Publications
APS Bulletin • Volume 13, Number 4, 2003
Articles
Improving Analgesic Drug Development: What’s Needed
Raymond Dionne, DDS PhD, and James Witter, MD PhD
The limitations of currently available analgesic drugs often result in failure to alleviate suffering in patients with chronic diseases and cancer, patients at the end of life, and in vulnerable populations. Consequently, the search continues for new analgesics with greater efficacy and less morbidity. Despite dramatic advances in the neurosciences, analgesic therapy during the past century has been largely limited to local anesthetics, opioids, and aspirin-like drugs (i.e., NSAIDs) with unique limitations in each class.
The mixing bowl of pain etiology includes a multitude of inflammatory mediators, neuronal pathways, and cytokines, with the potential for alteration by gene expression, contributing to plasticity in the nervous system manifesting in variable ways in patients with chronic pain (Samad, Sapirstein, & Woolf, 2002; Watkins, Milligan, & Maier, 2001). This multiplicity and adaptability makes it unlikely that a single “magic bullet” drug or therapeutic strategy will successfully modulate the complex processes of developing and sustaining chronic pain.
The expense and uncertainty of analgesic drug development also present barriers to the development of novel drug therapies to improve pain management, much less to prevent the development of chronic pain. The cost of drug development for a new chemical entity is an estimated $800 million, and is projected to increase to $1.9 billion for molecules now in early development that might be marketed 10 years from now (Nature Reviews Drug Discovery, 2003). With the high risk and high costs of drug research, pharmaceutical companies must rely on a limited number of highly successful products (“blockbusters”) to finance the continuing research and development that fosters pharmaceutical innovation (Miller, 2002). The current analgesic development paradigm results largely in a search for “improved” versions of already known analgesics. This traditional approach to drug development misses the mechanistic diversity across chronic pain in differing diseases and disorders, and patients’ genetic variability.
The Inflammatory Soup Thickens
The number of potential targets for analgesia has grown from the traditional few dozen neurotransmitters and inflammatory mediators that have been studied for decades to include an estimated 10 million single nucleotide polymorphisms (SNPs) in humans (Guttmacher & Collins, 2003). If only a small percentage of this variability contributes to the inflammatory/pain cascade, neural immune interactions, and the development of sensitization and variations in gene expression over time, this readily explains the differences in chronic pain mechanisms across various diseases and disorders. In fact, it is likely that no two individuals have the same “painome” activated at any given time. Yet, the quest continues for analgesic drugs with a unitary mechanism of action to minimize adverse effects and to be used by the largest possible population. Most commonly used non-clinical animal models (e.g., rat paw inflammation) and clinical trial models (e.g., oral surgery) have been validated with opioids and aspirin-like drugs and are biased for selection of molecules with similar mechanisms of action, rather than novel mechanisms and drugs.
Reevaluating the Analgesic Drug Development Process
Concern that emerging scientific opportunities may not be translating into improved therapy for pain prompted the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) to convene a workshop on how analgesic drug development can better address unmet clinical needs for pain management. This two-day meeting, attended by more than 250 people from the scientific, academic, clinical, and pharmaceutical communities, resulted in a series of conclusions and recommendations that provide a framework for changing the current approaches to analgesic drug development (Dionne & Witter, 2003).
Pain measurement is essential for assessing analgesia. At present, however, there is no generally accepted pain metric that permits comparisons across clinical trials, pooling of data for meta-analyses, and attempts to describe the individualized nature of pain by means of patient-oriented assessment (i.e., responder analyses). A necessary first step to address this methodologic need is to conduct studies to identify better outcome measures for pain and its relief in analgesic clinical trials. A subsequent workshop sponsored by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) described six consensus domains recommended to be included in all chronic pain trials (Turk et al., 2003), indicating this process is underway.
An important consensus that emerged from the NIH-FDA workshop was the acknowledgment that the FDA Analgesic Guidance document needs to be revised. This necessary revision will encourage development of new analgesics and treatment strategies, especially in the areas of chronic pain and combination drug therapy, and encourage the validation of individual responder analyses. In addition, the role of post-marketing safety monitoring and the use of large-scale outcome trials to better understand the long-term risks of chronic therapy were identified as crucial to the future of truly improved analgesics. Strategies to provide incentives for drug development for both broad chronic pain indications and more narrow disease-specific indications were also recommended. These incentives might be similar to patent extensions or to tiered claims structures (similar to rheumatoid arthritis) that encourage more robust development of analgesics for chronic pain. They also may facilitate better understanding of the epidemiology of pain.
