Pipeline GARY D. NOVACK, PHD,
SECTION EDITOR
Can I Use Those Eyedrops after the Expiration Date? GARY D. NOVACK, PHD
am frequently asked by colleagues and friends whether it is acceptable to use medications after the expiration date. They propose that medications are “good” long after their expiration date. For example, Cantrell et al chemically evaluated a number of long-expired oral medications and found that many medications still had at least the labelled amount of drug. Some even had 20-25% more, and one had 300% more. A few had much less than the labelled amount.1 If I am in a flippant mood, I respond to my colleagues and friends by asking: “Would you use milk after its expiration date” (Figure 1)? If I am in a more serious mood, I simply say: “No, it is not acceptable.” When the questioner then asks why, this opens the door for me to explain what goes into assigning the expiration date. The manufacture of ophthalmic drugs was covered in a previous article in this journal.2 In that article, my coauthor and I wrote “.The stability data is evaluated in order to assign an expiration date system for the product.” Drugs are evaluated to assure the proper identification, quality, purity, and strength of the drug. The requirements for stability testing are discussed in a series of International Conference on Harmonisation (ICH) guidance on
I
Disclosure: Gary D. Novack, PhD (PharmaLogic Development, Inc., San Rafael CA) consults with numerous pharmaceutical firms. © 2015 Elsevier Inc. All rights reserved.
quality (Q1A through Q1F [http:// www.ich.org/products/guidelines/quality /article/quality-guidelines.html]). The analytical tests performed on a product include the active ingredient and the potential development of any degradation products. All sterile products undergo a test for sterility. For preserved products, there is both a chemical assay of the preservative and a biological assay for the capability of the product to prevent growth of microorganisms (Antimicrobial Effectiveness Test). There are also tests for physicochemical properties (e.g., volume, pH, particulates). The expiration date is an extrapolation. That is, pharmaceutical scientists evaluate early stability data on a given lot and extrapolate the duration of time at which it is expected to still be within specification. Shown in Figure 2 is an example of the decreasing amount of active ingredient in a drug product. In this case, the specifications call for a 5% variance on the label claim amount of active ingredient. In this example, the calculated variance suggests that the product would be stable for 24-36 months stored at 25C and 60% relative humidity. Also evaluated for this product is the development of a degradation product. In the same storage conditions, the concentration of the degradation product was estimated to exceed the specification limit of 1.4% at approximately 27 months (Figure 3). One typically uses a conservative estimate e i.e., the lower 95% confidence interval for concentration of active (i.e., the lowest it might be)
and the upper 95% confidence interval for concentration of a degradation product (i.e., the highest it might be). For a liquid ophthalmic product, similar calculations would be performed for pH and volume. Also, sterile products must pass the sterility tests at each time point. These analytical data are all considered in setting an expiration date for a product. Finally, some formulations may fail because the particulate count rises or the formulation becomes unstable (i.e., the active ingredient falls out of solution or suspension). While such tests are conducted throughout the development of a new product, the final formulation and container/closure system (i.e., bottle and tip, or unit dose container) are not typically finalized until Phase 3. The duration of stability data on this final product can vary depending upon the duration of the Phase 3 clinical studies. However, in general, it is on the order of 12-18 months real-time stability. Stability studies can also be performed in exaggerated conditions (e.g., 40C/25% Relative Humidity [RH] for a product to be stored at room temperature, 25C/60% RH for a product intended to be refrigerated). These data are used to project (i.e., extrapolate) a shelf life, which is proposed to regulatory authorities in the New Drug Application. As noted above, both the manufacturer and the regulatory authority tend to be conservative in setting a shelf life for the initial application. As more data are obtained for the product, the company may submit them to the regulatory authority, proposing a longer shelf life.
THE OCULAR SURFACE / APRIL 2015, VOL. 13 NO. 2 / www.theocularsurface.com
169
PIPELINE / Novack
Figure 1. Expiration dating of milk.
