Principle #1: Engage Stakeholders
This is chapter three of the book Assembled Chaos. You can get a free PDF copy by joining the BioSci Community or you can purchase a copy on Amazon. Each of the subsequent chapters will be published as a post.
Minding the gap
If you have ever ridden on the metro in London, you know that the sights and sounds are iconic. The trains make a characteristic clacking sound as they pass through the tunnels and stations. The older trains seem to just barely fit in the tunnels. It’s also hard to miss the announcements, particularly, “Please mind the gap between the train and the platform.” My first trip to London after moving to Europe was for one of the early meetings of the U-BIOPRED project. When I first heard the announcement, I did not appreciate how symbolic the phrase “mind the gap” would become.
What I now appreciate is that consortium projects are about bringing together a critical mass of disciplines and stakeholders to bridge the “translational gap.” The translational gap, moving an innovation in the life sciences from proof of concept to widespread clinical adoption, has been called healthcare’s greatest challenge[i].
It can take more than a decade and cost up to $2 billion to bring a new therapy to market. On average, it takes seventeen years to go from research finding to clinical adoption, and what’s even more daunting is that the chances that any one innovation will make it into the clinic is 10 percent or less. Clearly, advancing life science innovations is a costly and slow process, so it’s no wonder that investors like Warren Buffet have sworn off investing in the life sciences until recently[ii]. Should you accept this as “just the way it is?”
Five elements are needed to bridge the translational gap:
Scientific validation
Regulatory approval
Clinician acceptance
Patient and caregiver acceptance
Payer acceptance
Most of us know and understand the scientific validation element the best. That is, however, only one of the necessary elements. If the others are not in place, the best science in the world will do little to impact the lives of patients.
When good science is not enough
The uptake of Biosimilars in the US is very low. Biosimilars are the generics of new biologic therapies, the difference between a brand-name therapy and the biosimilar being in the production process. Good science supports the similarity, safety, and efficacy of biosimilars. In addition, the FDA recognizes biosimilars and will approve therapies on the basis of bioequivalence. In other words, you don’t need to repeat the whole billion-dollar drug development process for each biosimilar. Even more convincing is the fact that there have been exponentially more biosimilars approved in Europe, leading to a depth of experience in their clinical use. There is no evidence of adverse safety or diminished efficacy of biosimilars.
Still, the use of biosimilars in the US remains low. I helped coach the dialogue between multiple stakeholders in a couple of workshops for the Biosimilars Forum. It proved to be a challenging task as there were some entrenched viewpoints. In preparing for the first workshop, I interviewed a number of people who represented different types of stakeholders. While there were multiple perspectives on why and how to drive the adoption of biosimilars in the US, I also discovered common ground. Everyone had put “doing something meaningful to help patients” as their “why.”
Patient and pharma stakeholders wanted to increase the access of patients to new and better therapies. Payers such as insurance companies and pharmacy benefit managers were focused on the sustainability of the healthcare system so patients would continue to get the healthcare they need. Of course, everyone had their own personal or organizational reasons as well, but finding that common ground helped shift a discussion of opposing viewpoints to a more meaningful dialogue.
As the dialogue unfolded in these workshops, it became clear that it was the acceptance of biosimilars that was holding back their adoption. Not outright rejection of their use, but processes and systems set up in a way that limited the ability to incentivize the use of biosimilars. Here in Europe, they had success because Biosimilars Europe conducted extensive multi-stakeholder initiatives to set up the right environment for their adoption. Granted, the health system is entirely different in Europe than the US, but the point is that good science and even regulatory approval are not a guarantee for achieving clinical adoption.
What you need is the equivalent of a bulldozer to help you get your innovations through the translational gap. A highly interactive consortium where multiple types of stakeholders interact and get to understand each other’s perspectives is that bulldozer. Research and innovation done at any point in the innovation value chain, from basic science to phase IV trials, that fail to take into consideration the perspectives of all stakeholders are just tinkering–unlikely to make a real difference.
Engaging stakeholders in research isn’t easy. While it is becoming more common in recent years, it is still something new that can seem like extra work. Often, the default is to relegate patient stakeholder involvement to things like advising on an informed consent form or material on a website, but if that’s all you do with patient stakeholders, you miss out on what I think is the “secret sauce” that makes multi-stakeholder consortium projects highly effective.
