Atlas of Fundus Angiography by Ulrich Kellner (2023, ...

Atlas of Fundus Angiography by Ulrich Kellner (2023)

"Atlas of Fundus Angiography is a comprehensive repository of knowledge on this imaging technique, elegantly illustrated for clarity. Its primary highlight is an advanced overview and comparison of the methodologies involved. The logical arrangement and user-friendly format facilitate the recognition of essential angiographic patterns and aid in making accurate diagnoses. This book provides practical insights and diagnostic criteria through clinical case studies, meticulously documented with 638 high-quality illustrations that include both pre- and post-treatment retinal imaging, as well as comparisons of fluorescein angiography, Indocyanine Green Angiography, autofluorescence, and optical coherence tomography. In conclusion, the Atlas of Fundus Angiography stands as a current and richly illustrated guide, indispensable for clinicians at all stages of their careers striving to master this essential technique."--American Journal of Ophthalmology "A valuable resource for novice ophthalmology residents."--Doody's Book Reviews, Atlas of Fundus Angiography is a comprehensive repository of knowledge on this imaging technique, elegantly illustrated for clarity. Its primary highlight is an advanced overview and comparison of the methodologies involved. The logical arrangement and user-friendly format facilitate the recognition of essential angiographic patterns and aid in making accurate diagnoses. This book provides practical insights and diagnostic criteria through clinical case studies, meticulously documented with 638 high-quality illustrations that include both pre- and post-treatment retinal imaging, as well as comparisons of fluorescein angiography, Indocyanine Green Angiography, autofluorescence, and optical coherence tomography. In summary, the Atlas of Fundus Angiography remains an up-to-date guide for clinicians at various levels seeking expertise in this fundamental methodological approach.—American Journal of Ophthalmology. An invaluable resource for emerging ophthalmology professionals."—Doody's Book Reviews

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Synopsis

Ocular fundus angiography is a critical examination technique that every ophthalmologist must master when dealing with posterior segment disorders. It features outstanding imagery and concise textual explanations of relevant disease entities commonly seen in clinical practice, presented in a double-page format. The exceptional photographic documentation is supplemented with meaningful commentary on pathogenesis, indications for angiography, and additional diagnostic considerations. The advantages of this approach include the latest classifications of early and late age-related macular degeneration (AMD), mastering standard angiographic methodologies, identifying key angiographic patterns, confidently interpreting angiograms, and keeping up to date with recent AMD treatment protocols, including intravitreal injections of VEGF inhibitors. The application of standard techniques such as fluorescein angiography and Indocyanine Green Angiography is described along with their advantages and limitations, including those of innovative methodologies like fundus autofluorescence, infrared reflectance imaging, and wide-angle imaging. Learn from the expertise of renowned instructors in various specialties.

Clinical impact of the worldwide shortage of verteporfin

Associated Data

Supplementary Materials

Appendix S1. The questionnaire addressing the verteporfin scarcity was distributed among key opinion leaders in medical retina from around the globe.

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Abstract

Introduction

Starting from July, a global shortage of verteporfin (Visudyne®) emerged: an essential medication required for photodynamic therapy (PDT). PDT utilizing verteporfin possesses a wide range of applications in ophthalmology, addressing conditions such as chronic central serous chorioretinopathy, polypoidal choroidal vasculopathy, and choroidal hemangioma. For these ailments, PDT is regarded either as the primary treatment or an essential therapeutic option.

Materials and methods

A questionnaire was distributed to leading experts in medical retina worldwide, monitoring the role of PDT in their respective countries and the consequences of verteporfin's shortage. Additional inquiries on alternative treatment modalities employed during the verteporfin scarcity were made to further assess the impact of this shortage.

Results

The responses to our questionnaire indicated that the shortage of verteporfin significantly impacted ophthalmological care globally and was viewed as a serious concern by a majority of the respondents. Despite ample evidence supporting the use of PDT in various chorioretinal conditions, substantial differences were noted in its application in routine patient care across different regions. Various alternative management strategies were observed during the shortage, including dosage reductions of verteporfin, application of alternative therapy strategies, and a centralized allocation system for the remaining verteporfin supply in certain regions.

Conclusion

The verteporfin shortage has considerably affected ophthalmic patient care internationally, potentially resulting in significant and irreversible vision loss. Collaborative strategies among stakeholders must be devised to avert future medication shortages of verteporfin and other unique ophthalmic drugs. Such measures could entail establishing mandatory stock systems, creating compulsory licensing frameworks with alternative manufacturers, or incentivizing competitive development through innovative public-private collaborations.

Keywords:

age-related macular degeneration, central serous chorioretinopathy, choroidal hemangioma, photodynamic therapy, polypoidal choroidal vasculopathy, verteporfin

Introduction

In recent months, a global deficit of verteporfin (Visudyne®, Cheplapharm Arzneimittel GmbH, Greifswald, Germany) has been reported. Verteporfin serves as a photosensitive therapeutic agent deployed during ocular photodynamic therapy (PDT) for patients with choroidal neovascularization (CNV), central serous chorioretinopathy (CSC), polypoidal choroidal vasculopathy (PCV), and various other chorioretinal disorders.

