been recommended for patients with acute coronary syndrome – a range of conditions related to sudden reduced blood flow to the heart.
Last December, an investigation by The BMJ found serious data integrity problems in the landmark clinical trial (PLATO) that was used to gain worldwide approval for ticagrelor, calling into question the drug’s advantage over cheaper rivals.
Now, as generic versions of the drug prepare to launch this year, The BMJ has expanded its investigation, looking at two key platelet studies that AstraZeneca claimed explained ticagrelor’s ability to treat acute coronary syndrome successfully.
It finds that the “primary endpoint” results (the trial’s key measurement) for both clinical trials were inaccurately reported in the leading cardiology journal Circulation, and reveals that more than 60 of 282 readings from platelet machines used in the trials were not present in US Food and Drug Administration (FDA) datasets.
What’s more, one active trial investigator never became a study author, while one author told The BMJ he was not involved in the trial, and most investigators, including the principal investigator, were unreachable or declined to be interviewed.
Victor Serebruany, an adjunct faculty member at Johns Hopkins University and ticagrelor’s most renowned critic, told The BMJ that “there are episodes of skyrocketing rebound and profound platelet inhibition after ticagrelor making patients prone to thrombosis or bleeding. If doctors had known what happened in these trials, they would never have started using ticagrelor.”
Circulation and AstraZeneca did not respond to a request for comment.
Serebruany added: “It’s been obvious for years that there is something wrong with the data. That the FDA’s leadership could look past all these problems—on top of the many problems their own reviewers identified and are now being discovered by The BMJ—is unconscionable. We all need to know how and why that happened.”
Professor Ntobeko Ntusi is the president and CEO of the South African Medical Research Council. (Photo: SAMRC)
By Catherine Tomlinson
Cuts to United States funding of health research could have “catastrophic” consequences, says Professor Ntobeko Ntusi, who is at the helm of the country’s primary health research funder. He says the South African Medical Research Council is “heavily exposed” to the cuts, with around 28% of its budget coming from US federal agencies.
After an unprecedented two weeks of aid cuts by the United States government that left HIV programmes and research efforts across the world reeling, the Trump administration took the drastic step of freezing aid to South Africa in an executive order on 7 February.
The order – which is a directive to the executive branch of the US government and holds the weight of law – was issued to respond to what the White House called “egregious actions” by South Africa. It specifically points to the Expropriation Act and the country’s accusation of genocide against Israel at the International Court of Justice as the primary reasons for the funding freeze.
While there are some limited wavers and exceptions to the cuts, Spotlight understands that these have so far been poorly communicated and many HIV services remain in limbo.
The funding cuts, following an earlier executive order issued on 20 January, are interrupting critical health research underway across South Africa and will ultimately undermine global efforts to stop HIV and TB.
The US is a major source of financing for health research in South Africa. Many of the country’s research institutes, groups, and universities receive funding from the US through the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), USAID, and the President’s Emergency Plan for Aids Relief (PEPFAR).
Over the past few weeks, these funding sources have come under siege by the Trump administration resulting in a gaping, and most likely insurmountable financing gap, for many health research endeavors in the country.
US spending accounts for just over half (55%) of all spending on global health research around the world. In 2022, the super power spent $5.4 billion on global health research, according to Impact Global Health – an NPO that tracks health research spending.
While the US gives money to global health research through several different government departments and programmes, the largest source of funding for global health research is the NIH. The NIH contributed 65% of global financing for HIV research between 2007 and 2022, according to Impact Global Health and 34% of tuberculosis research financing in 2023, according to New York-based policy think tank, the Treatment Action Group.
South Africa has the biggest HIV epidemic in the world in absolute terms and is among the top 10 countries in terms of TB cases per capita.
Catastrophic consequences
“South Africa is the biggest recipient of NIH funding outside of the US”, Professor Ntobeko Ntusi, president and CEO of the South African Medical Research Council (SAMRC), told Spotlight. “[T]he consequences will be catastrophic if [funding] is stopped… for science that is important for the whole world,” he said.