However, as noted in the ICH Q1A(R2) document, “There should be a direct link between the label storage statement and the demonstrated stability of the drug product.” As to the conservative aspect of setting a shelf life, in the early stages of product development with limited
data, a manufacturer may choose to create an overage (i.e., a bit “on the high side”) in order to meet the minimum requirements at the expiration date. Thus, as liquid may evaporate through plastic bottles, volume in the product at time of manufacture may be higher than the label claim. A
manufacturer could also add more active ingredient e but not too much, as the actual amount in the bottle at time of manufacture could not exceed the label claim by more than a small amount (on the order of 510%). One of the ICH guidances, Q1A(R2) describes evaluation of potential water loss for drug products packaged in semi-permeable containers. For example, for a product to be stored at room temperature, “.a 5% loss in water from its initial value is considered a significant change for a product packaged in a semipermeable container after an equivalent of 3 months’ storage at 40 C/No More Than (NMT) 25% RH. However, for small containers (1 mL or less) or unit-dose products, a water loss of 5% or more after an equivalent of 3 months’ storage at 40C/NMT 25% RH may be appropriate, if justified” (http://www.ich.org/fileadmin/Public_ Web_Site/ICH_Products/Guidelines/ Quality/Q1A_R2/Step4/Q1A_R2__Gu ideline.pdf). Among some of my colleagues and friends, there is a perception that manufacturers would prefer to have a short expiration date, so that patients have to buy more product. This is not the case. The shorter the shelf life, the more challenging the logistics for the manufacturer to produce the product, ship it to wholesalers, who, in turn, ship it to pharmacies, who maintain
Figure 2. Expiration dating: Stability of active ingredient. (From: ICH Harmonised Tripartite Guideline: Evaluation for Stability Data: Q1E (June 2004). 60% RH ¼ 60% relative humidity. http://www.fda.gov/ downloads/Drugs/GuidanceComplianceR egulatoryInformation/Guidances/UCM073 380.pdf.)
170
THE OCULAR SURFACE / APRIL 2015, VOL. 13 NO. 2 / www.theocularsurface.com
PIPELINE / Novack
Figure 3. Expiration of a degradation product. (From: ICH Harmonised Tripartite Guideline: Evaluation for Stability Data: Q1E (June 2004). 60% RH ¼ 60% relative humidity. http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInf ormation/Guidances/UCM073380.pdf.)
stock until they receive and fill prescriptions for the product. Pharmacies send expired product back to wholesalers, who, in turn, send it back to the manufacturers as contractually required. The manufacturers then compensate the wholesalers for the expired product. It is a non-trivial quantity e perhaps accounting for 10% of annual sales. Thus, there is a financial incentive to manufacturers to assign a longer shelf life, rather than a shorter shelf life. So, what might happen if a patient uses a bottle of eye drops beyond the expiration date? It might not meet the label specifications in any of a number of ways. It might be less potent than labelled due to degradation of the active ingredient, or it might be more potent due to evaporation. It might include a degradation product of unknown efficacy or safety. For example, aspirin (acetylsalicylic acid) degrades to salicylic acid, which may be of different activity than aspirin. In other cases, only the parent product may effectively penetrate ocular tissues; the degraded product, while still containing an active molecule, may not be able to effect the desired pharmacology. A product used past expiration date might be too acidic or too basic. It might also be non-sterile, or not able to kill microorganisms introduced by patient use. There might also be less volume in the bottle than labelled. In short,
an expired product might be neither safe nor effective. The expiration date is also based upon the assumption that the product is stored as labelled. Some products must be refrigerated at pharmacies and until administered to the patient (e.g., biologic VEGF inhibitors). Others must be refrigerated until dispensed to the patient (e.g., some prostaglandin analogues). So, even products stored outside of these requirements (e.g., the bottle of eyedrops taken to the beach in summer) may be out of specification even within the expiration date. So, patients and physicians should be even more concerned about product quality for the improperly stored product after expiration date. Back to my initial example, if a carton of milk is beyond its expiration date, you can usually tell immediately by its smell or taste. However, with most ophthalmic products, one cannot tell by casual inspection or even patient use whether it meets its specifications, and one does not know the clinical impact of such failure. Generic ophthalmic drugs may vary in concentration of active ingredient from the innovator product by 5% to 10%. Unfortunately, we do not know how this variation in chemistry (or other possible variations in container/closure systems) may affect the concentration of drugs in ocular tissue, or the drug’s efficacy and
safety. I previously posed the question as to how much variability can we accept in providing the best therapeutics to patients, especially considering the cost-conscious aspects of health care today.3,4 However, unlike the decision of a more affordable generic vs a more costly branded product, the decision on using out-of-date products seems to be an easy one. In the same way you select and use milk within its expiration date, you should also use medications within their expiration date. As to what to do with expired medications, use the various recycling programs available.5 ACKNOWLEDGEMENTS The author acknowledges the contributions of Elizabeth D. Moyer, Ph.D. (M/P Biomedical, Mill Valley CA).