The constrained supply of verteporfin resulted from manufacturing issues at a facility in the United States, the sole producer of verteporfin globally. Recent updates indicate that the medication may not be reinstated until the first quarter of 2024 (Cheplapharm Arzneimittel GmbH; European Medicines Agency).

This article reviews the use of PDT in ophthalmology and other medical fields, evaluates its efficacy for ophthalmic applications, and examines the ramifications of reduced availability on patient care across different parts of the world. Furthermore, the responses from international specialists regarding the usage variability of PDT for common treatment indications are analyzed. Finally, potential solutions to prevent similar future occurrences are proposed.

History of Photodynamic Therapy

PDT is the process of activating a photosensitive drug via laser treatment, generating free oxygen radicals that provoke localized cytotoxic reactions (Kwiatkowski et al.). The discovery of this phenomenon is attributed to Von Tappeiner et al. in the early 20th century, who observed that illuminating fluorescent dyes resulted in destructive action on paramecia. Earlier indications of this photodynamic response were noted in 16th-century patients with porphyria (Hurst), a disorder caused by an enzyme deficiency in heme synthesis. The accumulation of porphyrin metabolites leads to tissue or organ damage, especially under sunlight exposure (Batlle). Various contemporary photosensitizers derive from porphyrins, including the benzoporphyrin derivative, verteporfin (Santosa & Limantara). Following Von Tappeiner's observations, Figge et al. noted the propensity of certain photosensitizers to concentrate in neoplastic tissues. This characteristic led to PDT's exploration in treating malignancies by administering the photosensitizer either intraperitoneally or intravenously, followed by localized illumination with a light source to activate the photosensitizer and eradicate cancer cells (Diamond et al.). However, PDT's incorporation into standard care for oncology emerged only in the late 20th century. Presently, oncology applications of PDT primarily concern cutaneous cancers, while also assisting in various cancer types, preserving neighboring healthy tissue (Dolmans et al.; Nyst et al.; Allison et al.; Ozog et al.).

The initial generation of photosensitizers demanded prolonged illumination to achieve adequate effects. Additionally, these agents had long half-lives, requiring patients to shield themselves from sunlight for weeks post-injection to avoid skin complications. However, advances in various newer photosensitizers with shortened half-lives have enabled the diverse applications of PDT, especially in retinal disorders (Allison et al.). Verteporfin belongs to this category of advanced photosensitizers.

Photodynamic Therapy in Ophthalmology

Almost a century post the recognition of PDT's foundational concept, this method was introduced in ophthalmology in 2000 after the TAP Study demonstrated that PDT with verteporfin effectively slowed vision loss in specific forms of subfoveal choroidal neovascularization related to age-related macular degeneration (AMD) (TAP study group). This empirical evidence highlighted PDT's applicability beyond malignant tissue treatment toward addressing rapidly developing vascular structures in AMD. For numerous years, PDT constituted the standard treatment for AMD; however, it was less effective compared to intravitreal injections of anti-vascular endothelial growth factor (VEGF) in the ANCHOR study (Brown et al.). As a result, even though verteporfin is sanctioned for treating CNV attributed to AMD or pathological myopia (European Medicines Agency), its current practice in ophthalmology has shifted towards treating PCV, a specific AMD subtype, and off-label use for disorders like CSC and various types of ocular hemangiomas (van Dijk et al.; Raizada & Naik). Occasionally, PDT is also employed for choroidal melanomas (Quhill et al.) and retinal angiomatous proliferations (Saito et al.), but these instances are infrequent and will not be elaborated on in this document.

A typical PDT treatment entails a 10-minute intravenous infusion of verteporfin at a dose of 6 mg/m², diluted in 30 ml of intravenous fluid. After a 15-minute interval post-infusion initiation, verteporfin is illuminated using a diode laser with a wavelength of 689 nm. The spot of interest is exposed to light with an intensity of 600 mW/cm² for 83 seconds to achieve a light dosage of 50 J/cm² (European Medicines Agency).

Photodynamic therapy in central serous chorioretinopathy

Central serous chorioretinopathy (CSC) is delineated by specific choroidal abnormalities, such as thickening (termed 'pachychoroid'), venous congestion, and leakage, associated with serous subretinal fluid (SRF) accumulation, typically presenting in the macula. In cases where this fluid remains unresolved, subsequent damage to the retinal pigment epithelium (RPE) is likely (Cheung et al.; van Rijssen et al.b; van Dijk & Boon; Spaide et al.). The presence of this macular SRF may prompt symptoms such as blurred vision, loss of contrast sensitivity, metamorphopsia, and micropsia. Risk factors encompass male gender, type A personality, psychological conditions, steroid administration, and sleep disturbances, with initial symptoms predominantly occurring in individuals aged 30 to 50 years. If SRF persists beyond three months, alongside relapse occurrences and additional signs of chronicity on multimodal imaging, such as diffuse atrophic RPE alterations, treatment is usually recommended (Mohabati et al.; van Rijssen et al.b).