A Tropical Island Photo and True Empathy
One of the coping strategies you employ when training to become a physician is building an artificial barrier between yourself and your patients. You distance yourself by rationalizing that your circumstances are different. You haven’t smoked, or you don’t drink as much, or you don’t have a family history of the disease they are suffering from. This provides a way to handle being confronted with so many people who are suffering, many of whom die. It is, however, a poor coping strategy.
The intensive care unit is an interesting place, full of a lot of shiny objects and motivated people dealing with dramatic problems. It was in the intensive care unit at the University of Vermont Medical Center that I first met them. He was sedated on a ventilator, and she sat next to him. They had come in the night before. They were supposed to be leaving for a vacation, but he’d developed pneumonia and then severe shortness of breath. As I introduced myself, I noticed that a photograph had been taped to the ceiling above the bed. It showed a beach next to a brilliant blue ocean.
“Where is that?” I asked.
“That’s where we are supposed to be,” the woman replied. “St. Maarten.”
Suddenly, I could no longer distance myself from them. In a day or two, he was off the ventilator and sitting up in his bed. We talked about St. Maarten and their plan to reschedule their trip in a few months. He had Chronic Obstructive Pulmonary Disease (COPD), which explained why pneumonia had led to respiratory failure. I soon rotated off of that clinical service.
Two months later, I was working the night rotation--a strange shift because I would come in at 10 PM and go home in the morning. My job was to take care of all the other residents’ patients overnight. The shift work meant that I was socially removed from everyone around me. Around midnight, I was called to “pronounce” someone. When I entered the room, I stopped just past the doorway. A woman was singing to her just deceased husband. Taped to the ceiling above his bed: a photograph of St. Maarten.
As it turned out, the patient I had met two months earlier in the intensive care unit not only had COPD but also lung cancer. The cancer had blocked one of his airways, which led to pneumonia. On the x-ray, the pneumonia had obscured his lung cancer. Unfortunately, lung cancer is one of the most difficult types of cancer to treat. During my training and time as a practicing pulmonary critical care specialist, I had seen many patients suffer respiratory failure and pneumonia, but to this day, twenty-two years later, that one case remains vivid in my mind because the artificial barrier I’d built between myself and my patients had dissolved.
Knowing Your Why Is Not the Problem
When it comes to medical research, Simon Sinek, who developed the concept of “knowing your why,” is wrong. As Sinek points out, most people know what they do, but fewer people know how they do what they do, and even fewer know why they do what they do—and that is the problem. For most medical researchers, knowing your why isn’t the problem.
Whenever I ask a group of medical researchers how many know why they do what they do, almost everyone raises their hand. They do it because they feel motivated to help those suffering from disease–just like the stakeholders in the biosimilars stakeholder workshop. When I follow that question with, “How many of you know how what you’re doing will improve the lives of patients?” more than half of those who raised their hands lower them.
Fortunately, when you are engaged in a consortium project that aims to make a real difference and you have meaningful stakeholder involvement, particularly patient stakeholders, it becomes far more apparent how what you do will affect the lives of patients.
Design thinking[iii] is a process for developing a product or service in iterative cycles by moving through successive loops of prototype design, presentation, and feedback. The starting point of design thinking is empathy—empathy with the end user. Of course, you must understand how patients will use a new therapy or medical device, but empathy is important for another, even more powerful reason: as a source of inspiration and motivation. Everyone can benefit, like I did as a hospital resident, from the further awakening of empathy.
Encouraging individuals suffering from disease to tell their stories is an effective way to build empathy in a research team. Even if you’re a clinician scientist who sees patients all the time, it is inspiring to hear their stories and feel the sense of hope they receive from what you are trying to do. Needless to say, for some of your postdocs and students, such presentations may be the only contact they have with real individuals suffering from a disease.
In 2012, I attended the Innovative Medicines Initiative’s (IMI) patient engagement forum, chaired by Michel Goldman, director of the IMI, and Mary Baker, president of the European Brain Council[iv]. Mary is an ardent patient advocate, and her input into the discussion was anything but lightweight. After the first presenter, Mary asked a salient question and eloquently elucidated some important points. Overall, she made the day so much more interesting that I asked if I could interview her. She agreed to an interview. Now, when you talk to Mary, you quickly realize that she’s had a lot of experience in the European medical landscape. She started out advocating for Parkinson's disease as what she calls a “fist-pounding” advocate driven to increase the awareness and prominence of the disease.
