A plain-language summary (PLS) can play a key role in communicating clinical research more broadly to patients.
AUTHORS
Ka Weng Mah1, MSc; Ka-Wing Chong2, PhD; Kelly Lo3, BPharm; Victoria Elegant4, MBBS, DRCOG, FFPM
AUTHOR AFFILIATIONS
1Medical Capabilities Director, Japan and Asia Pacific Medical Affairs, Amgen
2Digital & Medical Education Lead, Japan and Asia Pacific Medical Affairs, Amgen
3Field Medical & Insights Lead, Japan and Asia Pacific Medical Affairs, Amgen
4Vice President & Head, Japan and Asia Pacific Medical Affairs, Amgen
This publication represents the consensus opinions of the authors and various members of MAPS, but does not represent formal endorsement of conclusions by their organizations.
The COVID-19 pandemic has swept across the world, affecting every country with ongoing and recurring waves of infection. Countries in the Asia Pacific region were the first in the world to introduce lockdowns, masking and social distancing measures. There was massive reallocation of healthcare resources across all countries, forming a concerted effort to combat the pandemic. These responses reshaped the healthcare ecosystem and pharmaceutical industry, particularly in the engagements with healthcare professionals.
In light of the ongoing disruptions, it is essential that Medical Affairs teams examine and better understand the healthcare and Medical Affairs landscape during and eventually after COVID-19 in order to set a clear path forward. Project Phoenix, the brainchild of the Amgen Japan and Asia Pacific (JAPAC) Medical Affairs team, was initiated to address this need. This project comprises of four stages (Figure 1) that serves as a model for reimagining scientific engagement during and post-COVID-19.
This paper shares key findings with industry peers in order to i) advance the footprint of Medical Affairs in Asia in the peri-/post-COVID era, and ii) encourage and explore innovative new ways of working.
Figure 1. The four stages of Project Phoenix developed by the Amgen JAPAC Medical Affairs team.
The evaluation the external and internal landscape comprised of a literature review of ten key articles (listed under Bibliography), an external survey of healthcare professionals (HCPs, n=210, conducted between 11 May and 12 June 2020) and an internal survey of medical science liaisons (MSLs, n=53, conducted from 2 to 8 June 2020) in Asia Pacific. This section summarizes the key findings from the literature review and surveys.
The pre-COVID-19 patient care pathway has been significantly disrupted, especially for chronic diseases. Consultations, elective surgeries and procedures and laboratory testing have been postponed or cancelled whilst diagnosis and treatment have also been delayed.1-3 Concurrently, remote patient treatment and telemedicine have increased in use including funding from government to accelerate uptake.1-3 Pharma has the opportunity to support patients through building and implementing digital and remote tools to engage and educate patients as well as ensuring consistent drug supplies, accelerating access to treatments and increasing the affordability of treatment during the crisis and recovery period.2
HCP surveys indicate that approximately 70% of HCPs reported a decrease in face-to-face patient visits, causing a severe backlog and financial strain on practices. Concurrently, there has been a >1500% increase in the use of telehealth and digital tools to support patients, though there are payment and reimbursement challenges.1-3 Physicians were of the opinion that Pharma could provide additional support on disease education and telemedicine for patients during COVID-19.2 Moving forward, there is a need to identify new ways to support healthcare systems, improve and increase Pharma-patient support models and use innovative collaborations to drive care delivery and conduct telemedicine/telemonitoring education.2
More than 50 pharmaceutical companies have halted new or ongoing non-COVID-19 trials,1 while 9 out of 15 of the top pharmaceutical companies have seen the majority of their sites reduce clinical trial activities.2 The main reasons for this are restricted site access and reduced availability of investigators and resources, whereby CROs are unable to send staff to monitor trials, and patients unable to access hospitals. As a result, Pharma needed to re-evaluate clinical trials operation and designs of protocols. For current trial operations, digital methods for site selection were initiated and remote monitoring was implemented. For upcoming trial designs, there is a need to identify and optimize opportunities for site and country selection based on geography, technology readiness, and plan for virtual / hybrid trials. Increased agility in evidence generation is required, utilizing innovative collaborations to decentralize trials, as well as to scale and accelerate virtual and digital clinical trials.1,2,4 In Australia, there is an initiative underway supported by government and other organisations to move towards teletrials. ,5
Plans for the launch of an estimated 390 products in 2020 through to 2028 have been disrupted.1 Furthermore, gaining stakeholder traction and patient acquisition are rising concerns for recently launched products. Driven by recent and current launch underperformance, the industry could rack up an estimated cumulative loss of USD$10 billion by 2028.1 Digital solutions to accelerate launches are required, for example, through virtual thought leader and omnichannel engagement. Portfolio investments need to be re-prioritized based on revised market expectations and product differentiability. To our knowledge, there were two major product launches being carried out fully remotely during the COVID-19 outbreak in China. Key learnings from these case studies will provide valuable information as companies seek to apply and improve for similar scientific campaigns in the future.
Pharma-physician engagement has seen a rapid transformation from face-to-face to digital interactions. However, there is a gap in virtual tools, and Pharma is working to build capability and infrastructure and prepare for long-term utilization of virtual channels. Based on our survey findings, regular scientific engagement is highly valued by our HCPs – 52% would like to interact monthly or more frequently, while 26% would like to interact every 3 months or less. The most preferred platforms to access Medical Education and Scientific Information among HCPs include live speaking webcasts, peer to peer discussions and on-demand web content. Results from the internal MSL survey showed that MSLs spend approximately 40% of their time on HCP engagement. The largest virtual competency gaps identified were the ability to conduct highly interactive virtual engagement sessions and to collect insights during virtual interactions.
Based on these findings, these are the potential impacts of COVID-19 on Medical Affairs operations.
COVID-19 has hastened changes in patient engagements and the hospital environment. The health care environment has quickly evolved, particularly in terms of interactions with patients and their caregivers. There is a marked increase in contactless care and virtual disease management (eg. telehealth).
