Risk averse

Administrative roadblocks set back life-saving research at UW

by

By now it’s well documented that UW-Madison lags behind most of its peers in turning its esteemed research into marketable goods. The question is what would it take for the university to get on track and become a pacesetter in the lucrative development of pharmaceutical drugs and cutting-edge medical treatment? One answer: a “major culture change spearheaded by top leadership.”

That’s the wake-up call sounded in a provocative study commissioned by UW Health and the UW School of Medicine and Public Health. Conducted by consultant Mary Westrick, who has 35 years of experience in clinical testing, the study lays out a series of stark challenges — both organizational as well as attitudinal — that threaten the campus’ declared goal to be a national leader in translating basic research into cutting-edge medical treatment.

Key to success, Westrick argues, is revamping the campus review of research projects that involve human subjects. UW-Madison’s existing clinical trial system, as Westrick and other critics describe it, is a quagmire of red tape that frustrates many campus researchers, while simultaneously failing to embrace standards that produce quality test outcomes.

UW’s existing clinical trials system places way too much emphasis, Westrick says, “on protecting the university from any risk, liability or adverse publicity.” This comes at a cost, she warns: “The result stifles potentially beneficial — even life-saving — research to patients with no counter-balanced benefit of increased patient protection.”

Westrick holds a master’s degree and doctorate in toxicology and pharmacology from Purdue University and has worked in early drug development in the private sector. This includes founding her own 200-employee research lab in Indiana, selling it and then taking an executive post with Covance, a global research operation with a sizable headquarters in Madison.

Westrick’s negative assessment, while fiercely contested by some UW administrators, is part of a determined movement on campus to embrace the linkage of medical education, patient care and research discoveries to produce breakthrough treatments. The stakes are very high for UW-Madison both in terms of science and commerce.

Rock Mackie, an entrepreneurial-minded emeritus professor of medical physics who is UW Health’s first chief innovation officer, summed up the reformers’ challenge a few weeks ago at a luncheon meeting of Madison-area tech executives:

“How can we unleash the power of the medical university to incubate ideas into companies? To grow both the Wisconsin economy and to improve healthcare?”

I secured the Westrick report late last year through a public records request that took five weeks to be filled. On the same day it was released, the university also sent me a blistering 2,100-word rebuttal written by UW-Madison’s Norman Drinkwater, interim vice chancellor for research and graduate education.

Drinkwater denounces the Westrick report as containing “significant omissions and errors.” Her recommendations, he continues, “are based on perceptions and or opinion treated as fact, without any apparent analysis of the extent to which such impressions reflect actual circumstances.” Nor does she acknowledge recent improvements in the protocol review process, including user-friendly software, he argues.

Westrick, in an interview, firmly pushes back, saying Drinkwater is holding tight to the status quo, while she sees compelling reasons for change. “Look at how much [medical] research the university does compared to its peer institutions,” she says. “If UW was as good as Norman would have you think, don’t you think it would be doing a lot more work?”

The university, long a research dynamo, is indeed showing worrisome signs of slippage fell out of the top five ranking for the first time since 1972.

While UW remains a powerhouse in securing federal support for basic research, it is noticeably weak in landing business-sponsored research, particularly for clinical trials for new drugs and medical techniques, according to National Science Foundation data.

“We’ve got gifted faculty, folks who are leaders in their fields, and we still can’t get clinical trials,” says Westrick, who is an adjunct lecturer in UW’s Master of Science in Biotechnology program.

To be sure, some notable UW trials are underway. Cellectar Biosciences is working with UW’S Mario Otto, an associate professor of pediatrics, on testing a drug at the UW American Family Children’s Hospital that targets high doses of radioactive iodine to cancer cells.

C.diff, a bacterium that preys on people with weakened immune systems, causes upwards of a half-million cases of diarrhea and other gut problems a year. UW’s Nasia Safdar, a physician in the Department of Medicine, is testing (in conjunction with Indiana University and the Medical College of Wisconsin) an oral antibiotic called vancomycin as a preventative to recurring cases of this scourge.

Dixon Kaufman, meanwhile, is running a clinical trial for California-based Medeor Therapeutics involving transplant recipients at 27 sites. The goal is to develop a cell-based therapy to reprogram the recipients’ immune system to accept a transplanted kidney without the need for long-term use of costly immunosuppression drugs.

That’s the good news.

The bad news is that in fiscal year 2017, the Madison campus ranked 50th in the nation for business-sponsored research at $25.7 million. Clinical trial expenditures were a tiny $11.8 million, 51st in the nation.

As Westrick suggests, UW-Madison trails such Midwest schools as the University of Chicago, Ohio State, Northwestern, Michigan State and University of Minnesota in both categories, as well as national leaders like Duke, MIT and Stanford. This mediocre performance has become a touchy point on and off the Madison campus.