REFERENCES 1. Cantrell L, Suchard JR, Wu A, Gerona RR. Stability of active ingredients in long-expired prescription medications. Arch Intern Med 2012;172:1685-7 2. Kaufman B, Novack GD. Compliance issues in manufacturing of drugs. Ocul Surf 2003;1: 80-5 3. Novack GD. Pipeline: Quality of generic ophthalmic drugs. Ocul Surf 2013;11:54-7 4. Chambers WA. Ophthalmic generics: are they really the same. Ophthalmology 2012;119: 1095-6 5. Novack GD, Moyer E. Pipeline: Where do unused medications go when they die? Ocul Surf 2013;11:139-42
THE OCULAR SURFACE / APRIL 2015, VOL. 13 NO. 2 / www.theocularsurface.com
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PIPELINE / Novack NEWS FROM PHARMACEUTICAL AND MEDICAL DEVICE COMPANIES Ophthalmic Products Related to the Ocular Surface d Ocular Therapeutix started enrollment in a Phase 2 trial of its sustained release dexamethasone for the treatment of dry eye (January 2015). d Nicox is in advanced development of AC-170, a topical ocular formulation of cetirizine for the treatment of ocular itching associated with allergic conjunctivitis (January 2015). d Santen received approval from the European Committee for Medicinal Products for Human Use for IkervisÔ, topical cyclosporine intended for the treatment of severe keratitis in adult patients with dry eye disease (January 2015). Ophthalmic Products Not Related to the Ocular Surface d Aerie completed patient enrollment in its Phase 3 clinical trial of AR-13324 for the treatment of elevated intraocular pressure (December 2014). d Aerpio completed patient enrollment in its Phase 2 study of AKB-9778, a human protein tyrosine phosphatase beta inhibitor and Tie2 activator, alone and in combination with ranibizumab for the treatment of diabetic macular edema (December 2014). d Akorn has filed an abbreviated new drug application (ANDA, generic) for difluprednate ophthalmic emulsion (January 2015). Akorn received FDA approval for Phenylephrine Hydrochloride Ophthalmic Solution, USP, 2.5% and 10% (January 2015). d Alcon received an additional approval from the European Commission for travoprost ophthalmic solution (TravatanÒ) for the treatment of elevated intraocular pressure in pediatric patients with glaucoma (December 2014). d Aldeyra Therapeutics filed an Investigational New Drug 172
d
d
d
d
d
d
d
application (IND) to conduct Phase 2 clinical testing of its NS2 for the treatment of noninfectious anterior uveitis (December 2014). Alimera received approval for IluvienÒ (fluocinolone acetonide intravitreal implant) in Netherlands (December 2014) and Portugal (January 2015). Alimera received marketing approval in Finland and Luxembourg for IluvienÒ (fluocinolone acetonide intravitreal implant) for the treatment of diabetic macular edema in some patients (January 2015). Allegro Ophthalmics and Hanmi Pharmaceutical have entered into a license agreement for ALG-1001 (an integrin peptide therapeutic) in the Republic of Korea and the People’s Republic of China (January 2015). Amarantus received orphan drug designation for MANF from the FDA for the treatment of retinitis pigmentosa (December 2014). Carl Zeiss Meditec will be supporting Oraya Therapeutics in its development of low energy radiation therapy for macular degeneration (December 2014). Clearside Biomedical commenced enrollment of the first patient in a Phase 2 randomized, controlled, masked, multi-center clinical trial for the treatment of macular edema associated with non-infectious uveitis using Clearside’s proprietary formulation of triamcinolone acetonide, CLS-TA, administered via suprachoroidal (SCS) injection using a proprietary microinjector (January 2015). Envisia initiated a phase 2a clinical trial to investigate the safety and tolerability of ENV515, a biodegradable particle formulation of travoprost, in patients with glaucoma (January 2015). Genentech received breakthrough therapy designation from the FDA for ranibizumab (LucentisÒ) for treatment of diabetic retinopathy (December 2014).
