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Proactive, pervasive, and strategic planning lead industry into future.
The National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH), turns 10 this December. NCATS initiatives aim to reduce frustration and failure in the journey from bench to bedside. “From the time you work on a drug in a lab to the time you put it in a patient, how can you do this more efficiently and effectively?” asks Lili Portilla, NCATS director of strategic alliances.
One key goal of Portilla’s work is to ease passage across the so-called “valley of death,” in which an academic researcher develops a promising new molecule as a disease treatment, but then does not know how to test their invention, apply for FDA approval, or bring it to market once approval occurs. This is the kind of expertise that a biopharma might have; NCATS brings academics and pharma companies together.
Portilla notes increasing biopharma interest in treatment for rare diseases since NCATS began. This is research that often begins in academic labs and which pharma has historically overlooked as the patient base for a rare disease drug is usually small. But pharmas have become increasingly interested in the incentives offered by the Orphan Drug Act, Portilla says, which grants seven years of commercial exclusivity for any drug that treats a rare disease. The Orphan Drug Act has been on the books for almost 40 years, and the pace of approvals for rare disease drugs continues to increase.1 While some health policy observers say that in some cases biopharmas are creatively slicing data2 to generate ever more approvals for rare indications, rare disease research is likely to continue.
In response, NCATS has developed a program to spur rare disease research collaborations between pharma and academia. And since its inception, NCATS has helped biopharma and academic researchers investigate whether a drug that had failed in one context could be repurposed to treat another disease.
Beyond rising interest in rare diseases, Portilla observes that biopharma companies now prefer to collaborate with academic partners once a molecule is more of a sure bet for eventual FDA approval. “Fifteen or 20 years ago companies would just license things without a lot of data associated with them. That doesn’t happen anymore,” Portilla says.
In discussions with a wide range of industry leaders, Applied Clinical Trials found that the current patterns of academic-pharma collaborations began somewhat as a marriage of convenience once NIH support for basic science research began to soften. This transactional foundation has led to continued breakthroughs in cell and gene therapy, along with new breakthroughs in immunotherapy, over the last decade and the use of real-world evidence within clinical trials may be on the horizon. IRB processes have become more centralized across sites too, and smaller biopharmas are increasingly getting into the game. Even so, some observers say that it’s still challenging to enroll in a clinical trial and that managing the inherent conflicts of interest between academic and biopharma missions remains critical.
Academic institutions once shied away from collaborations with researchers in biopharma companies, recalls Paul Nkansah, senior director for corporate partnerships at Johns Hopkins Technology Ventures.
“If you go back and look at academic institutions and their mission, they’re there to educate and provide a service to the community,” says Nkansah, who works to commercialize Johns Hopkins research and previously spent 14 years at Pfizer. “This idea of ‘let’s bring in a partner whose primary mission is actually to make profit’ was a very difficult thing for any academic institution to process,” Nkansah continues.
Eventually a pharma company might come to a university once it needed help in recruitment for a late-stage clinical trial, Nkansah says, but generally there was little interaction between the two parties.
This arms length approach changed after NIH support for basic science research began to flatten3 in the early 2000s, Nkansah says, following an unprecedented period in which the NIH budget doubled in just five years. The NIH budget flattening meant that multiple universities who had beefed up their grant-seeking activities during the budget doubling days were now competing for an ever-more fixed pie to conduct basic research, Nkansah recalls. This spurred a need to seek new funding for basic research from elsewhere.
Enter biopharma; Nkansah says that drug companies stepped in to fund basic science research once the NIH well began to dry up. A 2017 US Government Accountability Office report4 confirms that most of the molecules tested in clinical trials, and which biopharma companies commercialize if approved, originate in academic labs.
Besides the ability to fund research from the preclinical stage, and therefore have first dibs on commercializing any resulting treatments, Nkansah says that pharma leaders increasingly appreciate that much of the research into the biology of rare diseases, or how to address seemingly intractable neurological problems, is happening on campus. And academics who would like to see their work developed into real-world treatments are less wary of direct collaboration with people in pharmaceutical companies, Nkansah observes, perhaps with the exception of an old guard that still believes that never the twain should meet.
