Erroneous Assumptions in Drug Development
Constantin Reliu is having trouble finding employment in his home country of Romania because he is dead. Since 2003. Constantin left Romania in the early 1990s to be a cook in Turkey after he discovered his wife was unfaithful to him. Whether out of revenge or to acquire his assets, his wife had him declared dead 15 years ago. He returned to Romania in January after Turkey deported him for expired documents, only to get resistance at the Romanian customs border for reentry because, well he is dead. He took his case to court, because he could not find a job (because he is dead). Despite a personal appearance, the court ruled against granting him the right to be alive, because the statute of limitations had expired on overturning a death certificate. Constantin is in limbo.
The Romanian court, relying on entrenched laws and assumptions, failed to respond appropriately to this situation. This is not unlike many individuals and companies involved in drug and device development, who rely on archaic erroneous assumptions to guide their programs. Here are a few examples:
Erroneous assumption #1: Key opinion leaders are best poised to guide the development program.
Key opinion leaders (KOLs) might be very useful if used appropriately. If properly identified, they bring a level of expertise for the drug or device not available in most instances internally in a pharmaceutical, biotech or device company. They often arise in a university setting and have a specific focus on the disease at hand. But they often lack a deep knowledge of drug/device development, FDA regulations, and are biased toward answering academic questions. If the KOL guides the development strategy, the result is often a bloated trial design with investigational biomarkers or imaging techniques which serve to significantly drive up the cost and increase complexity which will inevitably lead to errors in trial execution. Increased trial complexity will result in more errors. These esoteric investigations, while of great intellectual value, are not of interest to the tightly regulated FDA. It also greatly enhances the burden on the investigators and coordinators, discouraging their participation initially, or decreasing their enrollment goals. Potential subjects are also reluctant to participate due to the number of interventions.
KOLs should be used to provide the needed expertise, but the trial design and execution should be straight forward, and the quickest, most cost-effective path used in the hands of seasoned drug/device developers. Isolate the arcane investigations suggested by KOLs to those who can provide a deeper understanding of the drug (e.g. mechanism of action) or ultimately enhance marketing if approved.
Erroneous assumption #2: The best contract research organizations, project managers, medical monitors and other staff are those with specific expertise in the disease/device being addressed in a development program.
In an ideal world, these companies and individuals will have both specific expertise and broad drug development experience. However, with increasingly esoteric diseases and specific indications being pursued, it is unlikely to find both qualities in a company or in a single individual. The vast majority of problems that arise in clinical trials are not disease specific, but more often relate to trial management. An understanding of how to avoid pitfalls in trials and avenues to suggest viable solutions results from engaging companies and persons who have extensive experience in product development, not an isolated expertise in the disease. Would you rather be operated on by a 34-year-old neurosurgeon who just completed a training program related to your specific tumor, or a 55 year-old surgeon with decades of experience in neurosurgery and a history of good outcomes?
This same concept applies to hiring decisions at small biotech companies who are looking for the ‘perfect’ medical monitor or project manager to hire onto their team. Extensive drug development experience should always trump disease-specific background. You need to look no further than pharmaceutical employment boards to appreciate that many companies are also looking for that ‘special’ oncologist or neurology expert. There are a small number of these individuals, and a single company is unlikely to capture them. Look rather for broad development and regulatory experience coupled with good business management and common sense.
Erroneous assumption #3: Design trials to exclude patients who may experience complications and put a black mark on the drug.
With a new chemical entity, it is reasonable to begin testing in healthy volunteers, who are most likely able to recover should an unidentified side effect of the drug be revealed. Early Phase 2 studies should also be rather restrictive in their inclusion/exclusion criteria, so the developer can best assess safety and efficacy, and not be burdened by ‘noise’ created by unrelated adverse events resulting from the patients’ concomitant medical conditions. Ultimately, the developer is desirous of a broad label, which will permit widespread use of the drug in the target population. Late Phase 2 and Phase 3 is the opportunity to identify, in a controlled manner, individuals who may not be candidates for the drug. The greatest historical disasters in pharmaceutical development are those in which issues with a drug were not revealed until after marketing authorization.