Westrick warns that UW’s poor record of hosting clinical trials will only worsen if it fails to improve its practices. She points to a new accreditation program for clinical trial sites that stresses quality-performance metrics that she says UW-Madison protocols simply do not address. The standards — promulgated by a collaborative she works with known as the Alliance for Clinical Research Excellence and Safety, or ACRES — is expected to become the global measure of high-performing test sites.

Whether UW-Madison will make all the necessary changes to reach the higher bar is not yet clear. Medical School Dean Robert Golden, who has been pushing hard for the campus to fully mobilize its healthcare strengths, says he accepts “many” of the Westrick recommendations but adds in an email that “others are not feasible or even desirable.” (See isthmus.com for more of the interview with Golden.)

A thriving local biotech industry has grown up around UW’s research prowess. But, as Isthmus has reported, the campus’ lagging record of business collaboration has become a friction point with local tech companies. Exact Sciences, the break-out cancer-test enterprise with 2,200 employees, and Stemina Biomarker Discovery, the tiny startup focused on early detection of autism spectrum disorder in children, turned in frustration to other research sites to conduct their clinical trials.

Exact Sciences has spent $69 million on research at the Mayo Clinic over 10 years, according to company president and CEO Kevin Conroy. He praises Mayo as an “amazing collaborator” with “incredible resources and total dedication to improving patient care.”

He says UW-Madison has just been too difficult to work with. “It could be getting the most advanced clinical trials and research. But it’s not happening today.”

The uneasy relationship between business and campus prompted the Wisconsin Technology Council to organize a behind-the-scenes intervention in fall 2016 and spring 2017 — two meetings in which WTC president Tom Still brought together Madison area health-tech leaders with UW officials.

“We wanted to inform the university of the speed bumps that young companies and investors were hitting on campus,” Still says. “It was all about ‘Hey, we’d love to do more business with UW.’” But these problems had to be addressed first: Confusion caused by hearing conflicting messages from different UW offices and the university’s lack of urgency in resolving issues. “For young companies and even older ones, time is money,” says Still.

And the outcome? “Collectively they took it to heart,” he says of campus leaders.

When I asked about the attitudinal issue that Westrick identified, Still replies, “It’s a cautious culture, to be sure.”

But elements of the UW administration are pushing for change.

The Medical School is recruiting a chief clinical research officer, whom Mackie bluntly describes as “a czar whose sole mission is to improve clinical trials on this campus.” Presumably the new czar will address the complaints Still’s group brought forward.

Meanwhile, The Wisconsin Alumni Research Foundation, which is UW’s patenting and licensing arm, has launched an ambitious therapeutics program aimed at developing new patentable drugs based on UW research. Given that WARF’s last lucrative patent has expired and licensing revenue has plunged, the success of this new initiative is hugely important to the campus. (Zemplar, a kidney-disease drug discovered by storied UW researcher Hector DeLuca, produced $500 million in royalties for UW-Madison before patent protection ended in 2016.)

The Westrick report, at a cost of $106,654, is another purposeful step to expand campus research. Among her tasks, Westrick sought to address complaints about a fusty, rule-obsessed UW administrative system that many campus researchers say impedes their work. A 2016 survey of 562 UW-Madison principal investigators found, for example, that nearly half said “that they had given up or almost given up pursuing a research project out of frustration” in gaining a campus review board’s approval of their research protocols involving human subjects.

“Incredibly frustrating, lengthy and inconsistent” is how one unidentified respondent described working with the Health Sciences’ Institutional Review Board.

While the survey results were posted online, the IRB Working Group report that analyzed the findings was not. (Isthmus obtained it through an open records request.) Delivered to Drinkwater as interim vice chancellor for research in February 2018, the report upheld the complaints of campus researchers.

Protecting research subjects should always be a priority, the 14-member panel says as a prologue. But it concludes the review board “failed to strike the appropriate balance between protection of human subjects and advancing the cause of high-quality research that itself contributes to the welfare of research participants.”

Like Westrick later in the year, the working group blames “an over-emphasis [on] regulatory risk management,” which created unnecessary delays and expense for researchers.

Westrick, who interviewed 140 people on and off campus for her study, took note of the 2016 survey results. “The level of frustration has not diminished and, if anything, has increased,” she writes. Almost all of the researchers she interviewed faulted the review system for being overly picky and for forcing repeated revisions, even for protocols approved in earlier clinical studies.

UW-Madison is hardly alone in grappling with these issues, says Greg Koski, the charismatic health expert who co-founded ACRES. “We’re at a turning-point moment,” he declares.