In general, the proceedings of the workshop support the need to enhance the scientific basis for the analgesic drug development and regulatory processes, especially in view of the large investment needed to progress through the many steps in each of these processes. Translating scientific advances into improved pain relief will require a cooperative effort among the pharmaceutical industry, regulatory agencies, funding agencies, the biomedical research community, professional societies, and clinicians to improve clinical trials methodology and outcome measures and better study the epidemiology of pain.
Transorganizational Integration of Analgesic Drug Research
The development of analgesic clinical trials methodology resulted from the pioneering work of early researchers such as Beecher, Houde, Wallenstein, Rogers, Beaver, Lasagna, Sunshine, and others. These “founding fathers,” along with members of the American Society of Clinical Pharmacology and Therapeutics (ASCPT), also provided significant input into prior analgesic guidance documents and the development of monographs for over-the-counter and older analgesic drug combinations that had been “grandfathered-in” before regulations for efficacy and safety evaluations were fully implemented in 1962. This scientific legacy defined a standard for well-controlled clinical trials, and launched an active and open scientific dialog for analgesic drug development among funding and regulatory agencies, pharmaceutical sponsors, and individual investigators.
To move forward in analgesic research, new thinking that encourages innovative research and development strategies needs to emerge. The scientific dialogue that occurs in research-oriented environments such as meetings of the ASCPT, the American Pain Society, and the International Association for the Study of Pain, along with a revitalized NIH Pain Consortium, can foster the analgesic drug development process. Joint symposia and other types of scientific exchange can be held on a rotating basis to engage the collective expertise of these organizations. Scientific and clinical issues related to the development, validation, and optimization of clinical models and outcome measures for analgesic drug development can be addressed on a regular basis, rather than the current 10-to-15-year revision cycle of the FDA Analgesic Guidance document.
Reengineering Pain Research to Optimize Outcomes
Recognizing that acute and chronic pain research and therapy represent a scientific continuum crossing diseases, scientific disciplines, and clinical specialties suggests transorganizational efforts are needed to translate scientific advances into improved pain relief. The pain research community (biomedical researchers, pain clinicians, pharmaceutical investigators, and regulatory officials) and other disciplines (including bioinformatics, brain and molecular imaging, and neural immunology) are needed to develop novel models and to collect and integrate the vast amounts of information that arise from genomic and proteomic investigations. This requires resources and organizational integration that do not exist at individual sites, nor are found in traditional “silos” of pain research. A diverse, integrated translation pain research structure can focus the resources needed to move beyond centuries-old opiates and aspirin-like drugs for the relief of pain into an era of individualized, targeted, effective, and safer analgesia.
References
Costing drug development [editorial]. (2003). Nature Reviews Drug Discovery, 2, 247.
Dionne, R.A., & Witter, J. (in press). NIH-FDA analgesic drug development workshop: Translating scientific advances into improved pain relief. The Clinical Journal of Pain.
Guttmacher, A.E., & Collins, F.S. (2003). Genomic medicine—a primer. New England Journal of Medicine, 347(19), 1512-1520.
Miller, H.I. (2002). A proposal for FDA reform. Nature Reviews Drug Discovery 1, 642-648.
Samad, T.A., Sapirstein, A., & Woolf, C.J. (2002). Prostanoids and pain: Unraveling mechanisms and revealing therapeutic targets. Trends in Molecular Medicine, 8, 390-396.
Turk, D.C., Dworkin, R.H., Allen, R.R., Bellamy, N., Brandenberg, N., Carr, D.B., et al. (2003). Outcome domains in chronic clinical pain trials: IMMPACT consensus recommendations. Manuscript submitted for publication.
Watkins, L.R., Milligan, E.D., & Maier, S.F. (2001). Glial activation: A driving force for pathological pain. Trends in Neurosciences, 24, 450-455.
The views expressed in this article are those of the authors. No official support by the U.S. Food & Drug Administration or the National Institutes of Health is provided or should be inferred.
James Witter, MD PhD, is clinical team leader in the division of analgesics, anti-inflammatory and ophthalmic drug products, of the Center for Drug Evaluation and Research (CDER) at the FDA.
Raymond Dionne, DDS PhD, is a senior investigator and chief of the pain and neurosensory mechanisms branch at the National Institute of Dental and Craniofacial Research, NIH.