Learning how to use the slit lamp is not easy. I think as ophthalmologists we take this skill for granted and forget the journey we undertook to master basic examination techniques. I vividly remember sitting in the clinic during my ophthalmology rotations as a medical student and wishing I could see what the consultant was seeing.

When I was asked to have a look through the slit lamp, I often ended up nodding and smiling to avoid the embarrassment of admitting that I had no idea what I was looking at. (The patient had probably moved their eye and what the consultant had wanted me to see was no longer in the field of view.) 

On rare occasions, an observer tube was connected to the slit lamp and, although this was somewhat useful, one had to be careful to not have it bang into one’s eye while crouching uncomfortably beside the slit lamp.

I had a revelation at the beginning of my ophthalmology residency some years ago when I witnessed the use of an anterior segment camera. Why not use this camera to teach people how to use slit lamps?

My consultants at the time seemed indifferent to this suggestion but one of my seniors agreed with me. So when the camera was not in use (the vast majority of the time), we used it in the clinic. It helped me to develop my clinical skills and I found it particularly useful for learning how to examine the cornea and recognize a huge variety of pathologies.

With the consent of the patients we saw, I made a video library, which I attached my notes to. Feeling vindicated, as well as passionate about the benefit of slit lamp cameras for ophthalmic education, I fought for a grant for teaching on slit lamps after securing a loaned device for a few months.

The feedback from junior doctors, nursing colleagues, and medical students was overwhelmingly positive. We even managed to connect a virtual reality headset to a beam splitter/slit lamp camera with real-time video output to create an immersive viewing experience. This set-up was presented at the American Academy of Ophthalmology meeting in 2018.

We were successful in securing funding of almost $19,000 to purchase a MediWorks digital slit lamp, and I spent just over a year using this system before having to move on to a new hospital as part of my registrar rotations in southwest England. We made the most of the time we had and I set up a YouTube channel with the support of my friends and colleagues, amassing thousands of followers. Some videos have received almost a million views.

When I moved to my new rotation, I was disappointed to find that, rather unsurprisingly, there was no slit lamp camera. The overwhelmingly complex and high-effort process of applying for funding for a slit lamp camera system was too much to contemplate at that time.

I stumbled across the MicroREC optical system (Custom Surgical) through an advertisement on social media. The device is predominantly used to connect a smartphone to operating microscopes, to allow the user to record surgical videos on their phone. However, it can also connect to slit lamps.

I was lucky enough to have a beam splitter for a Haag-Streit BQ900 slit lamp, which allowed me to use the optical system. I initially combined it with an iPhone 8 and subsequently an iPhone 12 Pro Max, with incredible results.

Normally in a National Health Service hospital in Britain, one is lucky if there is 1 slit lamp with a camera system and even luckier if an ophthalmologist can have their clinic in the room it is located in. I had a 4K slit lamp camera system that I could keep in my bag and use on any slit lamp for less than $1250! I further enhanced the system by adding a diffuse illuminator that I purchased from Eye2Mobile.

Slit lamp imaging is incredibly valuable and it amazes me that it is not seen as a fundamental part of the hospital eye service. Although diagrams in the notes are useful, there is no doubt in my mind that a photo is far more objective and useful when combined with a clinician’s impression of the patient’s condition.

Teaching clinical skills is far easier with the use of a slit lamp camera system: using an Apple TV device I can “cast” a real-time, live view of the slit lamp from my iPhone to a computer monitor. I successfully taught a medical student how to perform a fundus examination in just 1 afternoon, a skill that often takes weeks if not months to learn.

I was also able to teach a nurse practitioner how to perform Goldmann applanation tonometry proficiently over 2 clinics. The practitioner had been sitting in on 1 glaucoma clinic a week over the previous 2 years to try to learn this skill, without success.

Being able to see what the student sees allows one to provide critical, accurate, and useful feedback (eg, that the Myers rings are too thick or that one needs to move closer). Indeed, alignment to the center of the cornea, adjustment of the tonometer, and so on are only possible when one can see what the student is seeing and vice versa. 

