By Jeffrey J. Stoddard, MD
Overview
The role of the physician in innovation of new medicinal products and other health and wellness therapies is central. The specific roles and specific tasks for medically trained experts varies across the spectrum of innovation, and it is worth some time to consider these varied functions physicians play. These roles have been described in detail (1). In early pre-clinical strategic planning, pharmaceutical companies and biotech firms typically rely very heavily upon physician experts to help them identify areas of unmet medical need. Most of the work in the discovery phase of researh is in the hands of the basic scientists, but those hands are guided at the outset by physicians who recognize where innovation is most sorely needed; i.e. where there are gaps in the therapeutic armentarium. In early stage clinical trials (Phase I for example), physicians closely and carefully monitor the safety and tolerability of investigational early stage products, often in specialized research units. In Phase II dose-ranging studies and proof-of-concept studies, physicians have critical roles in assessing and analyzing the safety and efficacy data. In Phase III registration trials, including large, pivotal safety & efficacy studies, physicians have a critical role initially in designing the studies, drafting the study protocols, then in the execution or conduct of the studies, and finally in the analysis and interpretation of safety and efficacy results. Few Phase III studies of important new medicines have had their primary endpoints defined without the central input of medical doctors working within clinical development departments. Moreover, the clinical relevance of multiple observations seen during the conduct of clinical research requires interpretation of medically trained personnel. Upon completion of Phase III trials, analysis of primary, secondary and exploratory endpoints often requires careful clinical assessment by physicians who bring their clinical experience to bear on the process of interpretation of the results. Post licensure Phase IV studies as well as label extension studies (Phase IIIB) require physicians to again design and conduct these studies in order to assess risks and benefits of real world use of newly approved products. This article will look in turn at each of these roles and review some of the most critical roles that physicians play along the spectrum in the development and commercialization of new pharmacologic agents.
Research & Development
While most preclinical research is conducted by PhD research scientists with backgrounds in molecular biology, genetics, pharmacology, physiology and other basic science fields, physicians play a critical role in the initial designation of areas of high unmet medical need. Medical doctors are well aware of the diseases for which there is no adequate therapeutic intervention. It is this absence that indeed spurs many physicians to come to work in the health sciences industry, which is to a very high degree where innovation occurs. When drugs, vaccines or biologic agents come out of pre-clinical research (with abundant non-human animal model data behind them) and are ready to go into clinical trials, the first in human (FIH) Phase I studies (which involve healthy adult volunteers) typically come first. Specialized Phase I research units involve exceptionally close monitoring of patients exposed to the novel, investigational therapeutic agents and any signs or signals of adverse events are carefully scrutinized. If the novel drug, biologic, or vaccine is deemed to be safe and well tolerated in Phase I trials, it can then move to Phase II for proof of concept, and for dose-ranging. Phase II trial design nearly always involves physicians integrally in the drafting of the study protocol and the overall design of the study. Certainly, statisticians, regulatory experts and other technical personnel are heavily involved, but it is the physicians in development departments that routinely dictate primary endpoints for safety and efficacy in Phase II trials. Phase III trials (larger, more robust, and designed to provide pivotal efficacy and safety data), require heavy input from clinical development physicians. The physicians nearly uniformly are responsible for drafting the study protocols, defining all primary, secondary and exploratory, endpoints, defining inclusion and exclusion, criteria, and monitoring the research subjects’ experiences over the course of the trial.
Safety and Pharmacovigilance
The roles of experts in safety and pharmacoigilance have grown exponentially in recent years in their complexity, and in their importance. No longer are safety and pharmacovigilance personnel simply assigned to process adverse event reports in accordance to regulatory-driven “clocks”. In 2025, drug safety and pharmacovigilance personnel, in teams usually led by physicians, and comprised heavily of physicians, are responsible for proactive and multifaceted analysis of a host of data sources, all with the purpose of determining the safety of the investigational or the newly approved medicinal product. Large scale databases comprised of real world evidence (RWE) such as electronic health records (HER) are utilized in the immediate postmarketing launch phase of products to assess safety in real time and in actual use. Rapid cycle analysis (RCA) is now utilized routinely when new vaccines, biologics and drugs are launched. Rapid cycle analysis allows for expedited analysis of safety signals based upon existing data-gathering infrastructure, relying upon real world evidence all outside of clinical trials. Certainly epidemiologists, statisticians and other experts in population-based methodology and data science are involved in these analysis; however, physicians with a deep clinical understanding based on their clinical expertise are crucial in the in the interpretation of these large scale, analytic efforts.