Several therapeutic interventions have been employed for CSC, including focal thermal laser, micropulse laser treatment, oral eplerenone, intravitreal injections of anti-VEGF agents, and PDT. Alterations to the standard parameters of PDT treatment demonstrate efficacy similar to standard settings (van Rijssen et al.b; van Dijk et al.). For instance, verteporfin dosage may be reduced to 3 mg/m² (referred to as half-dose PDT), or laser settings may adjust to deliver light at a dosage of 25 J/cm² (designated half-fluence PDT). Evidence garnered from available studies suggests that these reduced settings retain comparable treatment outcomes while minimizing side effects (van Rijssen et al.b).

The European PLACE trial, the first major prospective investigation regarding chronic CSC treatments, revealed that half-dose PDT surpassed high-density subthreshold micropulse laser treatment in chronic CSC patients across both functional and anatomical outcome measures (van Dijk et al.). In this trial, total SRF resolution was achieved in 67.2% of PDT-treated patients at 7 to 8 months following treatment, in contrast to 28.8% among those receiving micropulse laser therapy (van Dijk et al.). Notably, a considerably higher increase in retinal sensitivity, as verified through microperimetry, was identified in eyes treated with PDT. Furthermore, a significantly larger proportion of patients with chronic CSC received positive functional improvements after PDT treatment when compared to those treated with micropulse laser. This superior treatment effect was consistent, regardless of whether focal or extensive leakage was recorded via fluorescein angiography (van Rijssen et al.a). A recent prospective trial in the Netherlands, the SPECTRA trial, confirmed that half-dose PDT also outperformed oral mineralocorticoid receptor antagonists like eplerenone for managing chronic CSC. With similar outcome assessments to the PLACE trial, SPECTRA demonstrated a complete resolution of SRF in 87% of PDT-treated patients compared to just 17% in the eplerenone group. Additionally, significantly improved gains in retinal sensitivity were observed in the PDT cohort. Comparatively, low rates of SRF resolution were also reported in the VICI trial, wherein eplerenone was compared to placebo in chronic CSC patients (Lotery et al.). Such findings endorse the pivotal role of PDT, particularly using reduced settings, for chronic CSC treatments where alternatives are practically nonexistent (van Rijssen et al.b).

Photodynamic therapy in polypoidal choroidal vasculopathy

Polypoidal choroidal vasculopathy (PCV) is characterized by CNV alongside sub-RPE aneurysmal vascular dilations (Dansingani et al.; Chaikitmongkol et al.; Cheung et al.). The terminology remains somewhat ambiguous, possibly deriving from the polyps' resemblance to intestinal polyps or the appearance of fresh and saltwater polyps. PCV may lead to hemorrhaging and fluid or protein leakage in the SRF, culminating in decreased visual acuity. While present in patients with neovascular AMD, it may also manifest in conjunction with other disorders linked to CNV, including CSC. In Asian populations, prevalence indicates that between 22.3% and 61.6% of individuals diagnosed with neovascular AMD show signs of PCV, compared to just 8% to 13% in White European patients (Wong et al.). The pathophysiology and its correlation with AMD remain subjects of ongoing discourse. A recently proposed classification of PCV subtypes aims to clarify this issue, distinguishing distinct etiologies (Van Dijk et al.). Recommended classifications encompass (1) PCV associated with AMD, characterized by a minimum of five macular drusen; (2) PCV without drusen presence, but showing either non-polypoidal CNV or a branching vascular network; and (3) idiopathic PCV without drusen, a branching vascular network, or non-polypoidal CNV. The diagnosis of PCV is notoriously challenging due to its resemblance to type 1 CNV in conventional neovascular AMD. Nonetheless, accurate diagnosis is crucial, as patients with PCV frequently respond poorly to monotherapy utilizing anti-VEGF treatments compared to their 'classic' AMD counterparts. Indocyanine Green Angiography is considered the gold standard for diagnosing PCV, though it is not universally accessible among ophthalmologists. Consequently, recent studies have sought to establish diagnostic criteria based on alternative imaging modalities, such as observing a sharply peaked RPE detachment coupled with a hyper-reflective ring on optical coherence tomography or identifying a red-orange nodule on color fundus photography (Cheung et al.). Once the diagnosis is confirmed through multimodal imaging, including ICGA, considerations for PDT alongside or in conjunction with intravitreal anti-VEGF injections may arise, as substantiated by various clinical trials. The EVEREST trial, executed by Koh et al., underscored the superiority of combination therapy with anti-VEGF and full-dose PDT compared to anti-VEGF monotherapy regarding polyp closure rates (77.8% versus 28.6%) after six months post-treatment (Koh et al.). The subsequent EVEREST II study revealed longer-term results, demonstrating greater gains in best-corrected visual acuity (9.6 versus 5.5 letters) and improved polyp closure rates (56.6% versus 26.7%) after 24 months for combination therapy over anti-VEGF monotherapy (Lim et al.). Moreover, the EVEREST II cohort showed a reduced need for anti-VEGF injections when combination therapy was employed (median of 6 versus 12 after 24 months). Additionally, another investigation established anti-VEGF monotherapy yielded favorable responses in 85% of patients, predominantly of Asian descent (Lee et al.). Although full-dose PDT prevails in treating PCV, half-dose PDT may yield comparable efficacy (Wong et al.). In summary, PDT is deemed a consideration for patients with PCV, primarily when responses to anti-VEGF treatments alone are insufficient.