She must have had some success as she was then asked to sit on the European Medicines Administration's board, an experience that began an evolution in her viewpoint. On the board, she witnessed what she describes as an unduly competitive environment, the consequence of a “very rivalrous society.”
"Everything was resolved into silos," she explained. This was hindering drug development. She added, “It’s a bit like a hose pipe: you can’t get the water to the plants because of glitches.”
Being a sociologist, this roused in her a sense of indignity, a feeling that was bolstered when she began working with Octavi Quintana Trias. Like Mary, Octavi also has a strong EU resume and has been the head of multiple directorates at the EU. He currently serves as head of the European Research Area[v]. Octavi and Mary pursue a similar mission. Mary describes him as a “very good team player,” and as such, he began to understand the frustrations of the industry.
In contrast, patient advocacy groups at that time lacked a good understanding of the regulatory process. Any time a drug was withdrawn, patient advocacy groups would begin pounding their fists on the metaphorical table because they didn’t understand why it had to be withdrawn. At one point, a pharmaceutical company self-reported a problem with a particular drug they’d made and asked that it be withdrawn. The company was then asked to produce a letter jointly with a patient organization explaining the situation. This act of collaborative communication was successful, and it became a touchstone for what was to follow.
Motivation for the IMI
Bearing witness to these events inspired what became the vision of the Innovative Medicines Initiative (IMI). The IMI was truly borne of out of a belief that in order to overcome regulatory hurdles, both a better understanding of disease and a stronger multi-stakeholder collaborative effort was needed. Clearly, the approach had to be collaborative because no single person, institution, or company could do it on their own. Octavi himself put it best in a talk[vi] at the European Intersectoral Summit (EISRI)[vii] conference when he pointed out that, “Science is not an issue of the scientists; it is an issue of society.”
As a member of the IMI's scientific board, Mary was treated as a full partner in discussions. During one such discussion, doubts were raised about funding work on hospital acquired infections. Some doubted that it was worth pursuing scientifically. Mary spoke up, telling them that hospital-acquired infections were a major concern for patients.
“Is that so?” came the response.
The topic was not thrown out.
As she points out, “Money, or lack thereof, and an aging society have started to put such pressure on the system that it is right, ethically good, and proper to start working together and to actually understand the seventeen years it takes to bring a medicine to market. It is also important to understand that the industry is not all about profit.”
Pierre Meulien, the second and current executive director of the IMI, summed it up nicely when he said, “I think interesting things happen at interfaces. Whether that be the interface between public and private, the interface between research and clinic, the research between clinical research and health delivery, I think all of these interfaces are going through very interesting times and are facilitating progress. They're also breaking down silos, and I'm interested in breaking down silos and creating new ecosystems that can be really productive in bringing innovation to patients as quickly as possible.”
If all you care about is the science, a multi-stakeholder approach isn’t essential, but medical research isn’t about the science alone. It is also about informing the practice of medicine. Can a project in the life sciences fail to consider how the project will make the desired impact on health and wellness? Surely not. As Mary Baker makes clear, the patient stakeholder perspective should be very important for deciding what to work on.
Another important interface is the interface between society and science. Science no longer occurs in isolation. As a consequence of our ability to better understand complexity, we’ve seen a convergence of diverse fields spanning physics to engineering to behavioral psychology to ethics and even social science, all of which need to be integrated if you want to move from a scientific finding to clinical implementation. Why pretend that these other factors are unimportant in the early phases of research? If anything, the engagement of multiple different stakeholders increases motivation.
The value of engaging multiple different types of stakeholders
We sat in a well-appointed meeting room in a new clinical research center. The computational modeler began his talk with a perceptible level of excitement. Clearly, he had done some research. As he moved from slide to slide, he laid out how he was able to find good literature that enabled him to add quantifiable parameters in the model. The results of his model were promising, but there was a problem.
Everyone waited until the elegant presentation was finished, then the questions came. Most of the questions started off with the typical congratulations, which were quickly followed by a profound “but.” You see, while the model was indeed impressive, it was modelling a phenomenon of little or no clinical relevance. It looked at the motion of cilia on airway epithelium, but while this might have relevance for some rare genetic disorders, it is not so relevant to common diseases. Even if it was, it’s hard to understand how a computational model of cilia motion helps answer a clinical question. Clearly, more interaction between different disciplines and the different stakeholders in the consortium was required.