When I interviewed Koski, the retired Harvard Medical School associate professor was on his 41-foot ocean-going Lord Nelson sailboat. No longer tethered to a house and car, Koski, 69, is something of a vagabond. He was docked in Tortola, capital of the British Virgin Islands, talking to me via WhatsApp. We had missed a connection a few days earlier when he was dealing with a 600-pound tree stump entangled in his anchor chain. (Such are the hazards of Caribbean hurricane debris.)

I sought out Koski because he has the breadth of experience to frame the UW-Madison debate in the broader history of university research. He spent 50 years at Harvard, from student to teacher, including a lengthy stint as an anesthetist at Massachusetts General Hospital. He gave up his clinical work to research and write on how a systems approach to improving clinical research could benefit everyone — patients, government and industry.

Eight years ago, at a meeting in Copenhagen, Koski helped co-found ACRES. Its goal: identifying “best practices” and building them into a voluntary accreditation program to raise the performance of clinical trials worldwide. Westrick, who has overseen 2,000 clinical trials, became a key contributor.

Underlying the ACRES initiative is the belief that the existing clinical trial system just isn’t good at producing consistent quality outcomes. Make that: Really not good. Koski describes it as a systemic failure rife with redundancy, delay and poor performance.

This is “Eroom’s Law” of clinical research.

You may have heard of Moore’s Law — the rubric of how computing power is constantly improving at lower and lower cost? The reverse — Eroom’s Law — is happening in new drug development. The number of approved new drugs is roughly at the 1950s level, “but the cost of developing a new drug has doubled approximately every nine years,” as Koski and his colleagues wrote in a discussion paper. A more recent study put the cost of developing a single new prescription medicine at an extraordinary $2.6 billion.

Costly and ineffective clinical trials are among the culprits.

As Koski tells it, 30 years ago universities began to look at industry-sponsored clinical trials as a way to expand both their research portfolios and their offerings to patients. And, of course, deepen their revenue stream. Corporate sponsors, in turn, liked the legitimacy that a university imprimatur provided for marketing their products once they became available after successful testing.

“But the truth was that academic centers were miserably inept when it came to doing clinical trials,” he says. “The word on the street was that they were slow, pompous and basically failed to enroll patients in the trials. They just didn’t comport well with the expectations of corporate sponsors.”

That’s around the time when privately run clinical testing operations entered the picture. They’re known as “contract research organizations,” or CROs. Dane County hosts two global giants: Besides Covance on the eastside, PPD is in Middleton. (Covance has 50,000 employees in 60 countries, and PPD has 21,000 employees in 48 countries, according to their websites.)

Long story short: The CROs prospered (today they constitute a $39 billion a year industry) because many drug companies saw them as a means to improve efficiency and reduce costs, in part by outsourcing clinical-trial operations to them, according to Koski.

Universities, in contrast, became the backwater of the business. Professors engaged in basic research looked down upon their colleagues who did this work, says Koski. “The simple truth is these ‘investigators’ — that’s in quotes — often did very little apart from oversight, while research coordinators did the actual work.”

Clinical trials were seen as cash cows, and standards for being a clinical investigator were essentially non-existent.

“It was a rather unseemly environment in some respects,” says Koski. “A physician at a university could be a clinical investigator for a drug company, and they could do it apart from their clinical practice. Unlike their grant-funded academic research, they didn’t have to account for their time and effort.

“Clinical trials were essentially a sideline business for some physicians,” Koski says. “But that began to change when people realized that academic institutions should, in fact, be legitimate clinical research entities in their own right.”

Koski is describing the genesis of what’s called translational research — refining laboratory discoveries into therapies to be tested in human clinical trials. “It became part of the actual academic culture for many institutions,” he notes. Harvard, Duke, Johns Hopkins and Washington University in St. Louis were early adopters. He does not mention UW-Madison.

The firewall that separated research from medical practice dates from the scandals of earlier decades when research subjects were unwittingly subjected to health risks. The most notorious example is the U.S. Public Health Service and the Tuskegee study of untreated syphilis in black males. It ran for 40 years before a newspaper exposé ended it in 1972. The federally mandated clinical protocol review that occurs today at UW-Madison and other universities is a direct product of that scandal.

Of course, nobody seriously opposes the requirements for disclosure and safety in human clinical research. But reformers like Koski argue passionately that its kludgy side product — the artificial and awkward separation of medical research from medical practice — has become a barrier to medical progress.

“The fundamental notion is that research and practice are all part of a continuum that should benefit the patient,” he says. That’s Koski’s rallying cry for change. The unanswered question is whether it will be heeded at UW-Madison.

All the stories in this series on UW-Madison research can be found at isthmus.com/topics/uws-challenge/