Relax the inclusion/exclusion criteria, in a safe and monitored fashion, going into Phase 2b and 3. It will result in a more comprehensive assessment of the drug, and certainly accelerate enrollment and time to NDA submission.
Avoiding some of these pitfalls will serve to streamline the development program and allow companies to engage the individuals most suitable to move the drug or device forward. Most importantly, the entire process should be overseen by highly seasoned drug development professionals. You don’t want a death certificate issued for your drug during development. Trust me, it can be hard to repeal.
Preventing physician burnout: caring for those who care for us
Aparna Shekar1,2, Gerald L. Klein, MD3, and Peter C. Johnson, MD3
1Ph.D. Candidate, Vanderbilt University, Nashville TN, 2Intern, MedSurgPI, LLC., Raleigh NC, 3Principal, MedSurgPI, LLC., Raleigh NC
- firstname.lastname@example.org email@example.com
Burnout syndrome is a widespread phenomenon that arises from chronic, unresolvable workplace stress that impacts quality of work and quality of life of the affected individual. It is characterized by physical and emotional exhaustion, decrease in performance, lethargy, cynicism, unhappiness and detachment from others and surroundings. Although there has been a large inflation in rates of burnout among several professions due to the current, unprecedented rates of competition and uncertainty in the global outlook, primary care MDs still remain one of the most vulnerable and particularly susceptible workforces. In fact, physician burnout rates have worsened since 2011 and presently, over half the physicians in the Unites States are suffering from symptoms of burnout1. Researchers over the past decade have focused on understanding the internal and external factors that contribute to burnout and have made significant strides in constructing interventions that can improve physicians’ quality of life. Studies and clinical trials aimed at preventing and treating primary care physician burnout are now arriving at the crossroads of a three-pronged approach involving knowledge, conversation and intervention at the professional and personal levels.
The causes of physician burnout are manifold and originate both from the individual’s surroundings and from within. The medical profession in the United States is a high-intensity environment that pushes physicians to be overworked and underappreciated. It promotes perfectionism, denial of personal vulnerability and requires delayed gratification throughout training and beyond. Medical practice has changed dramatically over the last ten years. It is now much more bureaucratic, regimented, and restrictive. A much greater emphasis is placed on following administrative requirements that has resulted in many physicians not being able to take their own patient notes during office visits, but rather use medical scribes or “professional patient note takers” They are required to complete countless insurance hospital, and governmental forms which are all time consuming. This has necessitated increased non-medical staff that require increased resources, physician management time, and costs. It is also important to consider that physicians experience a significantly higher-than-average frequency of distressing and emotionally painful experiences in the form of patient care that the average person does not experience. Few other professions have to make so many significant decisions that affect countless patients’ and their families’ well-being.
Immediate supervisors play an important role in caring for their employees’ well-being, absence of which can lead to unmet expectations on behalf of both entities. In many health care systems, physicians’ immediate supervisors are not medically trained, are focused primarily on business issues and therefore cannot properly relate to the unique stresses that physicians face. On the other hand, personality traits commonly seen in physicians that predispose them to experiencing burnout are feelings of guilt, compulsiveness to achieve perfect results and denial of mental and physical limitations. Many overworked physicians substitute their personal lives for successful careers; more often than not, they lack a support system in the form of family and friends that can help them maintain a healthy balance with their strenuous professional lives.
Forty two percent of physicians reported burnout in Medscape National Physician Burnout and Depression Report 2018 (Carol Peckman). Family physicians had the second highest rate with 47 percent burnout rate. The respondents claimed that the highest contributing factor is excess bureaucratic tasks. Other factors that confer susceptibility to burnout include but are not limited to physician gender, age, country of practice, financial status and family status. In 2015, the Association of American Medical Colleges reported that average graduating physician medical school debt was $183,000 (https://lendedu.com/blog/average-medical-school-debt/). This did not include undergraduate debt. Such a heavy debt burden fuels the flames of burnout, as does the constant threat of malpractice litigation. Female surgeons were significantly more prone to burnout and associated depressive-like symptoms arising from higher career conflicts, work-home balance conflicts and pressure to have children2. Studies characterizing physician burnout in Canada, UK, USA and the Middle East demonstrated a wide variability in scores among the three dimensions of burnout, possibly due to varying work environments1. Older physicians were less susceptible to experiencing burnout, as were married physicians.