That meeting became the initial stages of our attempts to integrate the different disciplines and stakeholders in the AiRPROM consortium[viii]. AirPROM was a highly ambitious project put together in response to a grant-funding call for projects that developed multi-scale computational models relevant to disease. The challenge is that what happens on a molecular level with genes and proteins is on a completely different time scale compared to what happens structurally in the body. AirPROM aimed to integrate molecular-level data for respiratory disease with laboratory cell work, physiological measurements, and structural changes evident on CT scans and MRI’s. The temptation was to ignore clinical relevance and focus solely on multi-scale modeling, but what then would be the point?
Insisting upon clinical relevance meant that there were more rounds of teeth gnashing and challenging dialogue around the different models and how they might be useful. In the end, the models in AirPROM were used in three different clinical trials and more than a hundred publications were produced.
The interface between computational modelling and clinical medicine provides a good example of the convergence of different fields in medicine. To achieve meaningful success, there needs to be a mutual understanding and input from data scientists, computational modelers, biologists, clinicians, and ultimately patients, industry regulators, and payers. Using computational models as a diagnostic, as a means to understand why a study failed, or to select patients for a particular therapy is a major paradigm shift.
It is reasonable to assume that the more paradigm-shifting an effort tries to be, the more important it is to involve all stakeholders in the earliest phases of a project. If you don’t there is a substantial risk that your efforts will have much less impact than they could. When your project fits within a proven paradigm of either diagnosis or treatment, stakeholder engagement becomes less important. Because of the past successes of medical research, most new advances have to be paradigm shifting.
If you have a project that is complex and aims to be both ambitious and to shift paradigms, you will be most effective when you engage multiple disciplines and multiple stakeholders. In these types of projects, being highly interactive is crucial. There’s almost no point in doing these types of projects if you aren’t going to have the different disciplines and stakeholders talk to each other a lot. It takes time to understand the various perspectives of people who think differently from you.
In a review article published in the New England Journal of Medicine in 2017[ix], authors Ramesy et. al. describe three different academic, foundation, and industry collaborations. The authors focus on venture philanthropy, where disease foundations form partnerships with industry and academia. The three collaborations they describe were both multi-disciplinary and multi-stakeholder consortium projects focused on cystic fibrosis, multiple myeloma, and type-1 diabetes. Each of these conditions is relatively uncommon, a fact that when combined with other factors meant pharmaceutical companies weren’t developing new therapies for these disease indications.
Patient needs inspired all three efforts, and all three benefited from the multi-stakeholder nature of their partnerships. Partners in the cystic fibrosis consortium got approval for a new therapy in four years. This rapid rate of translation resulting from multiple elements, such as having harmonized protocols, accessing existing databases, efficiency in multi-center trial launch, and working closely with regulators throughout the process. For multiple myeloma, similar efforts led to the approval of nine new therapies over fifteen years.
Interestingly, the type-1 diabetes consortium found that an immunosuppressive therapy accelerated islet cell loss. By working together with different partners, they began to understand the mechanism behind the unexpected finding and used that knowledge to define new treatment strategies. This kind of problem-solving illustrates what I like to think of as the superpower of consortium projects.
In the following chapters, we will discuss how you can get the most out of the interactions in a consortium project. The first step is to make sure you engage multiple stakeholders in a meaningful way.
Involving Stakeholders
During the course of U-BIOPRED, we organized a workshop at the European Parliament on patient stakeholder involvement. That workshop resulted in a manuscript titled From Tokenism to Meaningful Engagement: Best Practices in Patient Involvement in an EU Project[x] in which we described five best practices:
1) Involve early
2) Involve deeply
3) Include patients’ feedback on project progress
4) Include patients in dissemination
5) Allow patients to convey their own story
The fifth best practice is the most impactful. Early on in the U-BIOPRED project, we held an art contest, soliciting pieces of art from patients about what it was like to have asthma. Members of the U-BIOPRED project selected the winning entry, a powerful piece produced by a young woman who suffered from severe asthma. Everyone raved about her presentations at the annual consortium meeting and at the European Respiratory Society congress in front of a few thousand people.
As it turns out, gaining insight on the perspectives of other stakeholders is always valuable. It provides the necessary motivation for doing the difficult work of bridging the translational gap. It also helps you learn how to resolve conflicts.