With the backlog of patients as a result of the pandemic, we need to focus on how to teach basic clinical skills to junior doctors and allied health professionals in the most immersive and efficient way possible. Slit lamp camera systems or digital slit lamps are a low-hanging fruit that will enable the acquisition of this skill, and we have proved this in a small pilot study.

Having an optical system that allows you to capture procedures while performing them democratizes digital ophthalmic imaging, not just regarding the slit lamp but also in terms of surgical training, for which camera systems for operating microscopes are often prohibitively expensive.

Smartphone cameras are incredible: the quality of photos and videos that can be captured from a mobile phone these days is staggering. The latest devices can capture video in up to 8K for breathtaking quality.

Additionally, with the apps that come with many ophthalmic devices now, one can optimize the videos or photos captured and export or share them in various formats, including a low file size, compressed version, which allows for quick distribution on social media. This removes the need to purchase an additional camera system, and having the videos on one’s own device means they can be shared with colleagues (with patients’ permission, of course) when advice is sought out or watched at home to hone surgical skills.

The ability to conduct remote slit lamp video consultations was something we found particularly beneficial during the peak of the pandemic. I hope that ophthalmologists will increasingly come to realize the importance of digital imaging in clinical ophthalmology. Maybe in the future we will laugh at how we used to make diagrams on paper notes with colored pencils while reviewing slit lamp videos on 8K TVs.

Mamtora is an ophthalmology academic specialist registrar at Bristol Eye Hospital, England; chair of the Ophthalmologists in Training Group of the Royal College of Ophthalmologists; and host of the Eye to Eye podcast. He has no relevant financial disclosures.

1. Smith C. Teaching ophthalmology: mastering the slit lamp examination. 

Inspire Student Health Sciences Research Journal. 

Winter 2020. https://inspirestudentjournal.co.uk/wp-content/uploads/2020/10/Inspire-Student-Journal-Chanelle-Smith.pdf

Articles

This affordable device allows the view through a slit lamp to be shared in real time or recorded, for teaching and reference purposes.

Achieving high-definition slit lamp imaging via smartphone mirroring

Pierre-Henry Gabrielle, MD, PhD, fromthe University of Sydney School of Medicine, Discipline of Ophthalmology; Save Sight Institute, New South Wales, Australia; and the Department of Ophthalmology, Dijon University Hospital, Dijon, France, and colleagues from other European and Australian institutions reported that a comparison of ranibizumab (Lucentis; Genentech) and aflibercept (Eylea; Regeneron Pharmaceuticals) showed that both drugs are safe and effective for treating diabetic macular edema (DME).

The investigators retrospectively analyzed treatment-naive eyes with DME in which intravitreal treatment with either of the 2 medications (ranibizumab 0.5 mg or aflibercept 2 mg) began between January 1, 2013, and December 31, 2017. All data were collected in the Fight Retinal Blindness! registry.

A total of 534 eyes of 402 patients were included. Ranibizumab was injected intravitreally into 267 eyes and aflibercept into 267 eyes.

In this real-world observational study, data showed that the longitudinal adjusted visual acuity change over the 3-year period between ranibizumab and aflibercept using all eyes differed significantly (

< .001). However, the investigators believe that this was the result of the significantly larger gains achieved with aflibercept in the first 12 months. “The adjusted visual acuity change at 3 years after this initial superiority had diminished was similar,” they said, ie, adjusted visual acuity change +1.6 (−0.1 to 4.2) letters for ranibizumab compared with +2.4 (−0.2 to 5.1) letters for aflibercept.

However, the adjusted mean changes in the central subfield thickness (CST) remained significantly (

 < .01) different throughout the 3-year period in favor of aflibercept, ie, −87.8 microns (range, −108.3 to −67.4 microns for ranibizumab) compared with −114.4 microns (range, −134.4 to −94.3 microns for aflibercept). 

The investigators also reported that when patients had moderate baseline visual impairment (visual acuity ≤ 68 Early Treatment Diabetic Retinopathy Study letters), the vision improved faster in eyes treated with aflibercept up until 18 months of treatment compared with eyes treated with ranibizumab, which then stayed similar until 36 months of treatment. No difference was observed in patients with mild baseline visual impairment (visual acuity ≥ 69 Early Treatment Diabetic Retinopathy Study letters).

