Compounded medications for ocular surface disease

Most of us have found ourselves spending more time at home during the COVID-19 pandemic. One of us (EHL) decided to try his hand at baking pies from scratch. Four weeks (and untold sticks of butter) later, he was able to produce an apple pie quite passable by his standards. The ingredients were fresh and the kitchen clean, but there was no one looking over his shoulder to make certain. One pie took a few hours of active work to make – nothing fancy – but imagine his dismay seeing these on sale for $6 at the local grocery store. As a boutique, one-off baker, he couldn't compete with the large, high volume baker - and perhaps he wasn't meant to.

The history of pharmaceutical manufacturing shares some parallels. Few clinicians or scientists likely remember the local compounding pharmacy as the predominant source for prescribed medications, though this was the case as recently as the early 20th century. The transformation of the pharmaceutical industry (among others) through the mid-20th century saw a transition towards mass production and the provision of manufactured, higher quality, more consistent medications to a larger group of patients. Pharmacists also saw their role shift from producer to purveyor. Naturally, this process allowed for better distribution of prescription medications, as well as enabling evaluation of the clinical safety and efficacy of these medications via large-scale, controlled clinical trials. As reported previously in this column, this transformation was a result of improvement in science, public safety issues (“The Jungle” of Upton Sinclair, deaths of children due to a toxic excipient in sulfanilamide, and birth defects with thalidomide), and federal legislative response to the need for pure, safe and effective pharmaceutical therapies [1,2].

This testing, of course, was not limited to just clinical evaluation. Centralized production of medications allowed the U.S. FDA and other regulatory authorities to more easily set quality standards, which in the current era is required prior to approval and public release. This includes such data as expiration dates and sterility measures which are determined through a painstaking testing process: from visual inspection to analytical methods to microbial cultures and even to the effectiveness of container-closure systems. The testing and approval process ensures that patients receive what is labelled – nothing more and nothing less.

Despite the advantages of this modern system, this “one size fits all” approach necessarily falls short in providing some patients with a more individualized treatment regimen, particularly in the setting of treatments for which the formulation or indication is not approved by regulatory authorities. Today's compounding pharmacy fulfills largely the same role as it has for centuries, filling prescriptions for specific medications or formulations not available as marketed products. As the FDA largely leaves regulation of compounding pharmacies to their respective state boards of pharmacy [3], compounded medications do not need to meet the clinical or quality standards of approved treatments.

Nevertheless, the treatment of ocular surface disease, among other ailments, has in part relied on these pharmacies. Before topical cyclosporine gained FDA approved in 2003 (Restasis® 0.05% cyclosporine ophthalmic emulsion) for dry eye secondary to surface inflammation, it was prepared by compounding pharmacies from the approved oral medication (Neoral® cyclosporine capsules or cyclosporine oral solution) compounded with peanut or corn oil, or gum cellulose [4]. Today for some patients, it is still compounded in concentrations of up to 2% in various excipients including gellan gum.

Today, ophthalmologists prescribe compounded medications for patients with anterior segment diseases such as fortified antibiotic drops for corneal ulcers, topical antimetabolites for ocular surface squamous neoplasia (OSSN), and autologous serum eye drops (ASEDs) for recalcitrant dry eye. FDA's position on such use is that it is both ethical and legal “when an FDA-approved drug is not medically appropriate” [5,6]. In the U.S., the “practice of medicine” allows physicians to prescribe an approved medication for a given patient for any indication as they see fit (21 U.S. Code § 396).

In cases of severe ocular surface disease where prior treatments have failed, ASEDs appear to meet this criterion. It should be noted, however, that production of ASEDs (among the other aforementioned compounded medications) in compounding pharmacies and elsewhere comes with constraints: limited evidence of efficacy [7], uncertainty surrounding sterility and expiration, variability in manufacture, and cost, among others [8].

How do we reconcile these limitations with the recommendations we make to patients? As with many other decisions, it ultimately comes down to a discussion of risks and benefits. As risks decrease, we might become accepting of more modest benefits. ASEDs are overall well-tolerated with minimal risk of adverse effects [7]. And despite the lack of well-controlled studies, ASEDs can be anecdotally life-changing for some patients. As long as compounding can continue to demonstrate satisfactory safety, Mom's apple pie recipe is (and probably should be) here to stay. That said, there are numerous pressures on compounding pharmacies –scientific (i.e., analytical chemistry), financial (especially for the small independent pharmacy), medicolegal and state and federal regulatory.

Declaration of competing interest

Edward H. Lee MD has no relevant disclosure.

Gary D. Novack PhD consults with numerous pharmaceutical and medical device firms.

News from pharmaceutical and medical device companies.

Ophthalmic products related to the ocular surface.