To deal with the widespread disruption to physical activity, pharmaceutical companies are being forced to step up data analytics capabilities to improve engagement. Big data and business analytics should be prioritized to inform omnichannel planning and engagement strategies, R&D and reimbursement. AI technology can also be used to augment HCP capacity. This could be done through establishing partnerships with external digital health start-ups, gaining a deeper understanding of digital health needs for each TA, incorporating digital into evidence generation and bridging digital health collaborations with HCPs through MSL engagements.
While it is inevitable that in-person engagement activities will resume, it is acknowledged that there will be an increase in the use and acceptance of digital interactions moving forward. There is an expectation amongst HCPs that Pharma would embark on holistic individualized scientific engagements using advanced digital platforms and content transformation . With these expected changes, there lies an opportunity to evolve and redefine the MSL role to further enrich scientific engagements with OLs. There also needs to be an expanded focus on patient education, HCP education initiatives, advisory boards and publications.
Due to the widespread restrictions on movement and face to face interactions, it is apparent that there will be a noticeable shift in how clinical trials are conducted. Therefore, it is imperative that companies move into adaptive and collaborative trial designs and develop virtual trial capabilities, such as teletrials. There are plans to pilot these changes by incorporating virtual elements (e.g. e-consent, telemedicine) into future studies.
With the shift to digital and new capabilities, change management on culture and infrastructure is central to support the evolution of the organization. A new medical affairs phenotype and enhanced skill set is needed to deal with compliance, new ways of interaction, and new compliance regulations.
There may be a need to review current processes to increase effectiveness and efficiencies, redefine new capabilities, examine cross-functional roles and outsource tasks which are necessary but not a strategic part of the core Medical Affairs functions. There is also a need to update regulation and compliance. Medical Affairs should also work on building systems and platforms to automate activities which can be automated (eg. content development and chatbots), to free up staff for more innovative initiatives, as well as upskill internal staff capabilities for clinical trials, evidence generation and digital.
In view of the rapidly evolving patient/caregiver and HCP dynamics, these are the likely future realities in Medical Affairs:
It is anticipated that these realities will guide the development of future strategies by medical teams. There should be an emphasis on virtual engagements with HCPs, educational offerings (particularly digitized content) and evidence generation. Other areas of focus include clinical trials, change management, talent management and upskilling, digital and outsourcing in order to improve productivity. A robust change management strategy is required, with prudent resource allocation to ensure building of new capabilities.
In line with these future realities, strategies and solutions were identified and distilled to the following core recommended actions (Figure 2) to ensure that Medical Affairs are in the best possible position to adapt and thrive within the evolving healthcare landscape.
Figure 2. Core recommended actions for Medical Affairs teams.
The impact of the COVID-19 pandemic is evident throughout all industries including the healthcare and pharmaceutical industry. Medical Affairs activities were not spared, with disruptions to face-to-face activities and local/regional restrictions affecting every level of scientific engagement.
Amgen JAPAC Medical Affairs team’s Project Phoenix documents the “investigate, evaluate and formulate” steps that bridges the pre- to the peri-/post-COVID era for Medical Affairs teams, marking an essential milestone in the ongoing journey to improve patient outcomes and standards of care across the Asia Pacific region.
The authors would like to acknowledge the Amgen JAPAC Project Phoenix working team (Simone Kaenzig, Riaz Abbas, Jaey Koo, Viola Wan, Motoki Sato, Sheetal Mistry, Rebecca Kannourakis) and Anish Sule (IQVIA) for their support and assistance in analysing the read outs & providing advice. We thank Dr Ee Lyn TAN for editorial support.
Our industry partners (IQVIA, Mckinsey & Company, Indigene) provided reports and insights which helped give us an understanding of the medical affairs environment in this region.
The voluntary participation of MSLs and HCPs in the surveys are greatly appreciated.
As VP and Head of the Asia-Pacific Medical Affairs function at Amgen, Victoria Elegant saw COVID-19 a full two months before colleagues in other parts of the world. In fact, in January 2020 as news of COVID-19 outbreaks in China reached beyond the country’s borders, Elegant was finishing a ski trip to Switzerland. “The second I got off the phone with our crisis team, I went out and bought masks and hand sanitizer,” she says. Elegant was traveling with what she describes as a “big, international group of doctors,” and remembers that at least half the group was amazed by her reaction. “I passed out masks, saying ‘You will need these,’” Elegant says. Here the Medical Affairs Professional Society (MAPS) speaks with Elegant and colleague Ka Weng Mah, Director of Medical Capabilities, Amgen Asia Pacific about the takeaways for the practice of Medical Affairs afforded by their front-row seats to the pandemic, and also about results of a recent Amgen survey of healthcare provider preferences.
MAPS: You talked a little about Europe’s reaction to news of the pandemic – what did you see when you returned home to Hong Kong?
Victoria Elegant, VP and Head of the Asia-Pacific Medical Affairs function at Amgen
Elegant: Healthcare professionals in Hong Kong knew what was coming. In Asia, we went through SARS and there is a culture of wearing masks if you are sick to protect other people. Even flying back to Hong Kong in January, everyone on the plane and in the airport was wearing masks. In the middle of it, it was intense – trying to figure out what we needed to do for our staff, for patients, how to continue clinical trials.
Mah: As early as in late Jan/early Feb, many people in Asia were even more progressive than the governments, with calls to close borders immediately. The majority, almost 98.8% in many Asian countries, also took the initiative to wear masks.
MAPS: So, effectively, you had a two-month head start on the pandemic compared with the rest of the world. Did this put you in a position to see early transformations in the practice of Medical Affairs?
Elegant: Even before the pandemic, we had seen that we needed to do things differently and had appointed a Medical Affairs digital lead in July 2019. So when hospitals suddenly wouldn’t let us do face-to-face healthcare provider interactions, in a way, we were lucky and perhaps a bit ahead of the game: We had already laid the foundation for digital.
Mah: Previously, we had aspirations to drive digital transformation but it was just experimental. Then with COVID, it meant squeezing years of work in one month. What we said is that every MSL can be e-MSL, every event can be an e-Event, and it was COVID-19 that hastened the transformation of our business – the future we were working towards, came today.
MAPS: On the organization side, digital transformation was driven by the realities of the pandemic, but did you see the same adoption from healthcare providers?