South Africa plays a critical role in advancing HIV science, said Ntusi, adding that “many of the major trials that have advanced our understanding of both the effective strategies for HIV management, as well as understanding the mechanisms of disease emanated from South Africa”.
People in the US, for example, are now able to access long-acting HIV prevention shots, largely because of research that was conducted in South Africa and Uganda. Research conducted in South Africa has also been critical to validating new tuberculosis treatments that are currently the standard of care across the world.
Heavily exposed
Stop work orders were sent to research groups receiving USAID funding at the end of January. These stop work orders coupled with the halting of funding have already interrupted critical HIV research efforts, including efforts to develop new vaccines against HIV.
Ntusi said that the SAMRC is currently “heavily exposed” to the halting of grants from USAID and the CDC, with research programmes supported by USAID and the CDC already being stopped.
The SAMRC’s research on infectious diseases, gender-based violence, health systems strengthening, as well as disease burden monitoring are also affected by the funding cuts.
“In addition to support for HIV research, we have significant CDC grant funding in our burden of disease research unit, the research unit that publishes weekly statistics on morbidity and mortality in South Africa,” said Ntusi. “Our health systems research unit has a number of CDC grants which have been stopped [and] in our gender and health research unit we had a portfolio of CDC funding which also has been stopped.”
Along with programmes being impacted by the halting of USAID and CDC funding, Ntusi said there will also be major staffing ramifications at the SAMRC as well as at universities.
He said that if funding from the NIH is stopped “there would be huge fallout, we just wouldn’t be able to cover the hundreds of staff that are employed through the NIH granting process”.
The SAMRC’s combined annual income from US grants (NIH, CDC and USAID) is 28% of its total earnings (including both the disbursement from the SA government as well as all external contracts) for the 2025/2026 financial year, according to Ntusi. “So, this is substantial – effectively a third of our income is from US federal agencies,” he said.
Pivot away from infectious disease?
In addition to the executive order freezing funding to South Africa, it is unknown whether the NIH will remain a dominant funder of global health. Robert F. Kennedy Jr., the US health secretary nominee, has called for cutting to the NIH’s infectious disease research spending to focus more on chronic diseases.
Looking beyond health, Ntusi said the executive order halting aid to South Africa will be felt across a range of different development initiatives such as water and sanitation, and climate change.
Photo by Miguel Á. Padriñán: https://www.pexels.com/photo/syringe-and-pills-on-blue-background-3936368/
For oral medications that prevent new HIV infection to be effective, the patient must take certain actions, including attending doctor’s visits every three months and – most importantly – consistency.
These daily oral antiretrovirals, more commonly referred to as PrEP (pre-exposure prophylaxis), such as Truvada®, are extremely effective at HIV prevention, but only if they are taken daily as directed. Truvada’s efficacy is greatly compromised when taken inconsistently.
However, results from a recent Gilead-funded clinical trial (Purpose-2) led by physicians at Emory University and Grady Health System indicate that a twice-yearly injection of Lenacapavir offers a 96% reduced risk of infection overall, making the injection significantly more effective than the daily oral PrEP. The findings were recently published in the New England Journal of Medicine.
“Seeing these high levels of efficacy – at almost 100% – in an injectable that people only have to take every six months is incredible,” says Colleen Kelley, MD, lead author of the study and professor in the School of Medicine at Emory University. “This is a considerable and profound advancement in medicine, especially for people whose circumstances don’t allow them to take a daily oral medication, and for those among populations disproportionately impacted by HIV.”
In the randomised, double-blind, Phase III clinical trial comparing the efficacy of the two medications, 99% of the participants in the Lenacapavir group did not acquire an HIV infection. During the trial, only two participants in the Lenacapavir group, comprised of 2,179 people, acquired HIV. This compares to nine new HIV infections in the Truvada®group, which had 1,086 people. The trial showed that adherence to the injectable was higher than of the daily oral pill.
Kelley adds that while PrEP is incredibly effective at preventing infection, part of what made the injection more effective in the clinical trial was the challenges associated with adherence to a daily oral pill.