• •Allysta initiated its OASIS-1 Phase 2b/3 trial of ALY688 Ophthalmic Solution for the treatment of dry eye disease (June 2021).
• •Novaliq and Bausch Health announced results from its GOBI Phase 3 trial of NOV03 (perfluorohexyloctane) as a treatment for dry eye disease (April 2021), and also announced completion of enrollment in its second of two phase 3 studies (MOJAVE, July 2021).
• •Lumenis announced de novo authorization from the U.S. FDA for its intense pulsed light device for the management of dry eye disease signs due to meibomian gland dysfunction (April 2021).
• •Nicox completed enrollment in a Phase 2b trial of NCX 4251 (fluticasone proprionate nanocrystals ophthalmic solution) for the treatment of blepharitis (July 2021).
• •ReGenTree announced results of additional analysis of the phase 3 clinical trial, ARISE-3, using RGN-259 (which contains thymosin b4, for the treatment of dry eye syndrome (May 2021).

Ophthalmic products not related to the ocular surface.

• •Aerie completed enrollment in a Phase 3 clinical trial of netarsudil ophthalmic solution in Japan, comparing netarsudil to ripasudil in patients with elevated intraocular pressure (June 2021).
• •Amneal Pharmaceuticals received an Abbreviated New Drug Application (ANDA) approval from the U.S. FDA for a generic version of TobraDex® (Dexamethasone and Tobramycin Ophthalmic Suspension 0.3%/0.1%, July 2021).
• •Bausch and Clearside resubmitted a New Drug Application (NDA) for Xipere™ (triamcinolone acetonide suprachoroidal injectable suspension), which was accepted for review by the U.S. FDA (June 2021).
• •Biogen and Samsung Bioepis received a positive opinion from the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) for Byooviz, a biosimilar candidate referencing Lucentis (ranibizumab), also known as SB11 (June 2021).
• •Clearside Biomedical announced results from Cohort 1 of OASIS, its ongoing Phase 1/2a clinical trial of CLS-AX (axitinib injectable suspension) administered by suprachoroidal injection via Clearside's SCS Microinjector® in six patients (n = 6) with neovascular age-related macular degeneration (wet AMD, June 2021).
• •EyeGate Pharmaceuticals, Inc. commenced dosing in a phase 2 study of PP-001, an immune-modulating molecule and an inhibitor of dihydroorotate dehydrogenase for the treatment of ocular surface inflammation (June 2021).
• •Eyenovia presented results from its VISION-1 study evaluating the company's proprietary pilocarpine formulation, MicroLine™, for the temporary improvement of near vision in adults with presbyopia (May 2021).
• •EyePoint announced safety results from its phase 1 clinical trial of EYP-1901, a sustained delivery TKI, targeting wet age-related macular degeneration (AMD, (July 2021).
• •Genentech/Roche initiated two phase 3 trials investigating faricimab, an investigational bispecific antibody, in patients with macular edema following retinal vein occlusion (April 2021). The two firms also announced positive topline results from two Phase III studies, TENAYA and LUCERNE, evaluating faricimab in treatment of wet AMD (July 2021).
• •Genentech announced that the U.S. FDA has accepted their Biologics License Application (BLA) for its Port Delivery System – a permanent refillable eye implant, is designed to continuously deliver ranibizumab over several months for the treatment of retinal neovascular diseases (June 2021).
• •Glaukos completed patient enrollment in Phase 3 trials for its iDose travoprost sustained-release travoprost implant for the treatment of open-angle glaucoma or ocular hypertension (June 2021).
• •iSTAR Medical cleared an investigational device exemption (IDE) from the US FDA to start a trial with its MINIject, a surgical glaucoma implant (July 2021).
• •IVERIC bio announced completion of patient enrollment of GATHER2, a pivotal clinical trial of Zimura ® (avacincaptad pegol), for the treatment of geographic atrophy (GA). This protocol received written agreement from the FDA under a Special Protocol Assessment (SPA, July 2021).
• •Lenz Therapeutics (formerly Presbyopia Therapies) will be developing an eyedrop formulation of aceclidine for the treatment of presbyopia (June 2021).
• •Novartis reported that Beovu® (brolucizumab-dbll) met its primary endpoint in the phase 3 MERLIN trial for the treatment of wet AMD, but decided to terminate the study due to higher rates of intraocular inflammation with frequent dosing intervals (June 2021).
• •Noveome announced results of a Phase 1 open label clinical trial to establish the safety of ST266, a secretome biologic, when delivered intranasally in glaucoma suspect patients (June 2021).
• •Ocular Therapeutix commenced dosing in its phase 1 clinical trial of OTX-TKI (axitinib intravitreal implant) for the treatment of wet AMD (July 2021). The firm also completed its post-approval study requirements for its ReSure® Sealant (May 2021).
• •Oculis announced results from two phase 2 trials with OCS-02, its topical anti-TNF alpha antibody fragment candidate, in dry eye disease (DED) and acute anterior uveitis (May 2021).
• •Ocuphire started enrollment in ZETA-1, a Phase 2 trial to evaluate oral APX3330, an inhibitor of the reduction-oxidation effector factor-1 (Ref-1), in non-proliferative diabetic retinopathy (NPDR) and mild proliferative diabetic retinopathy (mild PDR, April 2021). The firm also announced results from its VEGA-1 Phase 2 clinical trial evaluating the efficacy and safety of topical ocular phentolamine in combination with low-dose pilocarpine in the treatment of presbyopia (June 2021).
• •Outlook Therapeutics completed dosing in its NORSE TWO safety and efficacy study evaluating ONS-5010 (bevacizumab-vikg) for treatment of wet AMD (June 2021).
• •Salvat completed phase 3 clinical trials in the US for its clobetasol propionate ophthalmic nanoemulsion 0.05% for the treatment of ocular inflammation and pain after cataract surgery (June 2021).
• •Santen Inc. received US FDA approval for its Verkazia™ (cyclosporine ophthalmic emulsion) 0.1% eye drops for the treatment of vernal keratoconjunctivitis (VKC) in children and adults (June 2021).
• •Santhera Pharmaceuticals announced results of a long-term phase 4 trial Raxone® (idebenone) in patients with Leber's hereditary optic neuropathy (June 2021).
• •Tarsus Pharmaceuticals announced results from its pivotal Phase 2b/3 Saturn-1 trial evaluating TP-03 (lotilaner ophthalmic solution, 0.25%) in patients with Demodex blepharitis (June 2021).
• •Unity Biotechnology announced results from its phase 1 safety study of UBX1325, a small molecule inhibitor of Bcl-xL, in patients with advanced disease from DME or wet AMD. The firm also started dosing in a Phase 2 study (July 2021).