Elegant: China changed almost overnight. But Japan and Korea are conservative countries and change can be more challenging. Asia is still a face-to-face culture. For example, the more people you have in a meeting with an important person, the more you show respect. These were attitudes we had to work on. We saw that we needed to facilitate this change management and get stakeholders to accept a new way of doing things. Therefore, back in April we performed a systematic review of industry reports, followed by internal (MSL) and external (KOL) surveys, in order to identify and drive the necessary new ways of working in this peri-COVID era.
MAPS: And what do you see now in these countries?
Ka Weng Mah, Director of Medical Capabilities, Amgen Asia Pacific
Mah: We spent so much time educating and bringing people up to speed, then all of a sudden we had way more transformation than we could handle. Korea had practically no virtual interactions but were forced to adapt and flipped overnight and now they are embracing digital completely. Japan, as well, embraced digital but now many healthcare providers in Japan are already wanting to go back to face-to-face interactions. Perhaps there is a cultural element to this, but there’s no way we can go back. The new world will be a blended one. I think that for a more digitally open country like China, it will go 50percent digital or more, while countries like Japan and Korea may end up being somewhat less.
MAPS: There must have been some element of excitement watching these initiatives that had been moving along slowly suddenly gain momentum?
Elegant: We had to do this transformation overnight, working 24/7 to get capabilities and systems in place. Big corporations have their challenges with innovation but MSLs have to do their jobs and meetings had to go ahead. We spent a lot of time trying to support teams and engage with them and figure out how they could managethis We also had to support the teams to find a balance between the work that needs to get done and also keeping themselves mentally and physically healthy in the new way of working.
MAPS: Does all this work and all this dramatic transformation simply bring you back to the level capabilities you had before the pandemic or is there some benefit to these activities beyond simply learning how to do your old jobs in a new world?
Elegant: One of the things that’s emerged for us is patients as an even more important stakeholder. The COVID process has led to the realization that the healthcare system is set up for providers and not necessarily for patients. It’s super inconvenient – generally – to be a patient. And now we see there are things we can do to help – things like delivering clinical trials supplies to patients’ homes or providing a 6-month prescription instead of a 1-month prescription or providing an ongoing supply of medications to homes for chronic conditions. One of the big things to come out of this pandemic experience is how to work with patients to amplify their voice, especially in Asia where the patient voice hasn’t been so strong. This inclusion of patients as core stakeholders opens our eyes to other non-traditional stakeholders in the patient-care continuum, for example caregivers, physical therapists, pharmacists, nurses, occupational therapists and others. It is not just physicians in this healthcare ecosystem and digital transformation gives us the opportunity to engage with some of these categories that have traditionally been overlooked.
MAPS: And how do you reach these people?
Mah: The gist is that someone needs to engage those important stakeholders as partners, not just when we need them every three years. The patients are, and will remain, at the core in everything we do. So this is our immediate priority to sort – who, when, how to reach out to them. Then we have to go sector by sector: A more democratized world, the patient voice, more virtual and digital as well so that everyone gets the information they need. I don’t think we’ve figured it out exactly who and how to reach out.
Elegant: One thing we learnt from the survey we conducted (see White paper) is that doctors want scientific interactions, so maybe they’re prioritizing their interactions with Medical Affairs, or maybe it’s just easier to have remote interactions with us. We find that it’s easier to have a remote interaction if you have an established relationship first, but setting up that relationship remotely can be challenging.
MAPS: Do you have any other takeaways from your survey of HCP preferences for continued MSL interactions?
Elegant: Certainly. If I were to point to one area of our report, I would look to our recommendations for the future. First, putting patients and their caregivers in addition to HCPs at the core/center of Medical activities. Second, successful Medical teams will use innovative, modern approaches in scientific engagements. And finally, leading Medical teams need to invest in (and incorporate) rapid and radical digital transformation to ways of working. We are focused on making sure that these transformations will be executed and embedded into our ways of working, in order to improve patient outcomes and standards of care in Asia Pacific.
Q&A with Medical Affairs thought leaders describing changes in Digital and Field Medical during the pandemic and beyond
Nothing could stand between Joseph Eid and his dream of becoming a doctor—not even gunfire.
Attending medical school in Lebanon at the height of the country’s lengthy civil war was a risk, but Joseph wanted to complete his studies in his home country. He vividly recalls a period when the war shut down the school and he traveled to the U.S. to spend the time off with family. It was a prudent plan, until a classmate contacted Joseph to let him know classes were starting again and he had to be back for a test on Monday. It was Thursday.
At the time, Lebanon was under military blockade, so he couldn’t fly back to school directly. Instead, he flew to Athens, then Cypress, then bought a ticket for an overnight speedboat to the Lebanese coast.
The boat left at 2 a.m. Sunday night. Just as Lebanon appeared on the horizon, the captain shut off the boat’s lights and told everyone to hit the deck. Then the bombing started. The passengers could hear splashes as the bombs and rockets exploded around the speedboat. Somehow, the boat survived the assault and so did Joseph.
He arrived in Lebanon at 4 a.m.—just four hours before his exam.
Joseph Eid was born in the late sixties, the youngest of four children. At the time, Lebanon was a peaceful and prosperous country—but that was changing. Shortly after he was born, the Six Day War erupted, and a full-blown civil war followed a few years later.
Growing up in a war zone was challenging, to say the least. Going to school was a risk every day, as militant groups often targeted schools. Over the course of the war, his family lost their home to the bombings as well as countless friends and family members.
Joseph’s father was in the army’s mechanized division and accountable for material procurement. After visiting multiple U.S. army installations to procure equipment for the Lebanese army, it became his mission to bring his family to the US to provide them a safer future.
From a young age, both parents taught Joseph and his siblings dedication, discipline, and commitment to education. Joseph recalls a year when he was eight years old that schools were shut down due to the war. When school was back in session, he had to complete two grades in one year to make up for lost time. A couple of years later, after he was awarded scholarships for his academic performance, the principle told him there was no need to take a final exam. Joseph’s parents sent him back to school to write the test anyway. They told him he shouldn’t be treated any differently from other students.
By the time Joseph started medical school, most of his family was living in the US. But Joseph chose to finish his schooling by splitting his time between Lebanon and France when the war situation got worse.