d
d
d
d
Isarna Therapeutics has submitted a Clinical Trial Authorization (CTA) application with the German Regulatory Authority to begin human studies on ISTH0036, a selective TGF-b2 antisense oligonucleotide, with potential therapeutic application in glaucoma, secondary cataract, and proliferative vitreoretinopathy (January 2015). QLT announced the results of evaluation of oral QLT091001 in patients with early agerelated macular degeneration and impaired dark adaptation (December 2014). Regeneron has received priority review for aflibercept for the treatment of diabetic retinopathy in patients with diabetic macular edema (December 2014). Spark Therapeutics initiated a Phase 1/2 clinical trial of SPKCHM, a gene therapy for choroideremia (January 2015).
NEWS FROM THE U.S. FDA AND OTHER REGULATORY AGENCIES d The FDA announced the membership of the Pharmacy Compounding Advisory Committee (December 2014). d The FDA is amending its regulations governing the content and format of the “Pregnancy,” “Labor and delivery,” and “Nursing mothers” subsections of the “Use in Specific Populations” section of the labeling for human prescription drug and biological products (December 2014). d The U.S. Institute of Medicine has released a report on “Sharing Clinical Trial Data” (January 2015). [See Drazen JM. Sharing individual patient data from clinical trials. N Engl J Med 2015;372:201-2.] d The U.S. National Institutes of Health (NIH) and the U.S. Department of Health and Human Services (HHS) issued separate notices announcing plans to enforce the sharing and reporting of trial outcomes, implementing requirements of
THE OCULAR SURFACE / APRIL 2015, VOL. 13 NO. 2 / www.theocularsurface.com
PIPELINE / Novack the FDA Amendments Act of 2007 (FDAAA [November 2014]). [See: Zarin DA, Tse T, Sheehan J. The proposed rule for U.S. clinical trial registration and results submission. N Engl J Med 2015;372:174-80.] Miscellaneous News Notes d Actavis was ordered by a federal district court judge to not discontinue sales of its now off-patent immediate release memantine (Namenda-IRÒ) in favor of its onpatent extended release memantine (Namenda-XRÒ, January 2015). d Aegerion Pharmaceuticals Chief Executive Officer’s public statement about his previous misleading claims about lomitapide (JuxtapidÒ) were apparently the result of FDA’s
d
d
d
warning letter, demonstrating the agency’s review of television media for industry claims (December 2014). Alcon received approval from the FDA for XtoroÒ (finafloxacin otic suspension), a new chemical entity fluoroquinolone used to treat acute otitis externa (December 2014). Due to differential expiration dates for patents on composition of matter versus use, Pfizer’s pregabalin (LyricaÒ) has generic competition in the U.K. for some indications (generalized anxiety disorder, epilepsy), but not all of the indications for this drug (neuropathic pain, [December 2014]). Janssen Pharmaceuticals is working with a consortia of
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d
global research institutions and non-government organizations to accelerate the development of its Ebola vaccine (January 2015). Novartis ZarxioÒ (filgrastim) was approved by an FDA panel for five indications. If approved by the FDA, this could be the first “biosimilar” to be approved in the U.S. (January 2015). Otsuka has agreed to purchase Avanir Pharmaceuticals (December 2014). Roche received FDA authorization for emergency use of its Ebola test (December 2014). The Tufts Center for the Study of Drug Development estimated the cost to develop a new drug is US$2.6 million (November 2014).