“What we see over time is that about half of people who start taking daily oral PrEP stop within a year due to various factors,” says Kelley, referencing healthcare disparities in general. “Having an effective injectable that is only needed twice annually is very significant for people who have trouble accessing healthcare or staying adherent to daily, oral pills.”
The inclusion of racially, ethnically, and gender-diverse participants in the clinical trial was notable because it was representative of populations disproportionately impacted by HIV in real time. For example, the trial groups were comprised of cisgender men and gender-diverse people at 88 sites in Peru, Brazil, Argentina, Mexico, South Africa, Thailand, and the US.
According to the study, the same populations that are disproportionately impacted by HIV are the same populations that have limited access to PrEP – or may have difficulty consistently taking the oral antiretroviral medication – ultimately highlighting the need for more options. The study also indicates that more than half of the new HIV infections nationwide in 2022 were among cisgender gay men, and 70% of those were among Black or Hispanic individuals.
Valeria Cantos, MD, associate professor in the School of Medicine at Emory University, physician at Grady Memorial Hospital, and the principal investigator for the clinical trial at the Grady research site, emphasized the importance of having trials that include populations truly representative of the patients that Grady serves.
“At Grady, our focus is on increased representation of underserved and vulnerable populations, acknowledging and addressing the distrust towards research held by some community members due to prior abuses or neglect of these populations by research institutions in the past,” Cantos says. “Grady is an established, trusted research site because of its commitment to equity.”
At the Grady clinical trial site, medical materials were available in Spanish, and bilingual staff members recruited and enrolled trial participants who only spoke Spanish. Cantos also indicated that the site enrolled participants who are representative of the populations that would benefit the most from Lenacapavir. In addition to Grady, the Hope Clinic and Emory Midtown Hospital were among the 88 sites supporting the clinical trial.
“We are not reaching everyone we need to reach with our current HIV prevention interventions, such as those who are disproportionately impacted by HIV and health care disparities,” says Kelley. “For people that are unable to take the daily oral pills, the injectable agents can really give incredible efficacy and be a game changer in helping them stay HIV negative.”
Since the Phase III clinical trial has been completed and submitted by the FDA for consideration, Kelley is hopeful that Lenacapavir may be approved by 2025 for commercial use.
A new thought piece led by the Harvard Pilgrim Health Care Institute with collaborators from Duke University and Kaiser Permanente Washington Health Research Institute highlights the challenges facing healthcare researchers and decision makers in the quest to improve population health in a constantly evolving healthcare landscape. The authors offer strategies to enhance the effectiveness of pragmatic clinical trials and increase their impact on real-world healthcare settings.
Pragmatic clinical trials, designed to inform health care decision-makers about the comparative benefits, burdens, and risks of health interventions, have seen a significant increase in interest over the past decade. Since 2012, the NIH Pragmatic Trials Collaboratory has supported 32 such trials, addressing critical issues like suicide prevention, opioid prescribing, and infection control.
Pragmatic clinical trials are designed to bridge the gap between research and care, and we believe this bridge can be built even more efficiently. – Richard Platt, MD, MSc
Pragmatic clinical trials compare treatments in everyday clinical settings, rather than under ideal conditions. However, the authors note that the adoption of trial findings by healthcare systems has been inconsistent.
“Our goal is to ensure that the findings from these trials are not only scientifically sound but also readily implementable in diverse healthcare settings,” says lead author Richard Platt, Harvard Medical School distinguished professor of population medicine at the Harvard Pilgrim Health Care Institute. “Pragmatic clinical trials are designed to bridge the gap between research and care, and we believe this bridge can be built even more efficiently.”
The authors identify key challenges and propose solutions to align trial goals with healthcare system needs, including:
Identifying relevant outcomes: Collaborate with healthcare leaders to determine the clinical or cost-saving outcomes that would motivate adoption.
Shortening trial duration: Designing trials to span 2-3 years to match the decision-making timelines of healthcare systems.
Conducting interim assessments: Utilizing interim analyses to provide timely information and potentially stop or modify trials early.
Considering costs: Understanding and planning for associated costs to ensuring interventions are sustainable post-trial.