It’s no surprise that Joseph brought that same fearlessness and gritted determination to his medical career.
Joseph took his tests in the US while still in medical school in Lebanon. After receiving his diploma, he completed his residency and fellowship in New York and New Jersey respectively. During the fellowship, he quickly rose in the ranks and was recruited to the faculty before graduating.
At Rutgers, Joseph was interested in more than just advancing his career—he wanted to solve problems and save lives. When he discovered that many sickle cell patients did well under pediatric care but struggled when they reached adulthood, he decided to do what he could to help. He applied to research grants, but after his applications were repeatedly rejected, he opted to open a clinic to help patients instead. He took training on sickle cell treatment and brought back what he learned to the clinic.
It was an extraordinary step that was life-changing for patients—and for Joseph. He proudly shares that most of his patients were able to go back to school and work because of the treatment and care the clinic provided.
Joseph Eid with his young daughter
But Joseph was a victim of his own success. He kept taking on more responsibilities, to the point where he was on call six months of the year. Now a newlywed with a young daughter, he recognized that it might be time to consider a career change so he could spend more time with his family.
In 2004, he decided to move out of academia and into the world of pharma. It was tough to leave, but he established an arrangement that would allow him to still see patients on a part-time, volunteer basis. He felt it was his duty to continue to care for his patients even after he left academia.
What drew Joseph to pharma was the rigor and scale of the work, which was so much greater than what he could hope to achieve in academia. Still, his experience in front-line medical care had ingrained a profound commitment to putting patients first.
“I knew that to deliver in pharma, I had to have the patient in focus,” he says. “That mindset stays with me today. In every meeting, I bring it back to the patient.”
Joseph cut his teeth in pharma at Roche, before moving on to Merck in 2009 as Executive Clinical Director. At Merck, his focus was late development, when the drugs were in phase 1-3 clinical stage. It was as close as he could get to seeing the science reach patients—exactly where he wanted to be.
In 2011, he took on a new role as senior project manager, where he came up with unconventional strategies and an ambitious vision for an anti-PD-1 antibody which revolutionized cancer treatment. After taking on a new role, Joseph’s leadership resulted in a tremendous increase in the size and importance of the Oncology Medical Affairs department within the organization. From 2014 to 2017, it grew from just three members to over 400.
Before long, word spread of his success and he was recruited by BMS to head up their entire Medical Affairs department.
Joseph Eid with his parents
In the first weeks at BMS, he spent his time listening and asking questions. He quickly realized the teams had their priorities confused. They were focusing too much on to do lists and not enough on their purpose.
To inspire the department, Joseph encouraged the teams to share their triumphs with each other. He asked each team to create posters illustrating their work, then he put them on stage behind him at his first town hall. The atmosphere changed immediately. Once they were given a voice and a chance to share their good work, the department was reenergized.
In recognition of the growing importance of medical, Joseph was asked to join the CEO team at BMS. Now, his ongoing role is to continue to improve the team’s engagement. As he leads the organization through the pandemic, patient care continues to be Joseph’s north star.
He believes that the key to success is reminding all 2,200 team members of the purpose of their work.
“People have to have something meaningful they are working toward,” he says.
Here are his top thoughts on leading truly purpose-driven teams.
For Joseph, the key to effective leadership is to remind team members of the remarkable impacts of their work by sharing patient stories and testimonials. Seeing how their drugs provide hope for people who are out of options has a tremendous effect on everyone, from executives in the c-suite to reps carrying the bag.
It is easy to forget that the decisions pharma people make affect the day-to-day lives of patients. Joseph recalls working with a team to write a protocol and becoming frustrated because it had so many “bells and whistles.”
“If you were a patient would you be able to do all that?” Joseph asked the team.
It was exactly the reminder they needed. The team set to work simplifying the protocol to ensure it was practical and easy to follow.
Over the years, Joseph and his teams adopted countless practices that go against the grain. They followed patient blogs to gain insights into what was on their customers’ minds. They engaged with patient groups and physicians. In trials, they often amended an ongoing phase 1 with more patients and indications to accelerate the clinical development rather than add new trials.
His approach is often unconventional, but throughout his career, he has learned that doing things differently pays off.
With COVID-19 transforming the way people everywhere live and work, there is no better time for new approaches. Daunting as it is, Joseph feels prepared to take on challenges resulting from the pandemic.
“Our mission in life is to make our work matter,” he says. “Everything we do touches patients.”
This article is graciously contributed by Excellerate: Patient-Focused Engagement for Pharma.
Download the full article here
By Robert Honigberg, MBA, MD, MS&T Consulting, LLC
Neil Belson, JD, Law Office of Neil A Belson, LLC
The 21st Century Cures Act, enacted in 2016, requires the U.S. Food and Drug Administration (FDA) to assess the use of Real-World Evidence (RWE) for applications that include new drug indications and satisfying post-approval drug study requirements. RWE can contribute to showing that a drug or medical device is safe and effective, within the context of the FDA’s “totality of evidence approach” for evaluating regulatory submissions. The FDA has approved both drugs and medical devices based on regulatory submissions which have included RWE.
KEY WORDS: Real-World Data (RWD), Real-World Evidence (RWE), totality of evidence, FDA
The 21st Century Cures Act (2016) requires the U.S. Food and Drug Administration (FDA) to assess the use of Real-World Evidence (RWE) for applications that include new drug indications and satisfying post-approval1,2. The FDA issued a final guidance document for medical devices in 2017, in which the Agency stated that the applicant could use Real-World Data (RWD) to support regulatory determinations under the right conditions3. While the FDA has not yet followed up with a guidance for pharmaceutical products, their 2018 Framework for FDA’s Real-World Evidence Program outlined the potential applications of RWE for regulatory decision-making regarding the effectiveness of marketed products4. In the instance of an original approval for a product, the FDA recommended that an evidence package could contain three types of studies: clinical pharmacology, non-clinical toxicology, and clinical studies. However, for post-marketing labeling changes (i.e., use in a new population or a new indication), the evidence package could include prior submitted evidence and new evidence, traditionally represented by randomized clinical studies but also RWE studies. What is important for Medical Affairs and Regulatory teams to understand is that regardless of study type, setting, or design, the FDA does not have to evaluate one study type (i.e., Randomized Clinical Trial (RCT)) only when making regulatory decisions. Instead, the FDA uses a totality of evidence approach, examining all available evidence in the regulatory materials submitted including the quality of the studies and context of the manufacturer’s request4.