Gene and cell therapy.

• •Adverum Biotechnologies provided an update on their ADVM-022 retinal gene therapy program from the INFINITY clinical trial in patients with diabetic macular edema (DME) and the OPTIC clinical trial in patients with wet age-related macular degeneration (AMD, July 2021).

• •Allergan results from its phase 3 GEMINI 1 clinical study, evaluating the efficacy, safety and tolerability of investigational AGN-190584 (pilocarpine 1.25%) in the treatment of presbyopia (July 2021).

• •Aurion Biotech announced preliminary findings from its IOTA trial of a cell therapy for corneal endothelial disease (July 2021).

• •Biogen Inc. announced topline results from the Phase 3 STAR study of timrepigene emparvovec (BIIB111/AAV2-REP1), an investigational gene therapy for the treatment of choroideremia (June 2021).

• •Editas Medicine commenced enrolling pediatric cohorts in their Phase 1/2 BRILLIANCE clinical trial of EDIT-101, a CRISPR based treatment of Leber Congenital Amaurosis 10 (June 2021).

• •Emmetrope Ophthalmics announced dosing for the first subject in a Phase 1, open-label, dose-escalation study of its EO2002, its non-surgical, magnetic cell-based therapy, for the treatment of corneal edema (July 2021).

• •Gemini Therapeutics announced initial data from its phase 2a ReGAtta study of GEM103 in patients with geographic atrophy (GA) secondary to dry AMD. GEM103 is an intravitreally administered recombinant human complement factor H regulator (rCFH) protein (June 2021).

• •GenSight Biologics reported additional results from its REFLECT Phase III clinical trial for GS010 (lenadogene nolparvovec), a mitochondrial targeting sequence intravitreal gene therapy, in patients with Leber Hereditary Optic Neuropathy (June 2021)

• •Lineage Cell Therapeutics reported results from its ongoing, 24-patient Phase 1/2a clinical study of OpRegen. an investigational cell therapy consisting of allogeneic retinal pigment epithelium (RPE) cells administered to the subretinal space, for the treatment of AMD with GA (July 2021).

• •Nanoscope Therapeutics announced results from its Multi-Characteristic Opsin gene therapy study for the treatment of patients with advanced retinitis pigmentosa (June 2021).
• •Ocular Therapeutix entered into a discovery collaboration with Mosaic Biosciences to identify new targets and therapeutic agents aimed at the treatment of dry AMD (June 2021).
• •Oyster Point Pharma expanded its product pipeline with the introduction of Enriched Tear Film (ETF™) Gene Therapy and proof-of-concept in vivo study results from its first gene therapy candidate, OC-101. The firm also formed a research collaboration with Adaptive Phage Therapeutics (APT) to leverage APT's PhageBank™ technology for the development of potential treatments for ophthalmic diseases (June 2021).
• •Vedere Bio II is developing mutation agnostic optogenetics technology to improve upon current gene therapies (May 2021).