THE OCULAR SURFACE / APRIL 2015, VOL. 13 NO. 2 / www.theocularsurface.com
173
SECTION EDITOR
Can I Use Those Eyedrops after the Expiration Date? GARY D. NOVACK, PHD
am frequently asked by colleagues and friends whether it is acceptable to use medications after the expiration date. They propose that medications are “good” long after their expiration date. For example, Cantrell et al chemically evaluated a number of long-expired oral medications and found that many medications still had at least the labelled amount of drug. Some even had 20-25% more, and one had 300% more. A few had much less than the labelled amount.1 If I am in a flippant mood, I respond to my colleagues and friends by asking: “Would you use milk after its expiration date” (Figure 1)? If I am in a more serious mood, I simply say: “No, it is not acceptable.” When the questioner then asks why, this opens the door for me to explain what goes into assigning the expiration date. The manufacture of ophthalmic drugs was covered in a previous article in this journal.2 In that article, my coauthor and I wrote “.The stability data is evaluated in order to assign an expiration date system for the product.” Drugs are evaluated to assure the proper identification, quality, purity, and strength of the drug. The requirements for stability testing are discussed in a series of International Conference on Harmonisation (ICH) guidance on
I
Disclosure: Gary D. Novack, PhD (PharmaLogic Development, Inc., San Rafael CA) consults with numerous pharmaceutical firms. © 2015 Elsevier Inc. All rights reserved.
quality (Q1A through Q1F [http:// www.ich.org/products/guidelines/quality /article/quality-guidelines.html]). The analytical tests performed on a product include the active ingredient and the potential development of any degradation products. All sterile products undergo a test for sterility. For preserved products, there is both a chemical assay of the preservative and a biological assay for the capability of the product to prevent growth of microorganisms (Antimicrobial Effectiveness Test). There are also tests for physicochemical properties (e.g., volume, pH, particulates). The expiration date is an extrapolation. That is, pharmaceutical scientists evaluate early stability data on a given lot and extrapolate the duration of time at which it is expected to still be within specification. Shown in Figure 2 is an example of the decreasing amount of active ingredient in a drug product. In this case, the specifications call for a 5% variance on the label claim amount of active ingredient. In this example, the calculated variance suggests that the product would be stable for 24-36 months stored at 25C and 60% relative humidity. Also evaluated for this product is the development of a degradation product. In the same storage conditions, the concentration of the degradation product was estimated to exceed the specification limit of 1.4% at approximately 27 months (Figure 3). One typically uses a conservative estimate e i.e., the lower 95% confidence interval for concentration of active (i.e., the lowest it might be)
and the upper 95% confidence interval for concentration of a degradation product (i.e., the highest it might be). For a liquid ophthalmic product, similar calculations would be performed for pH and volume. Also, sterile products must pass the sterility tests at each time point. These analytical data are all considered in setting an expiration date for a product. Finally, some formulations may fail because the particulate count rises or the formulation becomes unstable (i.e., the active ingredient falls out of solution or suspension). While such tests are conducted throughout the development of a new product, the final formulation and container/closure system (i.e., bottle and tip, or unit dose container) are not typically finalized until Phase 3. The duration of stability data on this final product can vary depending upon the duration of the Phase 3 clinical studies. However, in general, it is on the order of 12-18 months real-time stability. Stability studies can also be performed in exaggerated conditions (e.g., 40C/25% Relative Humidity [RH] for a product to be stored at room temperature, 25C/60% RH for a product intended to be refrigerated). These data are used to project (i.e., extrapolate) a shelf life, which is proposed to regulatory authorities in the New Drug Application. As noted above, both the manufacturer and the regulatory authority tend to be conservative in setting a shelf life for the initial application. As more data are obtained for the product, the company may submit them to the regulatory authority, proposing a longer shelf life.
THE OCULAR SURFACE / APRIL 2015, VOL. 13 NO. 2 / www.theocularsurface.com
169
PIPELINE / Novack
Figure 1. Expiration dating of milk.