“While Real-World Evidence analysis will not replace the randomized controlled trial, it already has been used as effective support data for drug and device labeling changes and for rare disease submissions.”
Bob Honigberg MD
Several applications for labeling expansions and other regulatory approvals have successfully incorporated RWD and RWE. The purpose of this Elevate article is to provide regulatory examples of how various companies have negotiated with the FDA and successfully utilized RWE within regulatory submissions.
Regulatory submissions that involve the submission of RWD can come from data sources that routinely collect health-related information such as claims data, electronic health records, patient reported outcomes (questionnaires and devices), registries, as well as public and private databases. The use of RWE implies the analyses of RWD through applied research methods, such as for historical controls, or other types of analyses using records that were initially collected from sources other than randomized clinical trials. It is important to first target an opportunity where the use of RWE will add to the “totality of evidence.” The role of RWD and RWE has been especially useful for rare diseases as well as for the expansion of labeling to a more broad or newly defined sub-population, and the evolution of procedural medical device techniques. Using a “totality of evidence” approach, one can determine if the new evidence from RWD sources or RWE analyses can add to the existing evidence to create a new evidence package that has value from a clinical and regulatory perspective.
A White Paper prepared in December 2019 by the Duke Margolis Center for Health Policy5 examined non-traditional study designs which have used RWE, including open-label, single-arm studies, retrospective observational and case series, retrospective cohort studies using RWD sources, non-inferiority studies, RWE-generated historical controls, the use of concurrent control groups, and the use of post-market surveillance and registry data. Table 1 is an adapted summary of examples of approvals and labeling changes for drugs using evidence generated from these non-traditional studies. This article discusses three pharmaceutical case examples in this communication: Ibrance for male breast cancer, Invega Sustenna for schizoaffective disorder and Brineura for treatment of a form of Batten disease. The article also examines the label expansion of a medical device based on RWE to include a minimally-invasive approach to aortic valve replacement using Transcatheter Aortic Valve Replacement (TAVR).
Ibrance (Palbociclib) was approved for metastatic breast cancer in 2019. The approval was based on two large randomized controlled trials (the PALOMA studies) in women and supported by clinical pharmacology and non-clinical toxicology studies. Evidence for clinical benefit in male breast cancer was noted from post-marketing reports, insurance claims data and electronic health records. Male breast cancer is a rare condition with a high unmet need for treatment; there were approximately 2,500 new cases and 500 deaths in 2019. The FDA submission included evidence derived from RWD sources including: the IQVIA insurance database, Flatiron Health breast cancer database, and the Pfizer global safety database. The FDA noted in its approval letter that “Given the extensive established efficacy and safety of the use of Palbociclib in women observed in randomized controlled trials, the additional RWE data provided in this application for the use in men, modest as it is, does support the expansion of the Palbociclib indication to provide for the treatment of men with metastatic breast cancer.”6
In 2011, the FDA approved the Sapien 3 device for TAVR, a novel approach that provided a minimally invasive alternative to open heart surgery for clinically appropriate patients. Post-marketing surveillance requirements included the collection of data in over 100,000 procedures in the Transcatheter Valve Therapy Registry, which included a subset in 600 patients that underwent the valve-in-valve variant of the procedure. Although this procedural variant was considered off-label, the valve-in-valve procedure was shown to be an improvement as it allowed the new valve to be placed inside the diseased valve. The FDA evaluated the clinical and functional data for this procedure from the registry to expand the indication for the TAVR-enabling device. The FDA announced that even though the United States had been only the 42nd country to approve the original TAVR device, through the use of creative regulatory procedures the United States became the first country to approve the new indication.
Invega Sustenna (paliperidone palmitate) is a centrally active anti-psychotic and the only once-monthly long-acting injectable (LAI) for schizoaffective disorder. There have been several expansions to the label since its original approval in 2006 for acute schizophrenia. In 2018, a labeling change was approved related to the time to treatment failure compared to oral anti-psychotics using an unconventional clinical trial design that was more representative of the disease population. Prior RCTs had excluded adult subjects with recent incarceration or substance abuse from the trial. The PRIDE trial, which was a randomized open-label pragmatic trial, recruited many subjects from jail-release programs, homeless shelters and soup kitchens. The trial was able to build on the existing evidence provided by published RCTs and include a broader and more representative population using an unconventional RWE clinical trial design that not only showed a time to treatment failure benefit but also a medication adherence benefit compared to oral anti-psychotics.
The FDA’s approval of Brineura (cerliponase alfa) in 2017 as a treatment for a form of Batten disease, is an example of the agency comparing a “single-arm” clinical study of a prospective drug treatment against a natural history “control” obtained from RWD. This use of natural history “controls” in single-arm clinical studies of prospective treatments for rare diseases has historically been among the most common uses of RWD to support regulatory approvals7. Brineura, an enzyme replacement therapy, was the first FDA-approved treatment for slowing the progressive loss of walking ability in patients with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). CLN2 disease is a rare inherited disorder which occurs in approximately two to four of every 100,000 U.S. live births. Signs and symptoms in the late infantile form of this disease typically begin between ages two and four. Individuals with this condition often require use of a wheelchair by late childhood and typically do not survive past their teens. The clinical trial which established Brineura’s efficacy was a non-randomized, single-arm dose escalation clinical study in 22 symptomatic pediatric patients. The “control” or comparator was a group of 42 untreated CLN2 patients from a natural history cohort (an independent historical control group). Patients treated with Brineura suffered fewer declines in walking ability compared to the untreated patients in the natural history cohort.8
The 21st Century Cures Act directed FDA to evaluate the use of Real-World Data (RWD) and Real-World Evidence (RWE) in regulatory submissions. The objective of this Elevate article is to examine some of the approaches accepted by the FDA for using RWE to obtain regulatory approvals for drugs and devices. It is important to select new indication and expansion targets where there is an opportunity for RWE analysis to credibly add to the existing evidence base using a “totality of evidence” approach.