Photodynamic therapy in choroidal haemangioma

Choroidal haemangiomas represent benign vascular tumors located in the eye's posterior segment. Two predominant forms exist: diffuse choroidal haemangioma and circumscribed choroidal haemangioma. The diffuse variant predominantly arises in individuals with Sturge-Weber syndrome, commonly characterized by a port-wine stain on the corresponding side of the face and diffuse choroidal thickening, arising from birth and potentially evident in early life.

Circumscribed choroidal haemangiomas typically present later in life and are noted for their localized tumor forms. In both variations, leakage from these tumors may instigate intra- and subretinal fluid, potentially leading to exudative retinal detachments and considerably diminishing visual acuity (Schmidt-Erfurth et al.). Conventional laser therapy generally aids in diminishing SRF and offers a temporary visual acuity boost, yet long-term results often reflect progressive acuity decline in many instances (Anand et al.). Although extensive research on PDT’s efficacy in these tumors is limited, available evidence advocates a favorable treatment response (Boixadera et al.; Sachdeva et al.). A review has also indicated that PDT is the preferred therapeutic option (Tsipursky et al.). Various protocols exist for performing PDT in ocular haemangiomas, such as employing bursts of verteporfin or adjusting fluence to a higher level of 100 J/m² compared to the conventional 50 J/m². Regardless, a complete dosage of 6 mg/m² of verteporfin is consistently utilized. Several radiation therapy forms, including low-dose (20 Gy) external beam therapy, are also effective in substantial choroidal haemangiomas, albeit with potential adverse effects on ocular and surrounding tissues (Karimi et al.).

Consequently, several ocular diseases are effectively managed via PDT using verteporfin, serving as the sole effective treatment option in certain scenarios.

Current Situation and Management in the Netherlands

With a national population approximating 17.5 million, around 700 Dutch patients undergo PDT annually (Nederlands Oogheelkundig Gezelschap). This demographic includes 80-85% chronic CSC cases, 10-15% PCV patients, and 5% for other indications like choroidal haemangioma. During the latter half of 2023, verteporfin supplies were restricted, enabling treatment for only 10-15% of PDT-indicated cases amidst available stock in the Netherlands. This unfavorable scenario garnered attention within major national news outlets. In response, the Dutch Ophthalmological Society and Medical Retina Working Group convened a national committee comprising retina specialists frequently engaged in PDT treatment from various centers, with the purpose of systematically allocating remaining verteporfin reserves based on prioritization criteria (Nederlands Oogheelkundig Gezelschap; Werkgroep Medische Retina van het Nederlands Oogheelkundig Gezelschap). This system was implemented to optimize PDT availability for individuals most susceptible to deteriorating visual function and irreversible consequences without appropriate treatment. Committee meetings were held biweekly to meticulously assess historical and multimodal imaging data for cases nominated by treating ophthalmologists across the Netherlands.

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Priority criteria were established for case rankings (Werkgroep Medische Retina van het Nederlands Oogheelkundig Gezelschap). For instance, prioritization was extended to children with choroidal haemangioma and functionally monocular patients (please refer to the criteria table). Disappointingly, this led to 85-90% of patients either receiving suboptimal treatments or having their therapies postponed until verteporfin availability was restored.

Table 1

Patients with one functional eye, or best-corrected visual acuity of 20/40 Snellen equivalent in the counterpart, and: Choroidal haemangioma featuring subretinal fluid in the macula; Chronic serous chorioretinopathy with persistent subfoveal fluid documented through optical coherence tomography, where the leakage source is not amenable to focal laser treatment; Polypoidal choroidal vasculopathy with foveal intraretinal or subretinal fluid or foveal hard exudates, deteriorating despite regular anti-vascular endothelial growth factor (VEGF) intravitreal treatments; Non-inflammatory choroidal neovascularization with foveal intraretinal or subretinal fluid exceeding 200 μm in height or foveal hard exudates, worsening despite ongoing anti-VEGF intravitreal treatments. Children below 18 years old with choroidal haemangioma showing subretinal fluid in the macula

While exact figures substantiating this are lacking, it can be surmised that numerous patients experienced compromised visual function due to this shortage, and some may have suffered irreversible vision impairment. Furthermore, once verteporfin supplies are restored, it is probable that PDT treatments will need to be performed at a higher volume than previously anticipated due to delayed administration. Collectively, this verteporfin shortage poses a serious concern. Medication shortages represent a common occurrence; for instance, 70 drug shortages were recorded in the Netherlands during 2022 (Koninklijke Nederlandse Maatschappij ter Bevordering der Pharmacie). In this report, medication shortages were defined as instances of national unavailability projected to last over 14 days.

