Publication bias, Open-Labeled Trials and Sky Rocketing Costs- Past, Present and Future of Repository Corticotropin Injection?

ABSTRACT

Repository corticotropin injection (RCI) has recently gained attention in the field of ocular inflammatory disease. Data supporting the use of RCI therapy in ocular inflammation are limited to case reports or small series subject to publication bias toward positive results. How this therapy differs significantly from oral corticosteroids, which are significantly cheaper, is unknown. Clinical trials to investigate the efficacy of RCI are currently limited to open-labeled non-comparative studies. Side effects of RCI are not insignificant, have been reported in other fields of medicine, and require further scrutiny. Finally, the price of RCI has skyrocketed with average yearly cost of therapy estimated to be between $480,000-$850,000 with allegations of the RCI manufacturing drug company providing remuneration to induce healthcare providers to prescribe RCIs but without any repercussions from a regulatory standpoint. The significant cost of RCI combined with lack of evidence-based guidance on efficacy, safety, and indications for use in ocular inflammation warrant caution in utilizing this therapy.

Ophthalmologists treating patients with refractory ocular inflammation, including noninfectious uveitis (NIU), continuously look for medications to expand their armamentarium for these challenging conditions. Evidence of efficacy and safety of current off-label and Food and Drug Administration (FDA)-approved therapies for NIU have been presented through randomized controlled trials, pooled case series, and larger cohort studies. Demonstration of “effectiveness” of a medication to the FDA became a requirement in 1962, when Congress amended the Federal Food, Drug, and Cosmetic Act to add that to obtain market approval, manufacturers must demonstrate the effectiveness of their products through the conduct of adequate and well-controlled studies.¹ But what about the use of medications that were FDA-approved for ocular inflammation prior to this amendment that have not demonstrated clinical efficacy for their indication, including repository corticotropin injection (RCI)? In place of evidence from multi-center phase III randomized placebo-controlled blinded clinical trials, ophthalmologists and other subspecialists are left to determine potential efficacy from case reports and small case series of patients who have responded to such drugs.^2,3 Given potential biases of reporting only cases with positive responses, these smaller series do not provide the same information on specific indications for use of this type of therapy. Regulatory agencies such as the FDA are unable to detect these potential biases in reporting and as a result, do not make any changes in drug approvals unless multiple substantial claims regarding safety and therapeutic failure are voluntarily raised by patients and/or health care professionals. In this issue, a small series of patients by Oh, et al, with ocular sarcoidosis treated with repository corticotropin injection (RCI) demonstrated that not only did most patients not have efficacy with this medication for their uveitis or optic neuritis, but that systemic adverse effects and cost played a significant role in discontinuation of this therapy.⁴ This study provides a cautionary tale regarding the importance of understanding indications for use of RCI in patients with ocular inflammatory disease, especially given the potential for complications and not insignificant costs to patients and/or healthcare systems.

The FDA approved RCI in 1952 for the treatment of multiple conditions, including infantile spasms, multiple sclerosis, rheumatologic conditions such as rheumatoid arthritis, respiratory diseases such as sarcoidosis, and ophthalmic diseases, including anterior segment inflammation, posterior uveitis, and optic neuritis.⁵ During this time, newly developed drugs had to demonstrate safety and have adequate labeling for safe use, but there was no requirement for demonstration of efficacy. While the FDA packaging label includes clinical studies on the effectiveness of RCI as treatment for infantile spasms, there are no reports of clinical trials demonstrating effectiveness for ocular inflammation. There have been cases of use of ACTH (corticotropin) in intravenous and intramuscular formulation for the treatment of uveitis, including sympathetic ophthalmia and Harada’s disease, but some of these were used in conjunction with other corticosteroids.^6–8 Drugs designated as orphan drugs have to adhere to strict guidelines by the FDA, including evidence of safety and effectiveness through well-controlled trials; even off-label use of drugs, such as immunosuppressive therapies in the treatment of uveitis, are held to standards set forth by well-designed clinical or large cohort studies providing evidence of safety and efficacy for their use. RCI holds neither of these designations and yet it lacks substantial evidence for efficacy and safety in the treatment of ocular inflammatory disease.

A retrospective review of the use of RCI in patients with uveitis was published in 2019 by Mallinckrodt Pharmaceuticals, the company that now manufactures and distributes RCI.⁹ This study selected patients and prescribers who used RCI from a national database and then surveyed 21 ophthalmology prescribers regarding patient status before and after RCI use, demographics, visual impairment, and concomitant medications. Symptoms and signs with a severity scale (mild, moderate, severe) were collected prior to RCI use, but clinical outcomes were based on physician’s assessment of outcomes, including patient’s current status (“improved”, “same” or “worse”), and improvements in certain clinical parameters such as vision, pain, vitreous haze, vitreous flare, and macular edema. There were no objective measures or data reported and no information was collected on reason for discontinuing RCI. While some studies in the pulmonary literature on use of RCI in sarcoidosis do include patients with ocular involvement, there is no specific data on the response of ocular disease to RCI treatment.¹⁰ In the 2 studies reporting the use of RCI in patients with uveitis, all 4 of the patients had prior control of inflammation on other therapies (tocilizumab or gevokizumab) as part of clinical trials but had denial of insurance coverage for these medications or others (adalimumab) leading to the use of RCI. ^2,3

On clinicaltrials.gov, there are currently 3 clinical trials examining the use of RCI in ocular inflammatory disease that are actively recruiting patients: 1 phase IV open label single group assignment study for RCI in retinal vasculitis, 1 open label study for ocular sarcoidosis, and 1 phase I study for RCI in postoperative proliferative vitreoretinopathy. All active studies are small with 40 participants or fewer and all are open-label with no placebo or other comparison group making it unlikely that these trials will provide the data necessary to demonstrate efficacy of RCI or the appropriate indications or subset of uveitis that may respond to this therapy. Of 3 studies that have been completed or terminated, 1 study was discontinued due to logistical challenges with enrollment and 2 studies with results showed lack of efficacy with enrollment of 5 patients or less.