Everyone else, Nkanshah says, is interested in a “true partnership” that leverages the strengths that academics and biopharmas bring to the table.
“Academic partnerships are my passion,” says Bayer’s Global Open Innovation Head, Chandra Ramanathan, who also says that the best biopharma-academic partnerships leverage the unique strengths of both parties. When Ramanathan assesses whether to enter a new academic partnership, considerations include whether the partnership is likely to focus on new disease targets, offer a more efficient means of drug discovery using artificial intelligence, or yield new treatment modalities such a biologic, or cell or gene therapy.
Ramanathan points to Bayer’s partnership with the Broad Institute, which began in 2013, as an example of innovation like the kind he described. At first, this partnership focused on finding new treatments for cancer. In 2015, it expanded focus to include cardiogenomics, and in 2018 evolved again to focus on precision cardiology treatments. That step included opening a joint lab5 housed at the Broad, which includes Bayer and Broad scientists working side by side to develop high-resolution maps of single cells as a way to better understand how cardiovascular disease spreads and could potentially be treated.
Although the cultural barriers between academia and biopharma that Nkansah describes were real, they weren’t so formidable that the two sectors truly had nothing to do with each other. It’s easy to find calls for collaboration6 between biopharma and academia from a decade ago or longer.
What is different today, says Sandy Smith, RN, MSN, AOCN, senior vice president, clinical solutions and strategic partnerships of clinical trial services provider WCG Clinical, is that much more genetic information to inform personalized treatments is now available.
“A lot of what’s driven this is the Human Genome Project. There are so many things to begin to break open and study,” Smith says, causing biopharmas and academic institutions to partner in a more concerted way to identify and test new treatments and eventually file for FDA approval.
The full advent of personalized genomic medicine may be sometime in the future, but Smith sees direct benefit of pharma-academic partnerships right here and now.
“Just in the last eight years or so, seeing what’s happening in immunotherapy,” Smith finds new fruit in these collaborations. Many new immunotherapies for different types of cancer have been approved in recent years, Smith says, which pharma companies brought to market after partnering with academic researchers who conducted the foundational research. And although the academic work behind cell and gene therapy is now decades old, Smith sees an increasing acceleration within the last decade in bringing such products to market.
Looking forward, Smith hopes that increasingly robust, digitized medical records will enable real-world evidence to be used as a synthetic data arm in clinical trials. Rather than running every new trial as an isolated data gathering event, the idea here is to incorporate real world experience into a trial’s data sources.
Smith says that medical records are finally detailed enough, and interoperable enough, to make incorporating real world evidence into clinical trials possible. So the need to longitudinally follow people for decades to see how they fare on a treatment, an inherently laborious task that Smith was part of in a prior position, may start to decrease.
Everything touched on so far—rare disease drug development, biopharma funding of basic science/preclinical work, designing immunotherapies, refining gene and cell therapies—will eventually need to be tested in humans to ensure that they are safe and effective. This often means that a potential treatment will need to be tested in multiple locations, each of which might have its own local practices for managing clinical trials. The resulting confluence is challenging for study sponsors to navigate, according to James Riddle of the clinical trial solutions provider Advarra, which has helped coordinate gene and cell therapy trials for roughly a decade.
In 2016, Riddle says, the NIH began to require that all multi-site clinical trials have a single IRB7 as a condition of funding. Gone were the days of wildly disparate informed consent processes, which meant that participants in different trial sites had a different understanding of the trial. The trend toward centralized IRBs began roughly a decade ago, Riddle estimates, but accelerated in the wake of NIH’s action. It’s less likely now that a university will run its ethics reviews in house, he says.
“If you want National Institutes of Health money, and you have a multi-site project, you have to devise a single IRB strategy—which the commercial IRB’s have been doing for decades,” Riddle says. This centralized IRB strategy has overlapped with the period in which biopharma and academic interests have becoming increasingly enmeshed.