Current Situation and Management in the Rest of the World

The verteporfin shortage has far-reaching consequences for patients and the ophthalmic community globally. Nonetheless, the shortage's impact varies based on geographic factors. In spite of evident efficacy data supporting verteporfin-assisted PDT for the aforementioned conditions, treatment guidelines may diverge significantly by country, or even regionally within a given country, or be entirely absent (Mehta et al.). In the Netherlands, PDT is the standard approach for chronic CSC patients, but availability or use for this indication may not be feasible in other areas globally. The urgency of this critical situation led us to assess the standard practices for treating various retinal diseases across the globe, as well as to investigate how the verteporfin unavailability has affected patient care. We reached out to prominent experts in medical retina throughout Europe, Asia, and the United States who are acquainted with the authors of this article and asked them to complete a questionnaire addressing the following areas: the significance of PDT in their local ophthalmology practices and how the current deficit has influenced patient management? (Refer to Appendix S1 for the exhaustive list of questions).

Results of the International Questionnaire on the Role of PDT and Effect of Current Verteporfin Shortage

This questionnaire was distributed to 18 retina authorities operating in the United Kingdom, France, Germany, Israel, Switzerland, Spain, Italy, Denmark, Sweden, the Netherlands, Singapore, Japan, and the United States. Out of these, we received responses from 15 retinal specialists hailing from 12 different countries, leading to a response rate of 83%. All questionnaires were conducted between December 2022 and January 2023.

Notable variances were observed among countries regarding PDT application in regular clinical circumstances (Refer to Table 2). For chronic CSC, the predominant treatment choice listed was PDT in most countries. In Italy, approximately 50% of chronic CSC cases underwent PDT, while others received conventional laser, MR antagonists, nutritional supplementation, or acetazolamide tablets. In the United States, it was noted that 25-50% of chronic CSC patients were treated via PDT with others resorting to MR antagonists. In Japan, conventional laser therapy was utilized when leakage from the dye was apparent on fluorescein angiography. PCV was generally treated using either anti-VEGF or anti-VEGF combined with PDT. Treatmen variations were also highlighted; in some countries, only 0-20% of PCV patients received PDT, while in others, roughly 20-50% did.

Table 2

What is the primary treatment in your country in the normal situation? What percentage of patients do you estimate is treated with PDT in your country in the normal situation? Chronic CSC | PCV | Choroidal haemangioma | Neovascular AMD | Country | Primary treatment | % treated with PDT | Primary treatment | % treated with PDT | Primary treatment | % treated with PDT | Primary treatment | % treated with PDT | | Denmark | PDT | 100% | Anti-VEGF or Anti-VEGF + PDT | 30% | PDT | 100% | Anti-VEGF | <1% | | France | PDT | 75% | Anti-VEGF | 5% | PDT | 80% | Anti-VEGF | 1% | | Germany | PDT | 80% | Anti-VEGF | 5% | PDT | 90% | Anti-VEGF | <5% | | Israel | PDT | 90% | Anti-VEGF or Anti-VEGF + PDT | 5-10% | PDT | 90-100% | Anti-VEGF | 0% | | Italy | PDT | 50% | Anti-VEGF + PDT | 20% | PDT | 80% | Anti-VEGF | 1% | | The Netherlands | PDT | 90% | Anti-VEGF + PDT | 50% | PDT | 95% | Anti-VEGF | 1% | | Sweden | PDT | 75-100% | Anti-VEGF | 20-30% | PDT | 80% | Anti-VEGF | 0% | | Switzerland | PDT | 100% | Anti-VEGF or Anti-VEGF + PDT | 35-40% | PDT | 100% | Anti-VEGF | 2% | | United Kingdom | PDT | 80% | Anti-VEGF + PDT | 50% | PDT | 70% | Anti-VEGF | 5% | | United States | MR antagonist (1st) or PDT (2nd) | 25-50% | Anti-VEGF or PDT | 5-20% | PDT | 50-80% | Anti-VEGF | 0-10% | | Japan | PDT or conventional laser treatment | 20% | Anti-VEGF or Anti-VEGF + PDT | 5% | Conventional laser treatment or PDT | 15% | Anti-VEGF or Anti-VEGF + PDT | 2% | | Singapore | PDT or conventional laser treatment | 90% | Anti-VEGF or Anti-VEGF + PDT | 30% | PDT | 70% | Anti-VEGF | <5% |