The goal is getting different types of stakeholders to work together to solve problems and develop new opportunities. This is not easy to achieve. People often have many different groups or “tribes” to which they belong, and people usually try to fit in with a new tribe by moderating what they say. If stakeholders won’t speak their minds for the sake of fitting in, you risk losing the value of having a diversity of perspectives. Ironically, then, the best way to achieve stakeholder involvement is to first segregate stakeholders into like-minded groups. That way, you get the true perspective of a given type of stakeholder, because people tend to speak more openly and candidly when they feel part of a like-minded group.
Step 1: Form stakeholder groups
When you form a group, you should have more than one of each type of stakeholder in your consortium. Often, this happens naturally, but you need to bear it in mind when building a consortium. Look at your consortium members and see which types of stakeholders are present, then decide which different groups you need. For example, in a public-private partnership, you might have academia, industry, and disease foundations working together. You can then form these stakeholders into three distinct groups.
Step 2: Give the stakeholder groups a task
Nothing clarifies your thinking like having a task to complete. One simple and nearly always relevant task is deciding on research priorities. Even if you know your research priorities, it helps to have different stakeholder groups define which impact of the project is most important to them.
Step 3: Have the stakeholder groups form their own opinion
The individual members of each stakeholder group should interact to form a common perspective about the task at hand. This is often best done with a couple of online meetings.
Step 4: Bring the stakeholders together in small mixed groups
In general, everyone is most comfortable interacting in small groups. We’ve all been in big meetings where one or two people dominated the dialogue. Interacting in a small group serves as a warmup for a broader interaction. Every time we’ve done this, every person contributed to the larger group dialogue. Instead of a dialogue driven by one or two people, you get twenty, thirty, or even more active dialogue participants.
Step 5: Have a broad group dialogue
When you bring different stakeholders together in a large group, magic happens. This is best done with a visual framework, such as a flip chart or slideshow, and someone to facilitate the dialogue.
Step 6: Produce a report
A report of the dialogue helps to remind people of what took place. It can be a simple list, a graphic that summarizes the input, or a narrative text as long as it highlights the shared vision of the project and inspires.
Step 7: Embed stakeholders in the operational meetings throughout the consortium
In his book Team of Teams[xi], Stanley McChrystal shows how the U.S. military became effective in fighting terrorist networks in part by embedding individuals from different agencies in operational teams. This helped them break down barriers and build an understanding of different perspectives, which means it works well in consortium projects.
At BioSci Consulting the engagement of multiple stakeholders is central to our approach. If you need help finding a way to engage stakeholders that is more than just a token tickbox exercise get in touch.
References
[i] www.forbes.com/sites/davidshaywitz/2012/08/16/closing-the-translational-gap-a-challenge-facing-innovators-in-medical-science-and-in-digital-health/#4038475f4f80. Access: March 2020.
[ii] https://www.nasdaq.com/articles/warren-buffetts-berkshire-hathaway-dives-into-biotechnology-2020-02-15
[iii] Visser W. Cognititve artifacts of designing 2016. ISBN-10: 0805855114
[iv] https://www.braincouncil.eu. Access: March 2020.
[v] https://ec.europa.eu/info/research-and-innovation/strategy/era_en. Access: March 2020
[vi] https://www.youtube.com/watch?v=hPaumVAPzfA. Access: March 2020
[vii] https://eisri-summit.eu. Access: March 2020
[viii] https://www.europeanlung.org/en/projects-and-research/projects/airprom/home. Access: March 2020
[ix] Ramsey BW, Nepom GT, Lonial S. Academic, Foundation, and Industry Collaboration in Finding New Therapies. N Engl J Med. 2017 May 4;376(18):1762-1769. doi: 10.1056/NEJMra1612575.
[x] Supple D, Roberts A, Hudson V, Masefield S, Fitch N, Rahmen M, Flood B, de Boer W, Powell P, Wagers S; U-BIOPRED PIP group. From tokenism to meaningful engagement: best practices in patient involvement in an EU project. Res Involv Engagem. 2015 Jun 25;1:5. doi: 10.1186/s40900-015-0004-9. eCollection 2015.
[xi] McChrystal S, Collins T. Team of Teams: New rules of engagement for a complex world. 2015. ISBN-10: 1591847486
