Medical Affairs thought leaders discuss the Pre-21st Century Cures Act uses of Real World Evidence (RWE) in regulatory decision-making.
The Series Podcast Objectives are:
Podcast objectives include understanding how the medical affairs strategic planning process can drive decision making throughout the year
Medical Affairs thought leaders discuss the function, activities and opportunities for compliant collaboration with key internal partners.
Q&A with Medical Affairs thought leaders describing changes in Digital and Field Medical during the pandemic and beyond
• Develop leadership and motivational skills that will help Medical Affairs colleagues build cross-functional relationships and engagement, in order to successfully deliver integrated medical activities
• Awareness that effective collaboration requires modifying interpersonal interactions to account for different functions/nationalities having different backgrounds/cultures/ways of working/motivations
• Recognition that a major cause of disharmony/disengagement/demotivation is an individual feeling threatened in some way, and the implications of triggering a ‘threat’ response
• Knowledge of the SCARF model (NeuroLeadership Institute), its key components {Status, Certainty, Autonomy, Relatedness, Fairness} and their importance in triggering a ‘reward’ response
• Understanding of how the SCARF model can be applied by Medical Affairs colleagues in their everyday roles and interactions with colleagues
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.
Cerise James, MD, moderates this podcast in which Neil Belson, JD, discusses Real World Evidence and its impact to the biopharmaceutical industry.
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 |
This Medical Affairs Professional Society (MAPS) podcast features medical affairs thought leaders offering insights into the Medical Affairs strategic planning process
This special 75-minute MAPS Global Town Hall focuses on the challenges that are arising from the global Covid-19 pandemic and the emerging opportunity for Medical Affairs to provide strategic leadership.