In numerous countries, it was reported that no verteporfin supplies were available when the questionnaire was filled out. In responses from France, the Netherlands, and Singapore, it was conveyed that a limited verteporfin stock was still present. Notably, respondents from Japan and two-thirds of U.S. experts claimed to have faced no significant verteporfin shortages. This situation might arise from remaining inventories of verteporfin being released in the U.S. and Japan during the manufacturing issue timeframe. However, informants from the U.S. noted that PDT is employed less frequently, thus averting rapid shortages as experienced in other nations. Further inquiries revealed that retinal specialists in the U.S. maintain awareness of the robust evidence endorsing PDT’s role in retinal disorders, yet its adoption is constrained by insurance policies and regulatory guidelines. A considerable number of ophthalmologists lack access to the necessary laser equipment for conducting this therapy, and acquiring or repairing existing machines presents notable challenges. Consequently, referrals to alternate centers can pose significant barriers to access, compounded by the necessity for insurance validation and additional out-of-pocket expenses for patients. Conversely, there is no available information elucidating why the supply of verteporfin in Japan has not been disrupted.

Table 3

What is the approximate number of patients treated with PDT in your centre per year? Chronic CSC | PCV | Choroidal haemangioma | Neovascular AMD | Country and Respondent | Is PDT still available? | Normal situation | Shortage situation | Normal situation | Shortage situation | Normal situation | Shortage situation | Normal situation | Shortage situation | | Denmark | No | Unknown | 0 | Unknown | 0 | Unknown | 0 | Unknown | | France | Yes, but limited | | | | | | | | Germany | No | | | | | | Israel | Respondent #1 | No | | | | | | | | Israel | Respondent #2 | No | 50 | 60 | | Unknown | 3 | | | Italy | No | | | | | | The Netherlands | Yes, but limited | | | | | | Sweden | No | 500 | | | | | Switzerland | No | | | | | | The United Kingdom | No | | | | | | The United States | Respondent #1 | Yes, as usual | 18 | N/A | <5 | N/A | 1 | 2 | | The United States | Respondent #2 | Yes, but limited | Unknown | 5 | Unknown | 20 | Unknown | 25 | Unknown | | The United States | Respondent #3 | Yes, as usual | 48 | N/A | 48 | N/A | 10 | 20 | | Japan | Yes, as usual | 20 | N/A | 2 | N/A | 0 | 1 | | Singapore | Yes, but limited | 161 | <7 | 1 | <7 | 0 | 1 |

In contrast to the Netherlands, the distribution of remaining verteporfin ampoules occurred without centralized coordination in most countries. A similar selection system with predetermined criteria was implemented in France; however, ophthalmologists merely needed to assert that their patient met the requirements rather than providing multimodal imaging to substantiate this claim (Société Française d'Ophtalmologie). Within the UK, all remaining verteporfin doses were allocated to four national ophthalmological oncology centers (Royal College of Ophthalmologists). This priority allocation strategy aimed at treating ophthalmic tumors using PDT.

Various strategies for managing retinal diseases surfaced amid the verteporfin shortage (Refer to Table 4). For chronic CSC, a strategy of observant waiting and selective focal laser applications was favored. Some specialists reported employing anti-VEGF therapies for cases featuring CNV, while others resorted to MR antagonists. In the context of PCV, all respondents confirmed the deployment of intravitreal anti-VEGF treatments, and some utilized focal laser therapy as deemed appropriate. In managing choroidal haemangioma, the expected approach revolved around observing patients as they awaited PDT availability, whereas some practitioners leveraged argon laser therapy, brachytherapy, and anti-VEGF protocols.

Table 4

How are you managing these diseases in the absence of PDT? | Country and Respondent | Chronic CSC | PCV | Choroidal haemangioma | Neovascular AMD | | Denmark | Watchful waiting; if CNV exists: anti-VEGF; selective cases: focal laser | Anti-VEGF | Watchful waiting | Anti-VEGF | | France | Watchful waiting; focal laser | Anti-VEGF | Anti-VEGF | Anti-VEGF | | Germany | Anti-VEGF therapy; focal laser | Anti-VEGF | Anti-VEGF | Anti-VEGF | | Israel | Respondent #1 | Watchful waiting; perhaps focal laser; HSML under consideration | Anti-VEGF | Watchful waiting; brachytherapy | Anti-VEGF | | Israel | Respondent #2 | Focal laser if feasible; MR antagonists in certain instances | Anti-VEGF | Watchful waiting | Anti-VEGF | | Italy | HSML; MR antagonist. For CNV cases: anti-VEGF | Anti-VEGF | Mixed strategies | Anti-VEGF | | Netherlands | Watchful waiting; if possible, focal laser | Anti-VEGF; focal laser | PDT awaited | Anti-VEGF | | Sweden | HSML; focal laser | Anti-VEGF | Focal laser for two extrafoveal tumors; some patients awaiting PDT, for whom anti-VEGF and oral propranolol are discussed | Anti-VEGF | | Switzerland | In cases of extrafoveal leakage: focal laser; monitoring risk factors, HSML; for CNV or FIPED: anti-VEGF | Anti-VEGF; combined with focal laser if necessary | Waiting for PDT | Anti-VEGF | | United Kingdom | Watchful waiting | Anti-VEGF | PDT via oncology center referral | Anti-VEGF | | United States | Respondent #1 | N/A | N/A | N/A | N/A | | United States | Respondent #2 | Anti-VEGF | Anti-VEGF | Anti-VEGF | Anti-VEGF | | United States | Respondent #3 | N/A | N/A | N/A | N/A | | Japan | N/A | N/A | N/A | N/A | | Singapore | Focal laser if feasible | Anti-VEGF | Unknown | Anti-VEGF |