“By accommodating the priorities of healthcare leaders and introducing adaptive trial designs, we can generate actionable evidence that truly improves patient care,” adds Dr Platt.
The method can be used to explore treatment effects in people underrepresented in clinical trials
Researchers used real-world clinical data to attempt to emulate a randomised controlled trial testing the effectiveness of two blood thinners, apixaban and warfarin, to prevent stroke in patients with non-valvular atrial fibrillation. The study, led by Emma Maud Powell at the London School of Hygiene and Tropical Medicine, UK, and publishing August 29th in the open-access journal PLOS Medicine, provides a method to explore the effects of treatments in patients who are underrepresented or excluded from clinical trials.
Patients experiencing atrial fibrillation – a potentially dangerous medical condition in which the upper chambers of the heart beat irregularly – will often be prescribed blood thinners such as apixaban or warfarin to prevent a stroke. However, these treatment recommendations are based on results from randomized controlled trials, and it is unknown if they are applicable to populations of patients who were not included in the trial or present only in very low numbers.
In the new study, researchers used routinely collected health data from patients in the United Kingdom to attempt to emulate a previous randomized controlled trial that compared the effectiveness of apixaban and warfarin. They attempted to emulate the patient eligibility, selection and analysis approaches as the previous trial. They found that patients prescribed apixaban had similar outcomes to patients prescribed warfarin, but unlike the previous trial, they did not find that apixaban was superior. The researchers observed the differences in results may have been linked to higher quality of warfarin control, sub-optimal dosing of apixaban, and differences in the ethnicity of patients and use of concomitant medications compared with the clinical trial population.
Overall, the study established that using an existing randomised controlled trial (the reference trial) as a guide for the design of observational analysis of real patient data is an effective and valid way to estimate the treatment effects and risks of blood thinners given to patients with atrial fibrillation. The methods developed in this study can be used to investigate the effects of these medications in patient groups that are excluded from or underrepresented in these clinical trials, such as the elderly, those with multiple conditions and people with a higher risk of bleeding. This method can also help medical researchers to understand whether results from randomized controlled trials are transferable to “real-world” practices, and provides a framework that can be adapted to investigate treatment effects for other conditions.
The authors add, “Our study aimed to emulate a reference trial in oral anticoagulants in patients with atrial fibrillation using routinely collected UK healthcare data. Reference-trial informed design provides a framework for the study of treatment effects in patient groups excluded from or under-represented in trials.”
Cancer patients who participate in clinical trials hoping for better outcomes fare no better than those who do not, when setting aside the new treatment’s effect, according to the results of a study published in the Journal of the American Medical Association. The analysis found that while overall, trials had a positive benefit, this effect diminished after accounting for various factors common to trial participants such as being younger. Evidence of publication bias was also uncovered.
Participation in a clinical trial may confer a survival benefit to cancer patients is known as a trial effect, and results from access to effective new therapies (the treatment effect), but it is also thought that a trial’s closer monitoring provides a distinct benefit as well (the participation effect). The treatment effect only applies if the treatment proves to be effective, while the participation effect should apply regardless of treatment effect. But the evidence for the participation effect has been conflicting. A pair of reviews, one conducted in 2001 and the other in 2004, found no evidence of a participation effect.
The researchers therefore sought to account for biases and confounding in differences between routine care patients and trial patients. A search was performed for studies comparing survival outcomes for the two groups between January 1 2000 and August 31 2022, which turned up 12 791 records. After screening for eligibility and duplicates, this yielded 39 studies (85 comparisons) for analysis. These comparisons involved haematologic (21%), breast (16%), lung (14%), central nervous system (7%), prostate (7%), and pancreatic cancers (5%), as well as melanoma (6%). The remaining 24% consisted of bladder, cervical, colorectal, oesophageal, gastric, head and neck, kidney, ovarian, and solid mix tumours. One-third of the comparisons involved advanced or metastatic cancer.