“While our understanding of the potential applications of RWE and the appropriate standards for its use is still evolving, RWE will almost certainly have an increasingly important role in future regulatory submissions for drugs and medical devices.”
Neil Belson JD
|
1 |
PRODUCT |
SPONSOR |
DISEASE |
STUDY DESIGN |
|
Bavencio (avelumab) |
Pfizer and Merck KGaA |
Metastatic merkel cell CA |
Open-label single-arm multicenter trial |
|
|
2 |
Blincyto (blinatumomab) |
Amgen |
B-cell precursor ALL |
Open-label single-arm multicenter trial |
|
3 |
Brineura (cerliponase alfa) |
Biomarin |
Infantile Batten Disease |
Non-randomized single-arm dose-escalation study Non-randomized comparison with natural history cohort |
|
4 |
Carbaglu (carglumic acid) |
Recordati Rare Diseases |
Hyper-ammonemia |
Retrospective unblinded uncontrolled case series |
|
5 |
Cordarone (amio darone HCl tabs) |
Sanofi |
Arrhythmia |
Retrospective open-label self-controlled study |
|
6 |
Ibrance |
Pfizer |
Male breast cancer |
Retrospective cohort study using HER data, insurance billing data, and post-marketing studies |
|
7 |
Inactivated polio vaccine |
NFIP (March of Dimes) |
Polio |
Randomized blinded placebo-controlled trial with additional observed controls |
|
8 |
Intravenous ganciclovir |
Exela Pharma Sciences |
AIDS and CMV retinitis |
Retrospective non-randomized study |
|
9 |
Invega Sustenna (paliperidone palmitate) |
Janssen |
Schizophrenia, schizoaffective disorder |
Prospective randomized open-label active-controlled parallel-group trial |
|
10 |
Luthathera (lutetium Lu 177 dotatate) |
Advanced Accelerator Applications (Novartis) |
Somatostatin receptor positive GEP-NETs |
Randomized open-label, active-controlled multicenter trial Retrospective study |
Murali Gopal, MD, Vice President | Global Medical Department at Mallinckrodt
Murali Gopal, MD, remembers being a young clinician in the bygone era of giveaways during conference meetings when he would walk by pharma booths and pick up a water bottle or a tie or whatever they may be giving away. Would he ever wear the tie or use the water bottle? Probably not. But it cost him nothing and so why not? Now Murali compares this might-as-well approach to the biopharmaceutical industry’s traditional (and increasingly outdated) model of brand planning. As Vice President of the Global Medical Department at Mallinckrodt Pharmaceuticals, he is helping his organization evolve into a future that includes the contributions of science and business to attain the goal of innovation. Here the Medical Affairs Professional Society (MAPS) talks with Murali about the strategy he uses to guide this change – Integrated Brand Planning – which he not only credits with bridging the gap between science and business in biopharmaceutical organizations, but sees as a philosophy that has led to his personal development as a leader and decision-maker.
MAPS: Okay, you have to start by telling us how brand planning is like stocking up on conference giveaways.
Murali: Think about what happens when Medical Affairs comes over and says we can generate X, Y and Z data for an asset – if you’re a Commercial person and you’re trying to maximize the opportunity of the molecule, and have no financial downside or obligation…why wouldn’t you take all options? It’s the same mentality as conference swag: If you can get something for nothing, you do it. That may have worked well without today’s challenges. But now companies that still use this model place themselves at a disadvantage.
MAPS: You’re saying this model of saying yes to all possibilities for a new drug leads to inefficiencies?
Murali: Yes, I am saying that, and that it also leads to increased costs and the need for increased resources. At a previous position, we ended up with 7,000 different promotional materials for one molecule in one year. Some were used once and some just sat in warehouses. A handful of them would be the key materials that were used over and over. It was as if we were creating things for the sake of creating things and not focusing on what the external stakeholder may have felt was most compelling or intriguing. Another example can be that perhaps the organization may determine they need some data without fully understanding that it may take five years to conclude a particular study, or may cost, say, $3 million dollars.
MAPS: And how is Integrated Brand Planning different?
Murali: With Integrated Brand Planning, or what some organizations call the General Manager model, the GM becomes responsible for the profit and loss of a molecule. What this means is that everything becomes visible. Commercial, safety, R&D all becomes visible, because they’re all centered around some level of cost. It forces the organization to align on their priorities and to create targeted strategies.
MAPS: It sounds like you’re talking about a more integrated flow of information between science and business during brand planning?
Murali: Traditionally the separation between science and business was intentional. Many scientists felt, and some may still feel, that science and business need to be separated and if Medical Affairs or Commercial has input to science, it takes away some of the scientific credibility. I like business but I’m a scientist at heart – I want to be measured against the science we engage in, and fortunately the GM model allows us to do both so that I can continue to grow my business acumen as well.
MAPS: What do you mean?
Murali: Let’s say our end goal is innovation – we live longer today because innovation helped us learn to deal with illnesses that would have killed us in our 30s and 40s. And look at the effect of the cholesterol medicine race in the cardiovascular space, heart transplants, etc. or the vaccine industry in general. The biopharmaceutical industry has always struggled to articulate the impact of innovation on society. But combining the business impact and scientific development aspects together, we can now measure and even predict how a therapy is going to provide value, as well as, to understand its economic impact so that we can make better decisions.
MAPS: You’re saying business has a role in innovation?
Murali: Certainly. At a previous position, we hired a top scientist in their field to work with a new molecule. He had great relationships, knew the unmet need, knew what the molecule could do, but he didn’t take into account what other companies were doing, or the needs of payor organizations, or the high level of focus on pricing at that time. When we got ready to introduce the molecule, the potential price and utilization scared the payors – they said it was going to break the healthcare system and that we would need to somehow restrict who is eligible for the therapy, and if we couldn’t do that, possibly no one would get it. Our internal leader couldn’t accept these business realities and the drug was by many measures unsuccessfully launched. For me, that was a very poignant experience. The fact is, you need relationships with scientific leaders, but to run a therapeutic area, you need just as much acumen on the landscape and business side to marry with the scientific aspects to be successful.