The IRB process is meant to ensure that clinical trials begin on a sound ethical footing, in which every participant understands the risks and benefits of participation. Once a clinical trial is underway, oftentimes a Data Safety Monitoring Board (DSMB) will meet to assess emerging evidence about whether the new treatment’s benefits outweigh its risks. In this way, the DSMB must be a truly independent entity that isn’t swayed by either an academic or pharma partner. WCG and Advarra both offer centralized IRB and DSMB management services designed to ensure that these processes.
Perhaps unsurprisingly, established biopharmas like Novartis are well-positioned to partner with academic institutions and to capitalize on the commercial potential that such partnerships might bring. In a statement to Applied Clinical Trials, Novartis Director of External Science and Partnering, Ann Schlesinger noted that in 2020 Novartis recently launched the NIBR Global Scholars initiative to link Novartis scientists and academic scholars to fund novel science that may lead to new drug development. And large commercial players are also skilled at leveraging government funding to carry out their research efforts, as shown in the Operation Warp Speed effort in which the US government bore the cost for the clinical trials of COVID-19 vaccines.
But it’s not just the big players, notes Paul VanVeldhuisen of the contract research organization Emmes, LLC. “Smaller biopharmas and some of the emerging companies also seek government funding to do their research,” VanVeldhuisen says, pointing to substance use research as an example.
Emmes has long standing relationships with academic leaders in substance use research, such as New York University and Columbia University, and also knows how to access government funding from relevant entities such as the National Institute on Drug Abuse. But the smaller biotech that wants to test a promising new treatment for curbing addictive impulses to an opioid or to alcohol—research that may now incorporate greater use of genome-wide associate studies,8 but does not have this knowledge at its ready disposal—might look outward to a CRO. In a brokering role similar to that of NCATS, Emmes is in a position to bring the relevant parties together. “That’s our sweet spot,” VanVeldhuisen says.
All of the above is well and good, but perhaps that’s only as far as it goes if the vast majority of people do not participate in clinical trials. As Adrian Hernandez, executive director of the Duke Clinical Research Institute, points out, less than 5% of US residents ever participate in a clinical trial. Hernandez says there is no easy way for people to express their interest in joining a clinical trial, or easy ways for them to learn what trials are happening in the first place. This is because our clinical trial infrastructure is separate from the places where patients actually receive care; Hernandez recommends linking the two together. A listing of a patient’s clinical trial interests within their medical record, so they could automatically be alerted of upcoming trials that match these interests, might help to address this.
Recruitment is just one challenge. Once a clinical trial is underway, Hernandez says, “the costs and complexity of clinical trials have increased in a number of ways.” In particular, today’s trials are more data intensive than they once were, Hernandez says, as researchers try to address potential “what-if” scenarios of potential responses to a treatment as ways to reduce unknowns once it reaches the market. This requires more statistical and analytical resources, increasing costs.
Before recruitment begins, and certainly before the trial starts, it has to be designed. What are the endpoints? How will they be measured? What level of enrollment is necessary for statistical confidence in a trial’s results? In any biopharma-academic collaboration, Hernandez says, representatives of both entities must be at the table during the design phase. And ideally there would be multiple people with different types of expertise, a “team science” approach that Hernandez says could probe the blind spots in any emerging study design to make sure it does not have a hidden bias that tilts the study’s results one way or another rather than letting the data tell the tale.
Any such tilting would not necessarily be at the behest of the pharma partner, Hernandez notes: “Sometimes I find intellectual conflicts are stronger than financial conflicts.” Perhaps an academic partner is truly invested in seeing a molecule that they have spent years of their life on be vindicated in a clinical trial–an understandable, yet unacceptable, consideration when designing that trial. In another sign of how times have changed—similar to the raft of approved immunotherapies and possible use of real-world evidence in clinical trials—Hernandez suggests that principles of open science could shine sunlight on conflicts of interest that the trial designers themselves might not be aware of. This could involve posting proposed trial protocols and rationales, online for public comments, a sharp departure from current practice.
However, collaborations between academic and biopharma partners evolve, it seems clear that the fates of the two parties are inextricably intertwined in ways that were not always the case. Some observers are optimistic about what this will mean. “From my perspective I think academic and industry partnerships continue to flourish, probably even more so,” Smith says.
Marcus A. Banks is a freelance health journalist