Medical Affairs
During the course of conduct of the Phase III safety & efficacy trial designed to garner licensure of a new drug, biologic or vaccine, most sponsors will forge a medical affairs team to support the product launch. This medical affairs team must understand fully the requirements for a successful new product launch. Facilitation of adoption by prescribers and reimbursement by payers is entirely dependent upon the success of the work conducted by the medical affairs team. Medical affairs personnel, usually comprised of, and certainly led by physicians, understand the requirements for adoption into medical use of new medicinal products. Safety and efficacy data from the phase III trial may very well be adequate to attain licensure for the product, but rarely will such data allow for all of the requirements of a successful introduction of a new medicine to be met. One need only think about the various stakeholders that come into play when a new medicinal product is launched, and then to ask ‘what data do they require in order to adopt that product?’ Certainly payors are paramount in this equation, and will insist upon having credible value evidence in hand, weighing benefit risk and cost-effectiveness of the new product. Certainly payors will also require comparative information regarding the therapeutic class in which the new product enters. Is the new product equally efficacious more efficacious or less efficacious than its competitor drugs? What are the safety and tolerability considerations compared with other therapies in the therapeutic class? What about other considerations such as dosing regimens, ease of use, tolerability, and accessibility, supply & pricing? Payors will want to know the answers to all of these questions, and they will expect the sponsor to bring credible data to them to assess the competitive landscape. Prescribers, separately, will immediately look up upon a new product in through a comparative and/or competitive lens. Prescribers will want to know relative efficacy; i.e. is the new drug superior, equivalent, or is it inferior in comparison to other agents in that class? Is it equivalent to other therapies in terms of ease of use, route of administration, frequency of dosing, etc? And how does the safety profile of the new product compare with more ‘tried and true’ – albeit older – products? Is the safety dataset available at launch large enough to fully understand the safety profile of the new product? Are there important dosing, administration, supply, accessibility or other convenience factors that bear on a decision as to which product to prescribe? Finally, but perhaps most importantly, consumers will be very interested in understanding the product profile from the standpoint of the outcomes that consumers most care about. Whereas regulators may define primary efficacy endpoints in an arcane manner, consumers will often have very clear and very cogent appreciation for the outcomes that matter most in their eyes. So, patient reported outcomes (PROs) become very important in the assessment of new medicinal products, especially for patients and consumers. Finally, it is often the role of the medical affairs physicians in a company to pull all of these threads together and to weave from them a coherent narrative as to the optimal place in the therapeutic armamentarium of the new drug, biologic or vaccine. Some executives in some pharma companies will expect physicians to bring only very narrow technical expertise to bear on questions such as what clinical advantages might exist for company A’s product versus company B’s product. However, very importantly, physicians will understand better than anyone else within the company that not all data points, and not all lines of evidence are of equal importance. For example, if a newly launched product is less safe and less available due to manufacturing problems, is at best only equivalent in efficacy, but it offers some modest advantage with respect to dosing interval or half life, any physician will quickly conclude that such a product is, overall, markedly inferior to its competition, and unlikely to attain a top place (or potentially even an important share) within the therapeutic armamentarium. As a senior medical affairs executive in one major Pharma company, I was asked repeatedly to provide narrow technical expertise on singular advantages of the dosing regimen and the persistence of efficacy of a vaccine that had the following disadvantages clearly demonstrated:
-safety (serious adverse events of a certain type were uniquely attributed to the product at hand);
-efficacy (based upon respective dosing regimens tested in Phase III trials, point estimates of efficacy favored the competitor vaccines),
-supply and availability (manufacturing and supply chain problems hampered the product’s availability relative to the competitor vaccines which remained readily available);
-expert recommendations (most national expert panels afforded preferential recommendations to the competitor vaccines).
“Just put on blinders to the issues other than where our product might have advantages, and focus on those advantages exclusively, and create a medical narrative to drive use” — these were my marching orders. I found them to be untenable. The logic behind them was fundamentally flawed.
From this experience, and similar experiences, my own view is that physicians ought to have – and indeed need to have — a positioning within pharmaceutical companies and other healthcare industry firms where they’re allowed and encouraged to speak the truth as product profiles emerge through their development and commercialization cycles. If physicians in a pharma company are treated in the same way as sales personnel, marketing executives or other business functions, then such individuals are not likely to adhere to the Hippocratic Oath which they took, nor are they likely to speak up regarding the true picture of the company’s drug relative to the full context/full array of therapeutic modalities available (2,3). Physicians, in my opinion, need to always remember first and foremost their duty to patients and to consumers of the medicinal products that they develop in whatever capacity they find themselves positioned within the healthcare industry. At its core, this is the critical aspect of medical professionalism and medical professional ethics that has always been expected of medical doctors(4). This special set of expectations may face new pressures as technological innovations advance and business upsides evolve, but it fundamentally should not change.
REFERENCES
- Sweiti, H. et al. Physicians in the pharmaceutical industry: their roles, motivations, and perspectives, Drug Discov Today (2019), https://doi.org/10.1016/j. drudis.2019.05.021
- M. Heidelberg, A. Kelman, J. Hopkins, M.E. Allen, The evolution of data ethics in clinical research and drug development Ethics, Medicine and Public Health, Volume 14, 2020, 100517
- Sass, HM. (1989). Ethics of Drug Research and Drug Development. In: Wolff, HP., Fleckenstein, A., Philipp, E.O. (eds) Drug Research and Drug Development in the 21st Century. Bayer AG Centenary Symposium. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-74615-4_2
- Brody, Howard MD, PhD*,†. The Ethics of Drug Development and Promotion: The Need for a Wider View. Medical Care 50(11):p 910-912, November 2012. | DOI: 10.1097/MLR.0b013e31826c8767