MAPS: This sounds like a cautionary tale of science overbalancing business, but of course we have cautionary tales in which business overbalances science as well.
Murali: I believe there are companies out there increasing profitability and cost because they can, but there are also companies trying to do the right thing, and it all gets lumped together. Integrated Brand Planning creates checks and balances.
MAPS: Oh, interesting! And how is that?
Murali: It’s about collaboration at the stage of annual planning. Instead of Commercial proposing studies to R&D, or R&D proposing studies to Commercial, with Integrated Brand Planning, it’s a collaborative, open discussion from the start. Scientists don’t need to also be MBAs and Commercial doesn’t need to hold PhDs, but the dialogue helps scientists elevate their business acumen, and Commercial elevate their scientific acumen. You need the perspective of external stakeholders as well. Most companies will put the patient or a disease at the center of what they do, then you have your organization or company’s resources sitting in the next circle around this center, but there’s an external circle as well that includes: advocacy groups for that therapeutic area, politicians, KOLs in academia, clinicians, etc. This brings the awareness and impact of patient journey and access journey into the planning process.
MAPS: It sounds challenging to help organizations transition from the traditional, siloed way of doing things into this new model of collaboration. What do you do to help generate this?
Murali: Three things. First, I’m trying to educate the scientific organization this can work and not to be afraid, but rather to embrace it. Second, I’m trying to explain what good actually looks like by walking through my own process of evolution from previous experiences at other companies – maybe by seeing how it’s worked elsewhere, we can skip some of the painful learnings. Third, I try to lead by example by sitting in wherever I can as a leader for the Medical organization.
MAPS: With collaboration comes complexity…
Murali: These actions have helped me develop not just as a better leader, but as a better individual. Balancing business and science in this collaborative process of brand planning helps me to not look at things as only black and white. It affects how I approach complex challenges. Sometimes in a discussion, you find out how complex something is and it surprises you through all of the aspects that may need to be considered and planned for. That’s fun for me. How we work together to solve complex problems is fundamentally interesting to me. And when you’re constantly looking at all these variables to make decisions, you get better at it, not just with regard to business decisions, but life decisions as well. When there are things that are hard to pick between, you can use the same mentality to make a well-rounded decision. It might sound strange, but after engaging and leading in this process for so many years, I feel like I ruminate on decisions a lot less, and that I am more secure in my decision-making ability. Don’t get me wrong, it takes effort. You can go through the motions and not get anything out of it. But I dug into it. I really wanted to unpack how far we could take commercial and scientific collaboration and I think it’s facilitated my growth as a leader and attaining this level in my career and in my life.
It’s no secret that major forces have pushed the pharmaceutical industry to think differently about how it operates and how it can deliver greater value to society. The good news is that we’re seeing more connected, more agile and more outcomes-focused organizations arise from the disruption.
R&D teams have increasingly broken free from traditional scientific silos through increased internal collaboration and external partnerships with biotech and academia. They have embraced transformative science and technological advances and we are starting to see a new generation of medicines forged by our enhanced ability to capture, interpret and apply data.
Our engagement models have also adapted to changing stakeholder needs. More specialty products with more complex data mean that our clinical and access stakeholders are demanding deeper scientific exchanges to understand the patient impact and value to society.
Like many pharma companies, the role of Medical Affairs at Astellas has transformed in recent years, from a support function to a strategic organization to internal and external stakeholders.
Today, Medical Affairs is comprised of the most important and valued capabilities in the business, playing the role of key connector between internal pharma and external stakeholders.
We are driving scientific exchange and evidence generation with an ever-expanding external stakeholder community of healthcare professionals, scientific experts, health authority bodies, payers and patients.
Our role is not just limited to knowing what these stakeholders want and need. We’re fulfilling information needs through data-generation (clinical trials and real-world data analyses), data sharing through publications, medical information and scientific exchange, pinpointing the investments and activities that will drive the biggest impact for each of these groups. The result, ensuring the safety, efficacy, value and real-world utilization of our therapies are fully understood.
As Medical Affairs integrates its wealth of external insights into a consolidated and aligned strategy to guide its own global activities, it also needs to align with Commercial and R&D colleagues. Through governance and operational excellence, Medical Affairs ensures information needs and data are shared across organizations, as and when needed, to enhance the effectiveness and impact of all respective groups.
As our operating environment has changed, Medical Affairs has become a more business-savvy, scientifically influential, connected and agile function. While we’re making great progress, companies like Astellas know that the disruption won’t stop.
New challenges lie ahead, such as our ability to address wider societal issues and to create value for a variety of stakeholders that is wider than ever before. Another key challenge for us will be the use of artificial intelligence to generate data from combined big data sources, such as clinical health records, real-world data and the variety of ‘omics’ data sets. This information will need to be delivered in an increasingly digitally-savvy way, for example via interactive medical information websites and other digital channels.
We also know that downward pricing pressures are unlikely to go away. We will need to demonstrate how innovations create value to a wider variety of stakeholders than ever before. So, every commercial decision will have greater consequences.
With this mind, I believe that Medical Affairs professionals must continue to build on the range of capabilities that enable them to act as orchestrators of company strategy with R&D and Commercial functions. Central to this is effective leadership. Medical Affairs leaders need to be ready to interact with the C-Suite and inform corporate strategies because it is helping companies to make smarter decisions and focus performance measures on patient-centric outcomes. And that’s value creation that makes a real difference.
Charlotte Kremer, M.D.
EVP, Head of Medical Affairs,
Astellas Pharma Inc.
Eileen Sawyer didn’t always intend to work in pharma—in fact, she hadn’t ever planned to have a career in science.
Growing up in a Boston suburb, neither of her parents worked in the sciences. Her dad was a computer programmer and her mom edited college textbooks. But the family was always passionate about the natural world. Sawyer recalls spending family vacations at national parks, identifying plants and animals together. She’s a self-proclaimed science nerd. She loves the details and especially translating those details to application. Quality science is where it all begins.
In high school, she says she was a ‘big reader,’ and planned to become a writer. In college, that idea changed when she developed an interest in psychology. She loved learning how people think, and she especially liked studying the connection between psychology and biology.