Initially, the meta-analysis revealed a statistically significant overall survival benefit for trial participants (HR [hazard ratio], 0.76) when all studies were pooled without regard to their design or quality. But in study subsets matching trial participants and routine care patients for eligibility criteria, the survival benefits diminished (HR, 0.85). Finally, the survival benefit disappeared when only high-quality studies were pooled (HR, 0.91). They also disappeared when estimates were adjusted for potential publication bias (HR, 0.94).
Further analysis (using funnel plots and Egger’s regression test) indicated there was a publication bias against studies which lacked a participation effect.
In an accompanying editorial, Wilson et al. note that the participation effect explains that, “Patients in trials are generally younger, fitter, have fewer comorbidities, and come from higher socioeconomic groups; this enrollment bias largely explains the participation effect. The implications of this finding are important for understanding how trials are often viewed in clinical practice. The participation effect is often used to promote the view that “a clinical trial is the best treatment option, ‘but this may be a false narrative.”
Corresponding author Jonathan Kimmelman, PhD concluded: “Our findings provide reassurance that inability to enroll in a cancer trial doesn’t disadvantage a patient, at least in terms of survival. Our findings can help patients (and physicians) focus their consent discussions on the most relevant and evidence-based benefits of trial participation: the prospects of advancing the care of future patients.”
Randomized controlled trials, or RCTs, are believed to be the best way to study the safety and efficacy of new treatments in clinical research. However, a recent study from Michigan State University found that people of colour and white women are significantly underrepresented in RCTs due to systematic biases.
The study, published in the Journal of Ethnicity in Substance Abuse, reviewed 18 RCTs conducted over the last 15 years that tested treatments for post-traumatic stress and alcohol use disorder. The researchers found that despite women having double the rates of post-traumatic stress and alcohol use disorder than men, and people of colour having worse chronicity than white people, most participants were white (59.5%) and male (about 78%).
“Because RCTs are the gold standard for treatment studies and drug trials, we rarely ask the important questions about their limitations and failings,” said Nicole Buchanan, co-author of the study and professor in MSU’s Department of Psychology. “For RCTs to meet their full potential, investigators need to fix barriers to inclusion. Increasing representation in RCTs is not simply an issue for equity, but it is also essential to enhancing the quality of our science and meeting the needs of the public that funds these studies through their hard-earned tax dollars.”
The researchers found that the design and implementation of the randomised controlled trials contributed to the lack of representation of people of colour and women. This happened because trials were conducted in areas where white men were the majority demographic group and study samples almost always reflected the demographic makeup where studies occurred. Additionally, those designing the studies seldom acknowledged race or gender differences, meaning they did not intentionally recruit diverse samples.
Furthermore, the journals publishing these studies did not have regulations requiring sample diversity, equity or inclusion as appropriate to the conditions under investigation.
“Marginalized groups have unique experiences from privileged groups, and when marginalised groups are poorly included in research, we remain in the dark about their experiences, insights, needs and strengths,” said Mallet Reid, co-author of the study and doctoral candidate in MSU’s Department of Psychology. “This means that clinicians and researchers may unknowinglyremain ignorant to how to attend to the trauma and addiction challenges facing marginalised groups and may unwittingly perpetuate microaggressions against marginalised groups in clinical settings or fail to meet their needs.”
A massive and long-awaited study of an experimental tuberculosis vaccine has kicked off in South Africa. Marcus Low reports.
Photo by National Cancer Institute
By Marcus Low for Spotlight
The first jabs in a much-anticipated clinical trial of an experimental tuberculosis (TB) vaccine have been administered at a clinical trial site at the University of the Witwatersrand in Johannesburg. Up to 20 000 people are anticipated to take part in the study, according to study sponsor, the Bill and Melinda Gates Medical Research Institute (Gates MRI).
The study will be conducted at 60 different sites in South Africa, Zambia, Malawi, Mozambique, Kenya, Indonesia, and Vietnam. The researchers estimate that between 50% and 60% of the study participants will be in South Africa.
The experimental vaccine called M72/AS01E (M72 for short) made waves in 2018 and 2019 when it was found to be around 50% effective at preventing people with latent TB infection from falling ill with TB over a three-year period in a phase 2b clinical trial. In June 2023, it was announced that, after some delays, $550 million in funding had been secured for a phase 3 study of the vaccine. Medicines or vaccines are typically only registered and brought to market after being shown to be safe and effective in large, phase 3 clinical trials.