However, as noted in the ICH Q1A(R2) document, “There should be a direct link between the label storage statement and the demonstrated stability of the drug product.” As to the conservative aspect of setting a shelf life, in the early stages of product development with limited
data, a manufacturer may choose to create an overage (i.e., a bit “on the high side”) in order to meet the minimum requirements at the expiration date. Thus, as liquid may evaporate through plastic bottles, volume in the product at time of manufacture may be higher than the label claim. A
manufacturer could also add more active ingredient e but not too much, as the actual amount in the bottle at time of manufacture could not exceed the label claim by more than a small amount (on the order of 510%). One of the ICH guidances, Q1A(R2) describes evaluation of potential water loss for drug products packaged in semi-permeable containers. For example, for a product to be stored at room temperature, “.a 5% loss in water from its initial value is considered a significant change for a product packaged in a semipermeable container after an equivalent of 3 months’ storage at 40 C/No More Than (NMT) 25% RH. However, for small containers (1 mL or less) or unit-dose products, a water loss of 5% or more after an equivalent of 3 months’ storage at 40C/NMT 25% RH may be appropriate, if justified” (http://www.ich.org/fileadmin/Public_ Web_Site/ICH_Products/Guidelines/ Quality/Q1A_R2/Step4/Q1A_R2__Gu ideline.pdf). Among some of my colleagues and friends, there is a perception that manufacturers would prefer to have a short expiration date, so that patients have to buy more product. This is not the case. The shorter the shelf life, the more challenging the logistics for the manufacturer to produce the product, ship it to wholesalers, who, in turn, ship it to pharmacies, who maintain
Figure 2. Expiration dating: Stability of active ingredient. (From: ICH Harmonised Tripartite Guideline: Evaluation for Stability Data: Q1E (June 2004). 60% RH ¼ 60% relative humidity. http://www.fda.gov/ downloads/Drugs/GuidanceComplianceR egulatoryInformation/Guidances/UCM073 380.pdf.)
170
THE OCULAR SURFACE / APRIL 2015, VOL. 13 NO. 2 / www.theocularsurface.com
PIPELINE / Novack
Figure 3. Expiration of a degradation product. (From: ICH Harmonised Tripartite Guideline: Evaluation for Stability Data: Q1E (June 2004). 60% RH ¼ 60% relative humidity. http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInf ormation/Guidances/UCM073380.pdf.)
stock until they receive and fill prescriptions for the product. Pharmacies send expired product back to wholesalers, who, in turn, send it back to the manufacturers as contractually required. The manufacturers then compensate the wholesalers for the expired product. It is a non-trivial quantity e perhaps accounting for 10% of annual sales. Thus, there is a financial incentive to manufacturers to assign a longer shelf life, rather than a shorter shelf life. So, what might happen if a patient uses a bottle of eye drops beyond the expiration date? It might not meet the label specifications in any of a number of ways. It might be less potent than labelled due to degradation of the active ingredient, or it might be more potent due to evaporation. It might include a degradation product of unknown efficacy or safety. For example, aspirin (acetylsalicylic acid) degrades to salicylic acid, which may be of different activity than aspirin. In other cases, only the parent product may effectively penetrate ocular tissues; the degraded product, while still containing an active molecule, may not be able to effect the desired pharmacology. A product used past expiration date might be too acidic or too basic. It might also be non-sterile, or not able to kill microorganisms introduced by patient use. There might also be less volume in the bottle than labelled. In short,
an expired product might be neither safe nor effective. The expiration date is also based upon the assumption that the product is stored as labelled. Some products must be refrigerated at pharmacies and until administered to the patient (e.g., biologic VEGF inhibitors). Others must be refrigerated until dispensed to the patient (e.g., some prostaglandin analogues). So, even products stored outside of these requirements (e.g., the bottle of eyedrops taken to the beach in summer) may be out of specification even within the expiration date. So, patients and physicians should be even more concerned about product quality for the improperly stored product after expiration date. Back to my initial example, if a carton of milk is beyond its expiration date, you can usually tell immediately by its smell or taste. However, with most ophthalmic products, one cannot tell by casual inspection or even patient use whether it meets its specifications, and one does not know the clinical impact of such failure. Generic ophthalmic drugs may vary in concentration of active ingredient from the innovator product by 5% to 10%. Unfortunately, we do not know how this variation in chemistry (or other possible variations in container/closure systems) may affect the concentration of drugs in ocular tissue, or the drug’s efficacy and
safety. I previously posed the question as to how much variability can we accept in providing the best therapeutics to patients, especially considering the cost-conscious aspects of health care today.3,4 However, unlike the decision of a more affordable generic vs a more costly branded product, the decision on using out-of-date products seems to be an easy one. In the same way you select and use milk within its expiration date, you should also use medications within their expiration date. As to what to do with expired medications, use the various recycling programs available.5 ACKNOWLEDGEMENTS The author acknowledges the contributions of Elizabeth D. Moyer, Ph.D. (M/P Biomedical, Mill Valley CA).