Figure 1 depicts the average percentage of patients receiving PDT for various indications under normal conditions compared to the shortage period. The significant decline in patients treated for chronic CSC, PCV, and choroidal haemangioma is conspicuous.

Half of the respondents noted they were more inclined to consider half-dose PDT due to the shortage, opting for it in scenarios where they would have typically utilized a full dose. None indicated interest in exploring alternative photosensitizers to verteporfin, largely due to insufficient safety and efficacy data.

A consensus among more than 90% of our respondents agreed that verteporfin's absence represents a serious challenge with dire outcomes for patients necessitating PDT, while almost 75% completely endorsed this notion (measured via a five-point scale). Numerous respondents noted that measures at national or international levels (such as from the European Union) ought to be implemented to curb future shortages. Suggestions emphasized maintaining emergency stocks of crucial drugs among the proposed solutions.

Why is There a Lack of Verteporfin?

Verteporfin is manufactured exclusively by Alcami Carolinas Corporation (Charleston, South Carolina, United States) and supplied to Bausch Health US, LLC (Bridgewater, New Jersey, United States) and Cheplapharm Arzneimittel GmbH (Greifswald, Germany) for distribution within the European Union (Cheplapharm Arzneimittel GmbH). The marketing authorization holder (MAH) in Europe, Cheplapharm Arzneimittel GmbH, has notified national authorities—who subsequently communicated with national organizations representing ophthalmologists—regarding “technical defects in the filling machine” located in the U.S., which is responsible for producing Visudyne®. Recently, production was transitioned to a new line featuring equivalent machines housed within the same facilities. However, in July 2023, Cheplapharm Arzneimittel GmbH communicated that validation processes were hampered due to unforeseen technical complications, forecasting a projected delay in supply until early 2024 (Cheplapharm Arzneimittel GmbH).

Possible Solutions in Times of Shortage

During persistent shortages, multiple management options warrant consideration.

The foremost approach should contemplate alternative medications targeted towards certain patient subpopulations. In the current scenario, complementing existing therapies with alternative photosensitizers or therapeutic modalities could be contemplated. Several photosensitizers, such as PhotoPoint (Miravant Medical Technologies, Inc., Santa Barbara, Florida, United States), have previously been developed for PDT but were ultimately withdrawn due to inadequate efficacy, substandard characteristics, or adverse safety profiles (Ciulla et al.; Ziemssen & Heimann). Indocyanine green (ICG), primarily employed in retinal angiography, holds potential as a photosensitizer. Studies have evidenced ICG's antimicrobial effects through PDT, both in vitro (Wong et al.) and in vivo involving patients with periodontitis (Niazi et al.). Other investigations highlighted its efficacy for treating skin diseases, such as Kaposi sarcoma (Abels et al.). Nonetheless, no documentation is presently available detailing ICG's use as a photosensitizer in ophthalmology. At present, verteporfin seems to be the only agent with an acceptable profile, and sourcing a new suitable photosensitizer would likely demand extensive research and development preceding regulatory endorsement.

Alternative treatment schemes could be employed. For chronic CSC, various alternatives, including micropulse laser (van Dijk et al.) and oral eplerenone (van Rijssen et al.), have been explored. However, several randomized controlled trials have established that PDT using verteporfin guarantees superior treatment outcomes. One randomized study indicated that the administration of eplerenone failed to demonstrate superior results when juxtaposed with placebo (Lotery et al.). In evaluations of chronic CSC, physicians should be vigilant regarding any underlying type 1 CNV—a flat irregular pigment epithelial detachment featuring mid-reflective sub-RPE material—eligible for potential anti-VEGF interventions, like aflibercept, bevacizumab, brolucizumab, or ranibizumab. For PCV, intravitreal anti-VEGF monotherapy represents a viable therapeutic alternative, albeit a significant proportion of patients may not achieve complete response to anti-VEGF treatment (Lim et al.). In cases of choroidal haemangioma, multiple forms of radiation therapy have proven efficacious, but typically require specialized centers and may incur ocular side effects inclusive of cataracts, subretinal fibrotic changes, radiation retinopathy, and optic neuropathy (Karimi et al.). In addition, initiation of intravitreal anti-VEGF therapy could assist in mitigating SRF, though further evaluative studies are warranted.