While most cases of TB can be cured using a combination of four antibiotics for four or six months, TB rates are declining relatively slowly and it is widely thought that an effective vaccine would help bring TB rates down much more quickly. The World Health Organization estimates that at the level of protection seen in the phase 2b trial, the vaccine could potentially save 8.5 million lives and prevent 76 million people from falling ill with TB over a 25-year period. The one TB vaccine we already have, called bacille Calmette-Guerin (BCG), is over a century old and only provides limited protection against severe illness for children and no protection for adolescents or adults.
“Reaching Phase 3 with an urgently needed TB vaccine candidate is an important moment for South Africans because it demonstrates that there is a strong local and global commitment to fight a disease that remains distressingly common in our communities,” said Dr Lee Fairlie, national principal investigator for the trial in South Africa, in a media statement released by Gates MRI.
“South Africa also has considerable experience with TB- and vaccine-related clinical trials and a strong track record for protecting patient safety and generating high quality data essential for regulatory approvals.”
Fairlie is also the Director of Maternal and Child Health at the Wits Reproductive Health and HIV Institute at Wits University.
The initial response from TB activists was positive.
“TB Proof (a South African TB advocacy group) is delighted that the M72 phase 3 trial has been launched,” the organisation’s Ruvandhi Nathavitharana and Ingrid Schoeman told Spotlight. “Having an effective TB vaccine is critical for TB elimination efforts.”
While he said it is good to finally see the phase 3 trial of M72 get underway, Mike Frick, TB co-director at Treatment Action Group, a New York-based TB advocacy organisation, went on to say:
“The fact that we had to wait so long between phase II and phase III says everything one needs to know about the headwinds – financial, political, commercial – that TB research is up against.”
How the study will work
Half of the up to 20 000 study participants will receive the M72 jab and the other half a placebo. The vaccine is administered as two intramuscular injections given a month apart. After being jabbed, study participants, all aged 15 to 44, will be followed for four years from the date of the first study participant being enrolled to see if they fall ill with TB.
“The plan is to complete enrolment in 2 years,” Fairlie and Alemnew Dagnew, clinical lead for the trial, told Spotlight in response to written questions. They explained that the actual duration of the trial will depend on how long it takes for 110 people in the study to fall ill with TB. According to the Gates MRI statement, the study is expected to take around five years to complete.
According to Fairlie and Dagnew, the majority of study participants (around 18 000 people) will be people who are HIV negative and who have latent TB infection – that is to say people who have TB bacteria in their lungs, but who are not ill with TB. Latent TB infection is thought to be very common in South Africa and only around 10% of people with latent infection ever fall ill with TB. In the study, latent infection will be tested for using a type of test called an IGRA (Interferon-Gamma Release Assay).
Around 1000 HIV negative people with no TB infection will also be recruited to the study. This is being done to make sure the vaccine is safe and effective in this group of people – while latent infection will be tested for in the study, in the real world such testing may not always be feasible prior to vaccination.
It is anticipated that 1000 of the 20 000 study participants will be people living with HIV. Establishing how well the vaccine works in people living with HIV is important since around 13% of people in South Africa are living with HIV and HIV substantially increases the risk of falling ill with TB. The main phase 2b study of M72 did not include people living with HIV although another phase 2 study looked specifically at the safety and immunogenicity of M72 in people living with HIV – according to Fairlie and Dagnew, “that trial “was completed and supported the inclusion of such participants in a phase 3 trial”.
Smaller than previously thought
When funding for the phase 3 trial was announced last year, it was estimated that 26 000 people would participate in the study. That number has now been revised down to 20 000.
“As a result of ongoing discussions between the institute and our funders, the decision was taken to review the study protocol with the intent of simplifying the study given its size and complexity. This will not affect the safety of the trial. It is common to continue to refine a protocol. We found a way to expedite the study that would potentially allow us to offer the public health impact of this vaccine to those in need sooner. All partners, including the trial funders, are fully aligned to the protocol refinements,” Fairlie and Dagnew explained to Spotlight.