Other news about pharmaceutical and medical device firms.

• •Arctic Vision announced a licensing agreement with Olympic Ophthalmics for selected Asian countries for the iTEAR®100, an external neurostimulation device that increases acute tear production (June 2021).
• •The American Academy of Ophthalmology announced challenges with ophthalmologists acquiring repackaged Avastin for off-label use in treating retinal disease. This may be related to manufacturing and stability issues of recent batches (June 2021).
• •Nevakar created Vyluma, a new company to create treatments for ophthalmic diseases such as myopia (May 2021).
• •Pfizer discontinued the approved glaucoma therapy, phospholine iodide, although is providing additional limited inventory (July 2021).

Regulatory, government, and other research news.

• •Aetna insurance stated that despite strong opposition from the American Academy of Ophthalmology and American Society of Cataract and Refractive Surgery, it will require prior authorization for all cataract surgery procedures starting 1 July 2021 (June 2021).
• •Biogen received U.S. FDA approval for its aducanumab for the treatment of Alzheimer Disease. There has been extensive discussion regarding its approval based upon a surrogate endpoint, and the proposed cost, including editorials from the FDA on the benefit/risk decision [[9], [10], [11]].
• •The benefit/risks of the recently approved teprotumumab for the treatment of thyroid eye disease including pharmacoeconomic impact were discussed in a recent editorial (July 2021) [12].
• •A consortium of the leading medical writers' professional societies (American Medical Writers Association, European Medical Writers Association, and International Society for Medical Publication Professionals) issued a joint position statement on medical publications, preprints, and peer review (July2021) [13].
• •A new European law could boost clinical trials reporting requirements (July 2021) [14].
• •Cohen et al. reported found several inappropriate drugs found in over-the-counter cognitive enhancement supplements, including unapproved drugs (phenibut, vinpocetine and picamilon) (June 2021) [15].
• •Dello Russo et al. evaluated the discrepancy between overall response rate (ORR) in phase 2 oncology trials as assessed by local investigators and those assessed by masked reviewers. They found a relatively high discrepancy between these reviewers, and recommend that masked independent central review be used in ORR assessment (June 2021) [16].
• •United Healthcare (UHC) will allow patients to get 12 intravitreal injections per eye per year, reversing a previous policy that limited patients to nine injections per year (July 2021).
• •The U.S. Senate is considering legislation to more directly connect prescription drug pricing to clinical effectiveness (June 2021).
• •
  In this period, the U.S. FDA

  • •
    Issued a guidance on implementation of the Drug Supply Chain Security Act. This guidance identifies specific scenarios that could significantly increase the risk of a suspect product entering the pharmaceutical distribution supply chain; provides recommendations on how trading partners can identify a product and determine whether a product is a suspect product (June 2021).
  • •
    Presented an account of what went wrong at Emergent BioSolutions' Covid-19 manufacturing facility in Baltimore, where the cross contamination of Johnson & Johnson/Janssen and AstraZeneca vaccines led to the discarding of about 75 million vaccine doses (June 2021).
  • •
    Approved a new use for a marketed product, Prograf® (tacrolimus) based on a non-interventional (observational) study providing real-world evidence (RWE) of effectiveness (July 2021) [17].
  • •
    Granted Emergency Use Authorization (EUA) for the Pfizer-BioNTech COVID-19 Vaccine for the prevention of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to include adolescents 12 through 15 years of age. The firm also applied for full approval of this vaccine (May 2021).
  • •
    Approved a supplemental NDA (sNDA) for a new dose of valbenazine, a previously approved treatment of tardive dyskinesia (TD). In lieu of a clinical trial, the efficacy of the new dose of valbenazine versus placebo was demonstrated through clinical trial simulations based on a longitudinal exposure-response model [18].
  • •
    Updated their list of approved new drug application (NDA) drug products that are no longer protected by patents or exclusivities, and for which the FDA has not approved a generic abbreviated new drug application (ANDA) referencing that NDA product (June 2021).
  • •
    A recent Appellate court decision favored a plaintiff over FDA in the regulation of certain products as devices. This may impact a nearly 40 year old FDA regulation in which dispensers of ophthalmic drugs, when packaged with the drug being dispensed, are regulated as drugs. 21 CFR 200.50.
  • •
    Executed actions including notices of sterility lapses at compounding pharmacies, benzene contaminants in sunscreens, and withdrawal of hand sanitizers (due to their similar appearance to water bottles, July 2021).
  • •
    Stated its intent to prepare an environmental impact statement (EIS) to evaluate the potential environmental effects of revised conditions for marketing certain sunscreen products for over-the-counter (OTC) use without prior approval of a new drug application (NDA). (May 2021).
  • •
    Established a public docket to collect comments on evaluating the clinical pharmacology of peptides (May 2021) [19].