When Philip Farrell, MD, PhD, now emeritus dean and professor, Division of Pulmonology and Sleep Medicine, first assembled a research team to develop and conduct the first randomized clinical trial (RCT) testing the possible benefit of early diagnosis of cystic fibrosis (CF) in the early 1980s, the prognosis for children with the disease was poor. There was no accepted early diagnostic method and no effective treatment.
Cystic fibrosis is a hereditary condition, occurring in approximately one in 4,000 births. It causes normally slippery fluids in lungs and digestive system organs to become thick and sticky, resulting in lung and digestive impairment, risk of severe lung infections, malnutrition, and death. Before Farrell’s research project, children with CF were usually diagnosed between one and five years of age, already suffering from lung disease, diminished growth, and frequently severe, potentially fatal, malnutrition. The median survival was 27 years.
Today, long after the results of the trial were published and applied and owing to the many branching inquiries sparked by it, a baby born in the U.S. with cystic fibrosis has a life expectancy of at least 70 years. This year, that groundbreaking randomized clinical trial marks its 40th anniversary, while breakthroughs in knowledge and treatment of CF continue. The Farrell Research Group remains active today, investigating the benefits, risks, tests, and treatment of early diagnosis through newborn screening, while numerous research teams across the nation and the world join in the task of further understanding and treating the disease.
“I have never considered this study to be completed,” Farrell explained. “We are still pursuing questions that came out of the initial RCT.”
Farrell carefully selected his research team to meticulously plan the randomized clinical trial throughout 1983–84. With a research grant from the Cystic Fibrosis Foundation, the project was launched in 1984. The study was designed to use a new blood test that could identify CF through immunoreactive trypsin (IRT) in a newborn’s blood spot. There was, however, substantial resistance to diagnosing CF in newborns, as there was such limited treatment. The Cystic Fibrosis Foundation posited that it could provide no benefit; yet nonetheless, Farrell and his team persevered. His project’s hypothesis: “Early diagnosis of cystic fibrosis will be medically beneficial without major risk.”
In addition, there were ethical questions to be faced. “Norm Fost’s work addressing the ethical questions was crucial,” Farrell said, “Those questions could have shut us down.” Norman Fost, MD, MPH, now emeritus professor, Division of Child Protection, worked to clarify and fully consider the many questions related to the use of neonatal bloodspots and other ethical concerns through listening sessions with parents (with attorneys in attendance). The team developed a brochure that each new mother would receive. It explained in a paragraph the study and gave parents the choice to opt out.
The project made use of the mandatory newborn bloodspot screening performed through the Wisconsin State Laboratory of Hygiene (WSLH) to determine which newborns would become subjects in an early diagnosis, screened cohort and a standard diagnosis or control group. The screened cohort’s treatment was a special diet, high in calories, fats, plus pancreatic enzymes and antibiotics as needed. The control group would receive the same standard care so that the only difference was their older age of diagnosis.
The trial lasted more than 10 years, from when randomization of Wisconsin newborns began in 1985 to when the last enrolled child completed the protocol in 2012. The randomization/enrollment stopped in 1994 when the health benefits of the screened cohort were shown to be statistically significant, increasingly obvious, and clearly robust compared to the control group. It was the largest prospective pediatric research project since the 1954 polio vaccine field trials and the longest cohort study of any childhood disease. In 1997, the research group published its results in the New England Journal of Medicine in a report entitled, “Nutritional Benefits of Neonatal Screening for Cystic Fibrosis.”
“The study was full of convincing data,” Farrell recounted. “It made all those who had opposed the project change their minds — or stop arguing. Problems are opportunities, and we faced the problem of naysayers with our superlative, robust data and changed the course of CF diagnosis and treatment.” The project has resulted in more than 200 publications.
Besides Farrell, that research group included Department of Pediatrics members Elaine Mischler, MD, emerita professor; HuiChuan Lai, PhD, professor, Departments of Nutritional Sciences and Pediatrics; Mei Baker, MD, professor, Division of Genetics and Metabolism and director of the Newborn Screening Program at WSLH; then-fellow, Michael Rock, MD, now emeritus professor, Division of Pulmonology and Sleep Medicine; Fost, who provided expert advice and support in all bioethical issues; Audrey Tluczek, PhD, RN, emerita professor, School of Nursing; Anita Laxova, BS, now emerita research program coordinator, who joined in 1988; and Darci Pfeil, NP, who provided nursing care for the children, as well as the others listed in the above NEJM publication.
Considering the effect of the trial at its 40th anniversary, Baker, whose research includes developing new bloodspot screens for rare diseases in anticipation of their addition to the state’s list for screened conditions as treatments are found, expressed her assessment of its enormous value. “The Wisconsin cystic fibrosis RCT project certainly laid the foundation for CF newborn screening in Wisconsin, in the nation, and beyond. CF newborn screening in Wisconsin continues to evolve,” she explained. “With the adoption of next-generation sequencing technology, the newborn screening laboratory at the Wisconsin State Laboratory of Hygiene now can simultaneously detect 689 CF-causing variants. It is the most comprehensive panel at this time, and a relevant practice to the current discussion on genomic sequencing in newborn screening.”
Rock, who, after his work with the trial’s research team, served as the director of the UW Cystic Fibrosis Center from 1995 until last year, has returned after his official retirement to continue his contributions to the CF effort in a modified capacity. He considered the initial trial to be seminal, leading directly to the enormous advances in knowledge and treatments today.
He recalled how when early CF diagnosis became feasible, “skeptics stated that there could be more harm than good in instituting treatments pre-symptomatically, and that there could be significant psychosocial harm in the families of infants who had a false positive newborn screening test.” The CF RCT proved this assumption to be incorrect.
Reflecting on the 40th anniversary of the project, Rock said, “Forty years later, newborn screening for CF has been embraced by every state in the United States and by many countries throughout the world. The RCT provided unequivocal data on the utility of beginning pancreatic enzyme replacement therapy early in order to prevent malnutrition and stunting of growth. Now that the molecular defect of CF is known (chloride channel dysfunction due to the abnormal CFTR protein), CFTR modulator therapy can be started early in life. Indeed, such early therapy can result in a normal lifespan for people with CF.”
Farrell added that “newborn screening and CFTR modulator therapy have been doubly transformative.”
Four decades on, Farrell continues promotion of CF screening and research — and his teams have published 15 papers on CF newborn screening since 2022. At 40 years, he can provide advice and guidance for those researchers who, he says, frequently tell him they wish they had the time and money to pursue this kind of endeavor. “One should never allow time and money to be limiting factors,” Farrell said. “If you think of them as constraints, you won’t be able to think creatively and effectively. They are blinders. You can make the time, and if your project is well-planned — we took more than a year to plan the RCT — and your team is competent and cohesive, you will be able to find the money.” Farrell noted that he was able to bring in $12 million of direct costs grant support for the RCT even while serving as dean due to the project’s excellent team.
Farrell also promotes the study as an example of “The Wisconsin Idea” writ large — indeed, writ globally: knowledge acquired through research efforts at the University of Wisconsin moves outward to help many beyond academia. “Our study data convinced England and, in time, Ireland to do CF screening,” Farrell noted. “Small countries like Slovenia and Denmark were also very impressed by the data we eventually gathered that showed the easy person-to-person transmission of Pseudomonas aeruginosa that is such a risk to CF children.” This data led to a protocol of segregated clinic waiting rooms for patients organized by Mischler as a crucial innovation.
Farrell is currently engaged in efforts to introduce a CF neonatal screening pilot project in south India. Approximately 24 million babies are born in India per year: The Wisconsin Idea continues to expand ever outward.