In 2019, the National Institutes of Health (NIH) launched an ambitious global study to assess whether preemptively taking a relatively new treatment for multidrug-resistant tuberculosis (TB), called delamanid, could also prevent people from contracting the responsible mycobacterium from an infected person in their household. Known as the PHOENIx study, it has the potential to dramatically change TB treatment policies in the United States and across the world. The clinical trial network running the project, called Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG), has already spent nearly $70 million of NIHs money to enroll 5832 people from 31 sites in 13 countries where TB is prevalent.
But PHOENIx is now facing a dire threat to its successNIH itself. The agencys controversial new policy on foreign funding may as soon as 1 June shutter or dramatically curtail work at as many as one-third of ACTG sites, including 22 contributing data to PHOENIx. (The name is shorthand for Protecting Households on Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients.)
ACTG coordinates dozens of trials related to HIV, coinfections such as TB that often accompany it, and related complications such as heart disease. Its one of four NIH-backed global HIV clinical trial networks now shutting down other planned studies or halting new enrolment because their non-U.S. sites rely on subawards from a U.S. grantee. In a 1 May policy directive, NIH halted such subawards, saying it will instead require foreign collaborators funds to be awarded and tracked separately.
But the agency still has not described how foreign partners of U.S. groups can get such grants, only saying the process will be in place by the end of September. Nor has it explained to global networks such as ACTG how its foreign partners, many of whom had expected new subawards payments from NIH by 1 June, can keep their trial sites running, both to preserve good science and fulfill ethical obligations to their volunteer trial participants. Were told that therell be a new system put in place, but we dont have it, and until then, we have to figure out how to manage a very large number of sites and number of participants, says Amita Gupta of Johns Hopkins University, one of the global chairs of the PHOENIx study.
Clinical trial organizers say they are shuffling money to ensure all participants in ongoing studies can complete their courses of experimental treatment or at least be monitored for potential health problems resulting from those treatments. But to find that money, ACTG and its members have already had to forgo other research activities, lay off dozens of employees, shrink ongoing trials, and cancel at least six HIV-related trials that were scheduled to start this year. We are doing everything we can so something bad doesnt happen on June 1, says incoming ACTG Vice Chair Joseph Eron of the University of North Carolina at Chapel Hill, such as sites kicking participants out of a study prematurely.
PHOENIx, the largest TB trial ACTG has ever conducted, promised to tackle an issue that no pharmaceutical companies would have readily taken & up, Gupta says. How well delamanid blocks transmission of Mycobacterium tuberculosis is a really important question, because we dont have a good prevention for TB, she says. Because of how slowly the disease develops in a person and spreads, the study was supposed to run until 2027 to clearly assess the drugs value.
Worried that hundreds of millions of dollars and countless hours of work devoted to PHOENIx and other trials will now go to waste, ACTG leaders say they have written a letter to NIH Director Jayanta Jay Bhattacharya asking for help. They also noted the ethical concerns if foreign trial sites have to close, but have not had an opportunity to meet with the agencys senior leadership. NIH also didnt respond to Sciences queries on the pending cash crunch for ACTG sites or similar situations elsewhere.
Global clinical research, particularly on HIV, has already been hit hard by a series of other U.S. policy changes. In February, President Donald Trumps administration abruptly halted funding for the U.S. Agency for International Development (USAID), leaving some participants in trials it funded without their drugs or unmonitored while taking experimental therapies. NIH-funded studies hoped to avoid the same fate. But in a 7 February executive order, Trump banned federal dollars from going to institutions in South Africa, disrupting trials run there by ACTG and other research networks. The country is a particularly important location for the groups because of its high number of people living with HIV and strong research community. According to a report by the Treatment Action Group (TAG) and Doctors Without Borders, the South African funding freeze threatens at least 20 TB trials and 24 HIV trials.
Another blow to HIV trial networks came in April, when the Trump administration shut down all NIH money going to Harvard University, home to centers that manage patient data for ACTG and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network. Eron says it would be extremely difficult to move the centers to another institution in the middle of a grant cycle and the process would take months.
This months change to NIHs foreign subaward policy promises even greater global disruption unless the agency can provide more clarity. Two-thirds of ACTGs research sites are safe for now because their subawards were renewed before May, but the remainder will run out of money this week. For South African researchers, the NIH policy and the February executive order targeting the country are a double whammy, says Linda-Gail Bekker, an HIV/AIDS researcher at the University of Cape Townand even fewer options now remain for modifying trials so they can continue.
To pay for monitoring and treating clinical trial participants at its threatened foreign sites, ACTG will tap its central, approximately $34 million NIH grant, which normally supports activities such as laboratory analysis and new trial design. For example, this central grant could help make up the shortfall for two ongoing ACTG trial sites in Thailand affected by the subaward policy, says Khuanchai Supparatpinyo, an infectious disease researcher at one of these sites, Chiang Mai University. Although the funding limitation may affect our overall scientific research capacity, I would say that it will not affect our patients safety, he says.
But those central grant funds for ACTG and other networks have shrunk too, because a significant portion going to South Africa has been blocked. Were caught between a rock and a hard place here, says Judith Currier, an infectious disease researcher and outgoing ACTG chair.
ACTGs South African sites are in deeper trouble. Neil Martinson of the University of the Witwatersrand, who works on PHOENIx and other trials at two South African locations, says his group will wrap up some trials by accelerating visit schedules for trial participants, but the sites laid off 30% of their staff working on NIH-funded projects ahead of 1 June. And Catherine Orrell of the Desmond Tutu HIV Centre says that although she found a donor to support her ongoing trial seeking to improve adherence to HIV drug regimens, the money only covers employees salaries and data collection, not analysis. Weve had 4 years of investment in this study and wouldnt be able to deliver primary outcomes if the trial had to stop, she says.
When Science asked Bhattacharya about South Africas clinical trial networks in a 1 May interview, the director said he had turned those back on. And internal guidance to NIH grants staff seen by Science indicated there could be exemptions from the South African freeze to support health and safety of human participants in clinical trials/clinical research. But researchers say its not clear how to get those funds or appeal to the agency; an NIH employee with knowledge of the situation confirmed the funds remained frozen.
Bekker has already had to stop five studies testing ways to suppress HIV's replication in an infected person because of the South African funding freeze. She notes that trial participants sign onto the NIH-backed studies of experimental interventions with the understanding that the researchers would complete the work. They put their bodies on the line and now you actually arent able to answer the question that was intended, she says.
As the NIH foreign subaward policy threatens to close trial sites outside of South Africa, PHOENIx leaders are still trying to find ways to complete the study. [NIH has] come up with a policy thats making it really difficult to maintain the integrity of the trial, and were trying our very best, Gupta says. But if we cant keep staff and the lights on, then were going to have some real waste and that will just be a total tragedy.