“Some assumptions used to inform the design of the first protocol were deemed overly conservative, so the clinical team used slightly less conservative assumptions on vaccine efficacy and TB incidence rate, thus allowing for a reduction in the number of participants in the trial, while still retaining the primary goal of confirming the safety and efficacy of the M72/AS01-E-4 vaccine for prevention of TB, guided by the final results of the phase 2b study completed several years ago.”
Planning for access
The development of M72 has taken a somewhat unusual path – with the pharmaceutical company GSK leading development up to the end of phase 2b and then largely passing the baton to Gates MRI with the conclusion of a licensing deal in 2020. GSK has come in for some criticism for not moving more quickly after the initial publication of the phase 2b results in 2018. A ProPublica article published last year suggested that the development of M72 slowed because GSK were focussing on more profitable vaccines.
According to the Gates MRI statement, GSK continues to provide technical assistance to the Gates MRI, supplies the adjuvant component of the vaccine for the phase 3 trial, and will provide the adjuvant post licensure should the trial be successful. An adjuvant is an agent included in the vaccine that improves the immune response elicited by the vaccine – in the case of M72/AS01E the AS01E refers to the adjuvant made by GSK.
This ongoing dependence on a single company for the adjuvant has some activists worried. “We are concerned about reports that scaling this vaccine may be difficult due to limited availability of the vaccine adjuvant. Access for everyone who needs it should be part of the early phases of the research process – not an afterthought,” said Nathavitharana and Schoeman.
“The press release announcing the study’s start in several places refers to the ‘complexity’ of ‘developing and ensuring access’ to a new vaccine. Part of the unspoken complexity here is the opaque licensing deal GSK and Gates MRI signed in 2020 in which GSK gave rights to develop and commercialise M72 to Gates MRI while retaining control over the AS01E adjuvant,” Frick told Spotlight. “There are legitimate concerns that the fine print of this arrangement could work against equitable access, but terms of the licence remain unknown to the public.”
When asked about supply concerns, Gates MRI told Spotlight: “Gates MRI collaboration with GSK includes provisions to ensure there is sufficient supply of adjuvant for the clinical development and first adoption in low-income countries with high TB burden, at an affordable price, should the vaccine candidate be successful in phase 3 trials and approved for use. For broader implementation, GSK has committed to working with its partners to ensure there is sufficient supply.”
Disclosure: The Gates MRI is a non-profit subsidiary of the Bill and Melinda Gates Foundation. Spotlight receives funding from the Bill and Melinda Gates Foundation. Spotlight is editorially independent and a member of the South African Press Council.
Personalised treatment for the most common form of adult leukaemia helps patients survive for longer and stay in remission, a phase III trial has found. The trial, by the University of Leeds, has been identified as groundbreaking research by the New England Journal of Medicine and the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, where the results were presented.
The data shows that the duration of therapy can be individualised for each patient by using regular blood tests to monitor their response. In the trial, this approach resulted in significant improvements in both progression-free and overall survival in patients with previously untreated chronic lymphocytic leukaemia (CLL). The effect was stronger among patients with poorer outcomes to standard treatments, such as those with some genetic mutations.
Adult patients were given a combination of cancer growth blocking drugs over varied durations depending on how rapidly their disease responded.
The trial found that this approach significantly improved progression-free and overall survival compared to the standard treatment for CLL, with more than 19 in 20 patients in remission three years after starting treatment.
The study, named FLAIR, is a phase III randomised controlled trial for untreated CLL, taking place in more than 100 hospitals across the UK.
Lead author Peter Hillmen, Professor of Experimental Haematology in the University of Leeds’ School of Medicine, and Honorary Consultant Haematologist at Leeds Teaching Hospitals NHS Trust, said: “Our findings show that, for this group of patients, the treatment is very effective at tackling their disease and is well tolerated by them. This means that patients on our trial had better outcomes while also enjoying a better quality of life during their treatment. Most patients treated with the new combination have no detectable leukaemia in their blood or bone marrow by the end of treatment which is better than with previous treatments and is very encouraging.”