REFERENCES 1. Cantrell L, Suchard JR, Wu A, Gerona RR. Stability of active ingredients in long-expired prescription medications. Arch Intern Med 2012;172:1685-7 2. Kaufman B, Novack GD. Compliance issues in manufacturing of drugs. Ocul Surf 2003;1: 80-5 3. Novack GD. Pipeline: Quality of generic ophthalmic drugs. Ocul Surf 2013;11:54-7 4. Chambers WA. Ophthalmic generics: are they really the same. Ophthalmology 2012;119: 1095-6 5. Novack GD, Moyer E. Pipeline: Where do unused medications go when they die? Ocul Surf 2013;11:139-42
THE OCULAR SURFACE / APRIL 2015, VOL. 13 NO. 2 / www.theocularsurface.com
171
PIPELINE / Novack NEWS FROM PHARMACEUTICAL AND MEDICAL DEVICE COMPANIES Ophthalmic Products Related to the Ocular Surface d Ocular Therapeutix started enrollment in a Phase 2 trial of its sustained release dexamethasone for the treatment of dry eye (January 2015). d Nicox is in advanced development of AC-170, a topical ocular formulation of cetirizine for the treatment of ocular itching associated with allergic conjunctivitis (January 2015). d Santen received approval from the European Committee for Medicinal Products for Human Use for IkervisÔ, topical cyclosporine intended for the treatment of severe keratitis in adult patients with dry eye disease (January 2015). Ophthalmic Products Not Related to the Ocular Surface d Aerie completed patient enrollment in its Phase 3 clinical trial of AR-13324 for the treatment of elevated intraocular pressure (December 2014). d Aerpio completed patient enrollment in its Phase 2 study of AKB-9778, a human protein tyrosine phosphatase beta inhibitor and Tie2 activator, alone and in combination with ranibizumab for the treatment of diabetic macular edema (December 2014). d Akorn has filed an abbreviated new drug application (ANDA, generic) for difluprednate ophthalmic emulsion (January 2015). Akorn received FDA approval for Phenylephrine Hydrochloride Ophthalmic Solution, USP, 2.5% and 10% (January 2015). d Alcon received an additional approval from the European Commission for travoprost ophthalmic solution (TravatanÒ) for the treatment of elevated intraocular pressure in pediatric patients with glaucoma (December 2014). d Aldeyra Therapeutics filed an Investigational New Drug 172
d
d
d
d
d
d
d
application (IND) to conduct Phase 2 clinical testing of its NS2 for the treatment of noninfectious anterior uveitis (December 2014). Alimera received approval for IluvienÒ (fluocinolone acetonide intravitreal implant) in Netherlands (December 2014) and Portugal (January 2015). Alimera received marketing approval in Finland and Luxembourg for IluvienÒ (fluocinolone acetonide intravitreal implant) for the treatment of diabetic macular edema in some patients (January 2015). Allegro Ophthalmics and Hanmi Pharmaceutical have entered into a license agreement for ALG-1001 (an integrin peptide therapeutic) in the Republic of Korea and the People’s Republic of China (January 2015). Amarantus received orphan drug designation for MANF from the FDA for the treatment of retinitis pigmentosa (December 2014). Carl Zeiss Meditec will be supporting Oraya Therapeutics in its development of low energy radiation therapy for macular degeneration (December 2014). Clearside Biomedical commenced enrollment of the first patient in a Phase 2 randomized, controlled, masked, multi-center clinical trial for the treatment of macular edema associated with non-infectious uveitis using Clearside’s proprietary formulation of triamcinolone acetonide, CLS-TA, administered via suprachoroidal (SCS) injection using a proprietary microinjector (January 2015). Envisia initiated a phase 2a clinical trial to investigate the safety and tolerability of ENV515, a biodegradable particle formulation of travoprost, in patients with glaucoma (January 2015). Genentech received breakthrough therapy designation from the FDA for ranibizumab (LucentisÒ) for treatment of diabetic retinopathy (December 2014).
