By Terri Lewis, PhD.
(Editor’s Note: A Conference is being held this month in Chicago with the goal of trying to develop a reference protocol for the use of ketamine to treat CRPS—and perhaps to inspire some clinical studies. We’ll report on that this coming week. We asked Dr. Lewis for some thoughts about why more attention from industry or government hasn’t been focused on CRPS-or chronic pain generally- and she provided this background)
Guidance assists sponsors of drug and biological products intended to treat or prevent rare diseases to conduct efficient and successful development programs through a discussion of selected issues commonly encountered in the identification and treatment of drugs for rare diseases. Within the context of drug development programs, it is more difficult to address the context of a rare disease with which there is often little medical experience or recognition. These issues are more acute when the disease is rare or there is an overt refusal to acknowledge that the disorder exists at all – as often seems to be the case with chronic pain and its associated syndromes.
All drug development and treatment identification programs should have a firm scientific foundation. Because of both the numbers of persons affected, and the dispersal of clinical experience among a small number of clinical referral centers, the natural history of the majority of rare diseases is often poorly described if not simply ignored. This problem is compounded by chronic pain derived from medical harm or iatrogenic injuries.
A rare disease is defined by the Orphan Drug Act of 1983 as a disorder or condition that affects less than 200,000 persons. Most rare diseases, however, affect far fewer persons. However, chronic pain in all of its forms is estimated to affect 116 million adults in the USA (roughly 1 in 3) over the course of their lifetimes (Institute of Medicine, 2011,1999) making it among the most common under addressed healthcare challenges. More than 200 common and rare diseases generate chronic lifelong pain in affected individuals.
The majority of pain generating disorders are serious conditions with no FDA approved treatments, leaving substantial unmet medical needs for patients. Because these diseases may themselves occur at a low frequency, physicians often correlate the lack of curative treatment for the disease with a lack of need to treat associated chronic pain generated by the disease itself. It is not uncommon for patients to hear that because there is no treatment for the disease, pain care is taken off the table as an option. Increasingly, the public discussion confuses treatment for palliation with addiction and dependence. This flawed logic drives the development of impaired public policy and creates substantial challenges for affected consumers who have to live with the lifelong effects of progressive disease. In the aggregate, these diseases and the roughly 400,000 iatrogenic injuries that occur annually to add to this chronic pain generating total, create an urgent need to understand and address chronic pain in all of its expressions within the population.
Guidance exists to address important aspects of drug development for rare diseases and the design of treatment protocols. There must be an adequate description and understanding of the disease’s natural history, an important element in this foundation. Very little research has captured the development of the natural history of chronic pain development in humans, although animal studies are replete with observations and reports using animal models. Whether the natural history observed in animal studies is comparable to the experience of humans is unknown, but it does offer an excellent opportunity for patient generated research conducted in collaboration with researchers to develop an adequate understanding of the pathophysiology of both diseases that generate chronic pain and chronic pain as a disease process in and of itself.
Determination of a drug’s proposed mechanism of action, and identification of the nonclinical pharmacotoxicology considerations to support the proposed clinical investigation is derived from the study of the natural history of the disease. Knowledge about the disease’s natural history can inform important aspects of drug development by defining the disease population, the full range of disease manifestations, and identification of important disease subtypes. It is important to understanding critical elements in clinical study design, such as study duration and choice of subpopulations. Researchers must develop and select outcome measures that are more sensitive to determining whether the intervention results reflect changes in the manifestations of the disease or impact on symptoms associated with resulting pain as a symptom.
Developing biomarkers to support proof-of-concept (POC) information, guide treatment selection, allow early recognition of safety concerns, or provide supportive evidence of efficacy is an important outcome of these efforts. In some cases, these biomarkers can be used to help us understand associations between disease and manifested chronic pain symptoms. At this time, there is no agreed single set of data elements for chronic pain that adequately addresses all rare diseases – and insofar as chronic pain is concerned, the epidemiology work has not been done to identify these data elements or biomarkers.
The Orphan Drug Act provides incentives associated with orphan-drug designation to make developing drugs for small numbers of patients financially viable; however, the statutory standard for the approval of orphan drugs is not different from the standard for developing drugs for common conditions. The application of currently approved drugs to off-label uses is not addressed by the Orphan Drug Act, but is covered under experimental treatment under CFR Title 21.
In October, a group of physicians will gather in Chicago to examine the use of Ketamine, an anesthetic medication used widely for surgical applications described at this link – https://www.drugs.com/ppa/ketamine.html. The disease of concern is Complex Regional Pain Syndrome or CRPS (ICD-10 G90.5). This is characterized as a rare neurologic syndrome characterized by burning pain, tenderness, swelling, and changes in the skin color and temperature of a body part or extremity. Often caused by crushing injury, bone fracture, or surgery, the syndrome is characterized by severe burning pain in an extremity accompanied by sudomotor, vasomotor, and trophic changes in bone without an associated specific nerve injury. The skin over the affected region is usually swollen, changes color, and demonstrates hypersensitivity to tactile stimuli and erythema. In 2006, de Mos, et al., estimated the incidence of CRPS in the population at 26.2 per 100,000 persons. It may take several years to achieve proper diagnosis, which causes pronounced suffering, permanent disability, and frustration in affected persons.
All drugs and clinical protocols – for both rare and common conditions – must be based on demonstration of substantial evidence of effectiveness in treating or preventing the condition and evidence of safety for that use. Evidence of effectiveness should be obtained from one or more adequate and well-controlled studies in identified populations. The Reflex Sympathetic Dystrophy Association (rsds.org) is sponsoring the discussion in the hopes that a standardized protocol can be designed that will yield meaningful data for direction of sponsored research and treatment.
Additional reading –
Institute of Medicine (2011,1999). Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education and Research (Institute of Medicine Report)
Rare Diseases: Common Issues in Drug Development Guidance for Industry. Retrieved from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM458485.pdf
- de Mos et al., The incidence of complex regional pain syndrome: …, Pain (2006), doi:10.1016/j.pain.2006.09.008