Another possible strategy at a local level involves requesting pharmacists to compound medications for individual patients (Directive/83/EC). Nevertheless, for verteporfin, this alternative was regarded as unfeasible due to its complexity, as articulated by the Dutch Ministry of Health, Wellbeing, and Sports (Broekers-Knol). Moreover, no pharmaceutical-grade raw materials from alternative suppliers are available.

On an international scale, medication shortages should be reported to regulatory authorities who could respond with specific demands made to the marketing authorization holder (MAH) (European Medicines Agency). By definition, the MAH bears the responsibility for synchronizing demand with supply and formulating appropriate responses. However, it is uncertain whether they fully comprehend the patient impact of certain shortages. Consequently, managing stock needs is ideally orchestrated in cooperation with healthcare practitioners alongside patient organizations. Historical shortages of enzyme replacement therapies ignited international initiatives aimed at prioritizing patient needs, for instance, within the context of Gaucher disease (Hollak et al.). Similarly, though committees have been set up to establish prioritization criteria for verteporfin, these initiatives have predominantly unfolded at the national level (Werkgroep Medische Retina van het Nederlands Oogheelkundig Gezelschap; Société Française d'Ophtalmologie; Royal College of Ophthalmologists; Canadian Ophthalmological Society). In general, cases concerning ocular cancers were prioritized, followed by (functionally) monocular patients facing other retinal disorders. In some countries, retinal specialists were required to validate multimodal imaging with the nomination criteria for their patients.

An additional approach organized by healthcare professionals entails maximizing treatable patient numbers by reducing medication dosages. As previously addressed in this article, employing half-dose PDT has confirmed efficacy akin to standard full-dose PDT in both CSC and PCV contexts. A further decline to one-third-dose PDT was scrutinized in CSC yet demonstrated inferiority compared to half-dose PDT (van Rijssen et al.b). This strategy may enhance the number of patients treated per verteporfin vial.

Possible Preventive Measures for Future Shortages

Medication shortages are a prevalent concern. In 2022, 70 drug shortages surfaced within the Netherlands (Koninklijke Nederlandse Maatschappij ter Bevordering der Pharmacie). At present, MAHs are tasked with developing plans to preemptively address potential shortages (European Medicines Agency). For vital and unique products, incorporating qualified backups along with maintaining sufficient stock levels might prove essential (International Society for Pharmaceutical Engineering). Various European Member States preset minimum stock metrics; for instance, 2.5 months of stock has been recommended in the Netherlands (Koninklijke Nederlandse Maatschappij ter Bevordering der Pharmacie; Tweede Kamer der Staten-Generaal). However, regarding the current scenario, such provisions would have sufficed, as supply stoppages have endured over six months. Furthermore, MAHs may enjoin competitors to amplify production (International Society for Pharmaceutical Engineering). Nevertheless, patent protections and other regulatory exclusivities may restrict competition (Tomas & Peng). As long as patents remain valid, compulsory licensing might be explored, permitting governments to utilize a patented product without consent from the holder (t Hoen et al.). When patent protections lapse, competition posed by generic manufacturers in small patient populations becomes challenging, as manufacturers may not recover investments sufficiently (Beall et al.). As a case in point, the introduction of intravitreal anti-VEGF therapy as a superior treatment for neovascular AMD has drastically reduced the patient population necessitating PDT. This hurdle could potentially be mitigated by innovative public-private partnerships aimed at developing cost-based treatments. Nonetheless, setting up a new verteporfin manufacturing facility in the short-term proved unfeasible (Broekers-Knol). The implementation of any such measures may require financial outlays and could result in price increases.

Conclusions

The verteporfin deficit cascading from production inconsistencies at the singular manufacturing facility has profoundly influenced ophthalmological practices and patient outcomes on a global scale. PDT maintains a focal role in treating various chorioretinal afflictions, largely utilized off-label in scenarios where no fully equivalent alternatives exist. Consequently, this prolonged verteporfin inadequacy may have led to substantial and irreversible vision loss worldwide. Efforts should be initiated promptly to prevent future occurrences of such shortages.

Supporting information

Appendix S1. The questionnaire on the verteporfin shortage that was sent to key opinion leaders in medical retina from around the world.

Click here for additional data file.(26K, docx)

Notes

None.

NR and CEMH are associated with the platform ‘Medicine for Society’, an academic initiative focusing on sustainable access to medicines for rare diseases, funded by the National Postcode Lottery.

CMGC: Bayer, Novartis, Roche; IC: Genentech; CME: Bayer, Novartis, Roche; KBF: Bayer, Genentech, Novartis, Regeneron, Roche; FGH: Bayer, Genentech, Novartis, Roche; PKK: Bausch + Lomb, Bayer, Novartis, Regeneron; GQ: Bausch + Lomb, Bayer, Novartis, Roche; RT: Bayer, Genentech, Novartis, Roche; CCW: Bausch + Lomb; ROS: Bayer, Novartis. MJS, EHCvD, NR, CEMH, SA, AJL, KOM, YS, DZ, RMHD and CJFB report no relevant conflicts of interest.

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