Burnout is extremely deleterious to the personal and professional well-being of primary care physicians. Stress, decrease in job satisfaction and/or performance, rate of medical errors and desire or intent to leave the practice are common in those who are experiencing burnout. Physical symptoms can manifest as insomnia, muscle tension, headaches, and gastrointestinal problems. Additional effects of burnout and associated mental health neglect that have been observed in physicians and clinicians are depression, anxiety, sleep disturbances, fatigue, mental disorders, alcohol and substance abuse, marital dysfunction, premature retirement and perhaps most seriously, suicide. In spite of these serious consequences of burnout, stigmatizing physicians for seeking help and recovery options is prevalent to this day.
Physician burnout that leads to an increased physician turnover rate has tremendous economic costs3. A presentation by Stanford Medicine researcher Maryam Hamidi, Ph.D., at the American Conference on Physician Health in late 2017, showed that physician burnout costs their hospital at least $7.75M a year. Researchers at Stanford University, the National University of Singapore Business School and the American Medical Association evaluated the economic burden of physician burnout - they estimated the annual costs in the United States to be $3.4B of which 79% was attributed to the cost of physicians leaving the medical profession3,#. The negative impact of physician burnout on the well-being of an individual and the country’s medical economy makes it imperative to identify interventions for its large-scale prevention and treatment.
Understanding the causes of burnout has been instrumental in devising ways to intervene. An important tool to quantitatively assess an individual's experience of burnout is the Maslach Burnout Inventory (MBI), originally published by Christina Maslach and colleagues in 1981. The MBI has separate scales to evaluate each major attribute associated with burnout: emotional exhaustion, depersonalization and low sense of personal accomplishment. Significant landmarks have been achieved by research groups that conducted trials in hospitals using the MBI to not only assess physician burnout, but also to find effective interventions to improve their quality of life. A MEMO (minimizing error, maximizing outcome) study conducted between 2001 and 2005 established that adverse work conditions like time pressure and pace, chaotic hospital/clinic environments and unfavorable organizational culture contributed to stress, intent to leave the practice and other burnout symptoms in primary care physicians4. A HWP or Healthy Work Place study published more recently in 2014 designed interventions to improve communication, create changes in physician workflow and targeted quality improvement projects on clinicians’ concerns that decreased burnout and dissatisfaction and improved retention of clinicians in the study5. Other groups have documented the positive impact of professional coaching, positive psychology, mindfulness and organization-level interventions (including facilitated small-group curriculum and self-determination training) on keeping primary care physicians’ stress and burnout at bay6,7. These studies arrive at common focal points in burnout intervention: communication is key and emotional and organizational support is vital to physician well-being.
One proposed method of preventing physician burnout is a Clinical Physician Scientist Program (CPSP). This program is aimed at restoring and re-enforcing the scientific enthusiasm, creativity, and mental stimulation that physicians have, especially those in clinical practice-heavy primary care. It emphasizes how individual physician observation and creative involvement is important and can have an important influence.