d
d
d
d
Isarna Therapeutics has submitted a Clinical Trial Authorization (CTA) application with the German Regulatory Authority to begin human studies on ISTH0036, a selective TGF-b2 antisense oligonucleotide, with potential therapeutic application in glaucoma, secondary cataract, and proliferative vitreoretinopathy (January 2015). QLT announced the results of evaluation of oral QLT091001 in patients with early agerelated macular degeneration and impaired dark adaptation (December 2014). Regeneron has received priority review for aflibercept for the treatment of diabetic retinopathy in patients with diabetic macular edema (December 2014). Spark Therapeutics initiated a Phase 1/2 clinical trial of SPKCHM, a gene therapy for choroideremia (January 2015).
NEWS FROM THE U.S. FDA AND OTHER REGULATORY AGENCIES d The FDA announced the membership of the Pharmacy Compounding Advisory Committee (December 2014). d The FDA is amending its regulations governing the content and format of the “Pregnancy,” “Labor and delivery,” and “Nursing mothers” subsections of the “Use in Specific Populations” section of the labeling for human prescription drug and biological products (December 2014). d The U.S. Institute of Medicine has released a report on “Sharing Clinical Trial Data” (January 2015). [See Drazen JM. Sharing individual patient data from clinical trials. N Engl J Med 2015;372:201-2.] d The U.S. National Institutes of Health (NIH) and the U.S. Department of Health and Human Services (HHS) issued separate notices announcing plans to enforce the sharing and reporting of trial outcomes, implementing requirements of
THE OCULAR SURFACE / APRIL 2015, VOL. 13 NO. 2 / www.theocularsurface.com
PIPELINE / Novack the FDA Amendments Act of 2007 (FDAAA [November 2014]). [See: Zarin DA, Tse T, Sheehan J. The proposed rule for U.S. clinical trial registration and results submission. N Engl J Med 2015;372:174-80.] Miscellaneous News Notes d Actavis was ordered by a federal district court judge to not discontinue sales of its now off-patent immediate release memantine (Namenda-IRÒ) in favor of its onpatent extended release memantine (Namenda-XRÒ, January 2015). d Aegerion Pharmaceuticals Chief Executive Officer’s public statement about his previous misleading claims about lomitapide (JuxtapidÒ) were apparently the result of FDA’s
d
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warning letter, demonstrating the agency’s review of television media for industry claims (December 2014). Alcon received approval from the FDA for XtoroÒ (finafloxacin otic suspension), a new chemical entity fluoroquinolone used to treat acute otitis externa (December 2014). Due to differential expiration dates for patents on composition of matter versus use, Pfizer’s pregabalin (LyricaÒ) has generic competition in the U.K. for some indications (generalized anxiety disorder, epilepsy), but not all of the indications for this drug (neuropathic pain, [December 2014]). Janssen Pharmaceuticals is working with a consortia of
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global research institutions and non-government organizations to accelerate the development of its Ebola vaccine (January 2015). Novartis ZarxioÒ (filgrastim) was approved by an FDA panel for five indications. If approved by the FDA, this could be the first “biosimilar” to be approved in the U.S. (January 2015). Otsuka has agreed to purchase Avanir Pharmaceuticals (December 2014). Roche received FDA authorization for emergency use of its Ebola test (December 2014). The Tufts Center for the Study of Drug Development estimated the cost to develop a new drug is US$2.6 million (November 2014).
THE OCULAR SURFACE / APRIL 2015, VOL. 13 NO. 2 / www.theocularsurface.com
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