Eileen Sawyer, Vice President, Global Medical Affairs, UniQure
As part of her studies, Sawyer took an introduction to a neuroscience class—and fell in love with it. She enjoyed combining hard science with an understanding of psychology to discover why people are the way they are. It had a storytelling flavor that appealed to the writer in her.
She started working towards her Bachelor of Arts in Neuroscience, and spent her summers interning in labs that studied animal behaviour. Her new career goal became discovering connections between the brain and behavior that could improve healthcare, and after college, she pursued a PhD in Neuroscience research. She hoped to make scientific advancements that would contribute to development of new drugs to help people.
However, after her PhD, Sawyer began questioning if academia was the right fit. She continued on to her post-doc but felt frustrated. Their team was doing pre-clinical drug discovery, but there were stacks of studies sitting in file drawers waiting to be published. It was great science, but she longed to work more directly on creating new medicines. After all, she had gotten into science to help people. She realized that more than anything, she wanted to work closer to patients—and have a greater impact on their care.
That’s when she made the leap into pharma. Initially, she started by doing some freelance science writing and editing on the side. But the more she got to know the world of pharma, the more she realized that the best place to have the type of impact she wanted was in one of those companies itself, directly working on bringing new drugs to patients. To open up new opportunities, she tried old fashioned networking—asking people about what they do and reaching out to leaders in the industry. She got involved with associations in medical writing and communications and applied to dozens of jobs.
Months later, she got a call about an editing job. But by that point, she realized she didn’t want to just write—she wanted to work inside pharma. She declined the role and continued networking and applying.
Eventually, she got the call she was looking for—an interview at Alexion in scientific communications. The team that was hiring was preparing to launch a product for bone disease. The condition was rare, and severe. Babies were born with no mineralization in their bones and died because their chest couldn’t support breathing. Of course, the work was completely different from neuro, as it was all below the neck. Still, Sawyer knew immediately that she wanted to help.
The position at Alexion was a formative experience. Sawyer had a mentor she admired, and a role that allowed for plenty of exposure to all of medical affairs, from launch preparation to strategy. Their team worked in that crucial space between the science and the impacts on actual people. In real time, she got to witness science turning into effective medicine—medicine that made tangible impacts on patients.
She loved every minute of it.
After the drug was launched, Sawyer began looking for her next step, knowing that she wanted to find another role with the same level of impact. She found the perfect answer—working on gene therapy at uniQure.
When Sawyer started at uniQure as Director of Scientific Communications, it was small company with no Medical Affairs department. Six months into her tenure, she became the firm’s first Director of MA, and for the first two years in the role, she was a one-woman department. More recently, she has been able to build out the team and increase their impact.
Now, she leads more than seven people with different MA specialties ranging from communications and field medicine to health economics and strategy.
Sawyer’s MA team is focused on removing barriers to access to gene therapy. The barriers for patients fall into two main categories:
The health care provider or the patient either does not understand gene therapy or has misperceptions about it and how it can treat the condition. They may not even know a drug is in development. The answer to this challenge? Education.
Justifiably, patients and doctors have questions about the treatment. The MA team needs to work to understand those questions, bring them back inside to find answers, and then take those solutions back to the patients. Sometimes, this process requires supplemental studies or health outcomes research.
Sawyer saw a clear key to removing those barriers—listening to patients and physicians. To ensure they were receiving adequate feedback on their work, Sawyer and her team started early, reaching out to patients and physicians while publishing and announcing results from the phase 1 study.
As it turned out, listening to patients changed the team’s entire development program. From the conversations, they learned that the community wanted something completely different from the gene therapy than was expected. So, they went back to the drawing board, totally changing the design of the program.
Sawyer was responsible for presenting the change to thought leaders, MDs and top patient advocates. When she revealed the news at a small scientific meeting after the company announcement, there was an audible gasp in the room. The leaders didn’t think regulators would permit this type of change. However, when she heard from the community that provided the feedback, Sawyer was reassured that they had made the right decision. Patients and physicians were so pleased to see that the company responded to their comments, and it completely transformed their attitude towards partnering with uniQure.
“Our goal was to deliver what they need,” says Sawyer. “They saw that.”
Now, uniQure has patients provide input into everything from their protocol to their patient materials and scientific steering committees. Again, and again, Sawyer has seen them contribute remarkable insights the MDs hadn’t thought about. She recalls one patient at a steering committee who pointed out an issue with the wording in a particular passage. It mentioned barrier protection during sexual contact, and he asked, “How are you defining sex? How inclusive are you being?” The team used his feedback to rewrite the section with more inclusiveness and clarity.
The uniQure team after defending the switch to AMT-061 at the European Medicine Agency. Sawyer is sixth from right.
“Sometimes, wearing the medical hat you forget to think about how it would play in the real world. What does it really mean for someone’s life?” she says.
Sawyer is making it her life’s work to focus on the patient—the most important stakeholder in drug development. She wants to help them take ownership over their care and make informed decisions. To do that, they need access to information—both directly and via access to educated health care providers. Her team presents scientific findings at patient meetings as well as medical meetings, and they engage with patient association leaders around science and policy. They even involve patients in economics and outcomes research. The goal is to foster true partnerships while developing each drug.
“At the end of the day, it’s about giving the patient control,” Sawyer says. “The best scenario is for a patient to have many options and be empowered to choose the best choice for them. The role of pharma in this setting is to equip them with the tools to make those decisions.”
Throughout her career, she has never lost the desire that drew her to pharma. It’s the desire to turn cool science into medicine and make something that matters—something that will make someone’s life better. For her, a great day is one where she has the chance to talk to a physician and hear a patient story. Learning about the tangible impacts that the science is making on patients is what keeps her coming back.
We had a chance to sit down with Eileen. Enjoy watching our interview to see how she responds to questions about:
This article is graciously contributed by Excellerate: Patient-Focused Engagement for Pharma.
MAPS speaks with Beat Sümegi, SVP Medical with Sanofi, about major areas of change and the need to help Medical Affairs professionals build new skills to succeed in this world of increased responsibility and opportunity.