The program uses podcasts, webinars, and videoconferences to educate and communicate with the participants. The formation of a CPSP network is designed to reduce isolation and to enhance physician skills, medical interests and fascination. To prevent burnout, it turns their minds from solely mundane tasks to refreshing scientific exploration and accomplishment. Such a program would consist of the following elements, fashioned to promote scientific growth in the context of group communication. It emphasizes elements of scientific discovery in practice that might normally go unnoticed or unapplied. The program as designed recreates some of the most tried and true elements of graduate medical education in the practice setting to enhance creative thinking and group involvement. Facilitated by physicians who are experienced in practice, academia and industry, its elements are:
· Establishment of a Clinical Physician Scientist Program
o Core Program I: Eliciting Constructive Creativity
§ Writing and publishing Case Histories and Case Series
· How to more accurately read and interpret the medical literature
· The identification of significant medical cases for publication
§ Creating posters for medical conferences
§ Conducting (non-product) in-office clinical studies
§ The basics for conducting product clinical trials
o Core Program II: Fostering Enhanced Knowledge Sharing and Professional Growth
o Monthly/Quarterly Journal Club
§ Discuss relevant clinical articles
o Monthly/Quarterly Case History Discussion
o Monthly/Quarterly Clinical Research Discussion
While such a program requires that physicians invest some time, it is designed to reinvigorate them and help make them more productive in their routine daily activities. It works in concert with steps now being taken by health care systems such as the Southern California Permanente Medical Group. Its program, called “Complete Care” recognizes the intolerable time burden being placed on Primary Care Providers and counters this with a four-part program. The program coordinates sharing of some primary care activity with specialists, delegation of time consuming tasks to nurse clinicians and other licensed non-physicians, leveraging information technology to streamline scheduling and testing and finally standardizing care practices to make physician time more efficients8. The combination of healthcare system-wide workload and workstyle changes with focused attention on the growth of the individual physician is a promising plan to control physician burnout. The latter may be particularly important for those physicians in solo or small practices in rural environments but the approach is applicable to all physicians. Being a physician should be one of the most gratifying, stimulating, self- actualization careers one could ever hope to undertake. A new awareness of the causes and prevention of burnout will hopefully restore these features of medical practice. While there is probably not one cure for physician burnout, the use of the CPSP may be one helpful tool. Future studies are being planned to demonstrate the benefit of this program. The use of a CPSP may also stimulate scientific thinking, and help provide physicians with better tools to apply the medical literature for better patient care.
1 Kumar, S. Burnout and Doctors: Prevalence, Prevention and Intervention. Healthcare (Basel) 4, doi:10.3390/healthcare4030037 (2016).
2 Dyrbye, L. N. & Shanafelt, T. D. Physician burnout: a potential threat to successful health care reform. JAMA 305, 2009-2010, doi:10.1001/jama.2011.652 (2011).
3 Shanafelt, T., Goh, J. & Sinsky, C. The Business Case for Investing in Physician Well-being. JAMA Intern Med 177, 1826-1832, doi:10.1001/jamainternmed.2017.4340 (2017).
4 An, P. G. et al. Burden of difficult encounters in primary care: data from the minimizing error, maximizing outcomes study. Arch Intern Med 169, 410-414, doi:10.1001/archinternmed.2008.549 (2009).
5 Linzer, M. et al. A Cluster Randomized Trial of Interventions to Improve Work Conditions and Clinician Burnout in Primary Care: Results from the Healthy Work Place (HWP) Study. J Gen Intern Med 30, 1105-1111, doi:10.1007/s11606-015-3235-4 (2015).
6 Gazelle, G., Liebschutz, J. M. & Riess, H. Physician burnout: coaching a way out. J Gen Intern Med 30, 508-513, doi:10.1007/s11606-014-3144-y (2015).
7 Siedsma, M. & Emlet, L. Physician burnout: can we make a difference together? Crit Care 19, 273, doi:10.1186/s13054-015-0990-x (2015).
8 Arabadjis, S., Sullivan, E., How one California medical group is decreasing physician burnout, Harvard Business Review, June 7, 20
The Emergence of Population Health
by Peter S. Liebert, MD, MBA
Population Health is a new discipline, at least as so named. Years ago it fell under the rubric of “Health Promotion and Disease Prevention,” but now is a field of specialization that is embraced by public health professionals, medical school leaders, hospital CEO’s, and a broad spectrum of health care providers. It is time to understand the goals of Population Health and to be willing to participate in its application.
An Interview and Commentary by Kenya Oduor, PhD
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Building Trust in Pharmaceutical Analytics
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The Integrated Management Role of the Chief Executive Officer and the Commercial Chief Medical Officer
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ROGER MORGAN, MD, FACS, JOINS MEDSURGPI, LLC AS VICE PRESIDENT OF MEDICAL AFFAIRS
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Do Not Overlook These Issues Before you Select a CRO
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For Questions or comments: firstname.lastname@example.org / email@example.com
December 6, 2015