Dr Iain Foulkes, Executive Director of Research and Innovation at Cancer Research UK, said: “We are delighted to see these results from the FLAIR trial which show the importance and effectiveness of tailoring cancer treatment to the individual patient. Not only this, but the trial has found a way to do so without requiring frequent bone marrow tests which are more invasive and can be painful.
“The collaborative effort that went into this trial – involving researchers, healthcare professionals, funders and dedicated patients and their families – point to a new standard of care which could see real progress made against leukaemia.”
Chronic lymphocytic leukaemia is a type of cancer that affects the blood and bone marrow. It cannot usually be cured but can be managed with treatment. More than nine in 10 people are aged 55 and over when they are diagnosed.
Current treatments include chemotherapy, immunotherapy, or cancer growth blockers.
The FLAIR trial tested cancer growth blockers called Ibrutinib and Venetoclax (I+V), which are usually administered either continuously or for the same fixed duration rather than tailored to each patient’s response. This means that many patients may stop treatment too early, missing the full potential benefit from their therapy or continue therapy for longer than necessary. This could lead to a greater chance of relapse of their leukaemia and/or of treatment side effects.
FLAIR researchers aimed to discover whether it was possible to personalise I+V treatment duration for patients based on regular blood sampling and / or bone marrows, and whether this was as effective or better than standard treatment (FCR).
This regular blood and bone marrow monitoring gave researchers a more up-to-date picture of how patients were responding to I+V, and meant that the duration of I+V treatment could be tailored accordingly to each patient. In addition, it was found that basing the duration of treatment on less invasive, quicker blood samples was just as effective as using bone marrows, which can be painful and sometimes require sedation.
FLAIR was launched in 2014, recruiting 1509 patients with CLL. They were randomised to four treatment groups, each receiving a different treatment.
This part of the FLAIR trial compared two of the groups, placing 260 patients on I+V and 263 on the standard treatment, known as FCR. Almost three quarters were male, which was to be expected as CLL occurs more frequently in males. The average age was 62, and just over a third had advanced disease.
At the end of this stage of the trial, 87 patients had seen their disease progress, 75 of which were on FCR, and 12 on I+V.
To date, 34 of these patients have died during the trial. Of these, 25 were treated with FCR and only nine with I+V.
The patients on I+V underwent blood tests and bone marrows to monitor their response to treatment. The technique used is known as measurable residual disease (MRD) which allows clinicians to see the number of remaining cancer cells. The number of cells may be so small that the patient is asymptomatic. An MRD positive test result means that there are remaining cancer cells.
The research team now hope that this more personalised therapy approach, guided by blood test monitoring will be adopted as a new standard of care for patients needing first line CLL treatment.
Professor Hillmen said: “The results of the FLAIR Trial, led by the Leeds Cancer Research UK Clinical Trials Unit at the University of Leeds, are exceptional and herald a change in the way chronic lymphocytic leukaemia will be treated. FLAIR has been a huge collaborative effort over the last decade by the UK’s leading CLL specialists and by the haematology teams in over 100 hospitals throughout the UK. The participation of patient groups, individual patients and their families were critical to delivering such progress particularly through the challenges of the pandemic.”
The trial was co-ordinated by the Leeds Cancer Research UK Clinical Trials Unit at the University of Leeds. Deputy Director Professor David Cairns said: “The vision of the Leeds Cancer Research UK CTU is to improve the length and quality of survival for cancer patients on a worldwide scale. Our strategy to do this is to ensure that we build evidence to identify the correct treatment, for the correct duration, for the correct patient. FLAIR is a trial well aligned to our strategy, and reflects team science including clinicians, laboratory scientists, methodologists and operational experts working together to deliver important trial results. None of this would be achieved without the selfless commitment of trial participants who contribute their time and data.”
The FLAIR trial was funded by Cancer Research UK, Janssen Research & Development, LLC, and AbbVie Pharmaceutical Research and Development.
