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Based on external sources (Symphony Health Solutions, Centers for Disease Control and Prevention) and own projections, PAION estimates that approximately 43 million procedures using procedural sedation took place in the U.S. in 2013, predominantly outside the hospital setting.
The growth of the procedural sedation market in the U.S. has been driven for many years by the increase in medical interventions requiring procedural sedation, such as colonoscopies, as well as an increase in general demand for preventive screenings. According to iData Research, which examines historical trends and creates procedure forecasts in the U.S. drawing from an extensive collection of national- and state-level procedure databases, 26.7 million colonoscopy and endoscopy claims were reported in 2015 in the U.S., and the number is expected to grow at an average rate of 2.6% annually through 2020. PAION estimates that 75% of the colonoscopies and endoscopies claimed were conducted in an out-patient setting.
Regular colonoscopy screening for people aged 50 or older is recommended and covered by all major health insurance plans, including those under the Centers for Medicare and Medicaid Services (“CMS”), a U.S. federal agency that administers Medicare (the national social insurance program), since effective prevention is considered to reduce the likelihood of incidence of illnesses such as cancer, thereby reducing the suffering of patients and related financial burden to be borne by the payors. Statistics show that the rate at which people are diagnosed with colon cancer in the U.S. has dropped by 30% between 2005 and 2015 for those aged 50 years and older, partly due to more people getting recommended screening tests. Colorectal cancer is the third most diagnosed cancer and the third leading cause of cancer death in the U.S. Despite the decrease of colorectal cancer death rates as a result of early screening and detection, it was reported in 2010 that only 59% of people aged 50 or older, for whom screening is recommended, reported having received colorectal cancer testing consistent with current guidelines. The market for endoscopies in gastroenterology represents the most lucrative market segment for remimazolam in procedural sedation with approximately 20 million procedures per year in the U.S.
Currently, the most widely used products in procedural sedation are propofol and midazolam – both generic. PAION estimates that these two drugs each have a market share of approximately 50% in terms of volume of procedures performed in the out-patient market for colonoscopies in the U.S. The propofol label mandates the presence of an anesthesia professional throughout the procedure due to propofol’s potential for respiratory- and cardio-depressive effects, which results in additional costs and higher risks, since there is no reversal agent available for propofol in order to be able to quickly stop sedation if required. For midazolam, these side effects are less pronounced and have a different relevance, since an undesirably deep sedation can be reversed with flumazenil. Midazolam has a slower onset and a longer duration of action which can impact patient throughput and overall efficiency.
In the U.S. increased enrollment and screenings are expected to result in a performance-based payment system that will seek to better align payments with high quality of care measures. This would imply that cost-efficient medicines with clinical value will be used more extensively and that continued premium prices will be paid for innovative medicines with strong clinical profile. Thus, PAION believes that concerns related to the overall cost of procedures, driven by the need for anesthesia professionals monitoring during procedures using agents such as propofol, will impact the choice of drug products for procedural sedation. Costs related to anesthesia services in gastrointestinal endoscopy procedures alone were estimated at USD 1.3 billion in 2009. Accordingly, PAION expects reimbursement regimes under national and commercial healthcare systems, such as Medicare, which differentiate the amounts reimbursed to physicians and/or patients depending on whether an anesthesia professional’s service is used, may also positively impact the demand for products that do not require monitoring by an anesthesia professional.
PAION expects that remimazolam, subject to FDA approval with a safety labeling comparable to that of midazolam, could benefit from the pending changes in payment policies. Provided that it could be administered under the supervision of a proceduralist, remimazolam would be able to offer a competitive alternative to midazolam. This is based on its enhanced efficiency profile compared to midazolam.
PAION plans to submit an MAA in procedural sedation later this year, after having discussed at a pre-submission meeting with the EMA in February 2019 that the existing data package from the U.S. Phase III clinical development program will be sufficient for filing for market approval for remimazolam in procedural sedation in the EU. The submission is subject to EMA approval of the PIP.
In the EU, based on its own projections for procedural sedation, PAION currently estimates an annual peak sales potential of approx. EUR 75 million. In contrast to the U.S. market which has a large freestanding ambulatory surgery healthcare infrastructure, procedural sedation in Europe is mainly a hospital-based activity where anesthesiologists have the overall responsibility for the sedation of patients. This entails a high potential for synergies with the planned commercialization of remimazolam for use in general anesthesia.
 Liu, H. et al. (2012): Utilization of Anesthesia Services During Outpatient Endoscopies and Colonoscopies and Associated Spending in 2003-2009, The Journal of the American Medical Association, 2012 307(11):1178-1184; Al-Awabdy, B. and Wilcox, C.M. (2013): Use of anesthesia on the rise in gastrointestinal endoscopy, World Journal of Gastrointestinal Endoscopy, January 2013 5(1): 1-5.