While corticosteroids have been the mainstay of treatment of inflammatory diseases, long-term use is associated with significant side effects. As a melanocyte-stimulating hormone, adrenocorticotropic hormone (ACTH) which makes up RCI, may counteract proinflammatory cytokines at sites of local inflammation as well as promoting secretion of cortisol, corticosterone, aldosterone and other androgens from the adrenal cortex. While there are reports of RCI having improved side effect profiles compared to other corticosteroids, the current study and others have revealed that RCI is not without its own significant adverse effect profile.^11,12 In the Oh, et al study, 4 of the 6 patients experienced side effects severe enough to warrant discontinuation of therapy.⁴ In studies on the use of RCI for the treatment of pulmonary sarcoidosis, side effects have played a role in discontinuation of therapy for a significant number of patients. In one retrospective pilot study on the use of RCI for sarcoidosis in 47 patients, of the 18 (38%) patients who discontinued RCI within the first 3 months of therapy, 67% discontinued therapy due to side effects, including peripheral edema and agitation, and 22% due to cost.¹⁰ In another single-blinded study on the use of different doses of RCI in pulmonary sarcoid patients, of 18 patients enrolled in the study, 1 patient discontinued therapy and 7 other patients required dose reduction due to side effects, including jitteriness, headache, edema, and nausea.¹³ Most published reports on the use of RCI include follow up times between 6 weeks to 15 months which may suggest a more favorable side effect profile than what was seen in the Oh, et al study, which included patients with follow up times of up to 58 months. Clinicians need to be aware of the risk of potential adverse effects with RCI over the entire course of therapy and its potential effects even after the therapy is stopped.

In addition to discontinuing therapy due to adverse effects, several patients in the Oh, et al study and in other studies have had discontinuity of therapy with RCI due to cost.⁴ The average yearly cost of oral corticosteroids such as prednisone is estimated to be 40 USD per year compared to the average yearly cost of RCI of 480,000-850,000 USD (approximately 40,000 USD per 5 ml vial) in the United States. The cost of this therapy has not gone unnoticed by other subspecialties, with multiple editorials in the internal medicine and rheumatology literature highlighting the high cost of this therapy and lack of evidence of efficacy from randomized clinical trials.^14–16 Also noted has been the potential conflict of interest in some of the smaller studies that have been published on the use of RCI in various inflammatory conditions, with multiple authors often having received consultant fees from the manufacturer or studies were funded in part by the pharmaceutical company. The authors of one series of uveitis patients treated with RCI raised the question regarding the use of RCI as a maintenance therapy in chronic NIU given its high cost.³

The cost of RCI has soared in the past 20 years through various pharmaceutical company acquisitions, going from 40 USD per vial to 1650 USD per vial in 2001 after Questcor acquired the drug and then overnight to 23,000 USD per vial in 2007.¹⁷ The company justified the cost increase due to infrequent use of the drug for infantile spasms. Mallinckrodt pharmaceutical company acquired Questcor pharmaceuticals in 2014 and since this time, the cost of RCI has continued to rise as the company has also begun to market RCI aggressively for use in other inflammatory conditions. The Department of Justice has investigated Mallinckrodt after allegations that the company has violated federal Anti-Kickback Statutes by providing “remuneration to induce healthcare providers to promote and prescribe” RCI and the company paid 15 USD million to resolve these claims.^18,19 FDA-approved medications, including RCI, are reimbursed by the Center for Medicare and Medicaid Services (CMS); an analysis of Medicare expenditures revealed that spending on RCI was more than 1 billion USD between 2011 and 2015 and that a small number of subspecialists prescribed RCI 100 times more than their colleagues.²⁰ Mallinckrodt paid more than 9 million USD to physicians in 2019, with more than 75% of these payments for consulting or speaking engagements by physicians.²¹

In the interests of our patients, ophthalmologists must advocate for evidence of efficacy and safety by way of randomized clinical trials for potential therapies for ocular inflammatory diseases, regulation of drug costs, and improved transparency regarding pharmaceutical companies’ methods of promoting their products. One potential method to do this could be improved reporting and communication among subspecialty societies, regulatory agencies, and the public. Clinicians, in addition to regulatory agencies, need to consider the following criteria prior to adoption of new therapies: clear indication for use, strength of recommendations, sufficient duration of study to be representative of real-world use, associated risks/adverse effects, frequency of occurrence of these adverse effects, potential ways to mitigate risk/side effects, potential for bias from sponsor, and publication bias. More evidence-based guidance on efficacy, safety, indications for use, and duration of treatment is needed for RCI in ocular inflammatory disease; until this exists, we must be circumspect in our use of this medication given the not insignificant side effect profile and substantial cost to our patients.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.