They concluded: “Aflibercept and ranibizumab were both safe and effective for DME over 3 years in daily practice, although aflibercept had better anatomical outcomes. The faster and larger visual gains at 1 year observed in eyes treated with aflibercept when the presenting visual impairment was moderate (visual acuity ≤ 68 letters or 20/50) were no longer significant by 18 months as already described in a [randomized clinical trial (RCT)].The medium-term real-world treatment outcomes of ranibizumab or aflibercept for DME seemed to be somewhat inferior to those reported in RCTs.”

1. Gabrielle PH, Nguyen V, Creuzot-Garcher C, et al. Three-year treatment outcomes of aflibercept versus ranibizumab for diabetic macular edema. Data from the Fight Retinal Blindness! registry. 

, 2022;42(6):1085-1094; doi:10.1097/IAE.0000000000003428

The investigators retrospectively analyzed treatment-naive eyes with DME which received intravitreal treatment with either ranibizumab 0.5 mg or aflibercept 2 mg. All data were collected in the Fight Retinal Blindness! registry.

Fight Retinal Blindness! registry data: Ranibizumab and aflibercept safe for treating DME over 3 years

Dry eye disease (DED) was first defined in 1995. Since then, its definition has been revised to include a complex, multifactorial etiology that includes hyperosmolarity, tear film instability, ocular surface inflammation and damage, and neurosensory abnormalities.

A characteristic feature of DED is disruption of the epithelial barrier at the ocular surface. Exposure of the corneal epithelium to increased osmolarity promotes inflammation, causing a cascade of events leading to apoptosis. Neurogenic chronic inflammation and disease severity worsen with inflammation induced by tear film instability and hyperosmolarity.

Cryopreserved amniotic membrane (CAM) is a promising therapy for corneal nerve regeneration and accelerated recovery of ocular surface health in patients with DED. CAM helps to improve a number of problems, such as pain, corneal staining, overall dry eye signs and symptoms (eg, discomfort, visual disturbances), corneal nerve density, and corneal sensitivity.

CAM is a biologic corneal bandage designed to treat damaged corneas by creating an environment for regenerative healing. Prokera is the only FDA-cleared CAM product and supports the corneal healing process without harmful adverse effects. With early intervention, its CryoTek preservation method maintains full biologic components to help rapidly restore the cornea’s own healing capabilities.

Ocular surface disease (OSD) is an underrecognized and underappreciated problem that is difficult to treat. It often affects the cornea, and treating it is not in the typical retina specialist’s skill set. Anti-VEGF therapy has become the standard of care for treating macular edema and a range of other retinal diseases. However, intravitreal (IVT) injections require proper access and antiseptic techniques, which can cause corneal problems.

Betadine is the biggest culprit. Although it has a good track record of being a great antimicrobial and antiseptic, it can cause corneal toxicity, especially with repeated use. When patients have postinjection pain, it’s typically related to ocular surface disruption due to the betadine application. Although patients complain about the pain of the IVT shot at first, this quickly dissipates, and it’s common for patients to call in even after a few hours following injection, when they suddenly notice incredible pain (usually from the betadine) in their eye.

I have made some modifications in my practice. Rather than using a lot of betadine all over the eye, I use a more targeted approach. In some patients, for example, I will soak a Q-tip in betadine and place it over the affected area.

OSD symptoms are rarely due to nonadherence. Instead, when patients read, watch TV, drive a car, or use a computer, they stare; and when they stare, they don’t blink, which exacerbates OSD symptoms. This eventually leads to DED and OSD. Patients who undergo IVT therapy are more likely to have blurry vision due to their retinal pathology. It is human nature to stare when you don’t see well.

When patients present with dry eyes, I tend to start them on artificial tears. If a patient shows persistent signs and symptoms despite using tears frequently, then I use punctal plugs. If the patient is having dry eye problems and needs IVT shots, this process may exacerbate their symptoms. If the patient is very symptomatic, I would potentially give the patient a trial of Prokera or anther amniotic membrane. I explain that it may be uncomfortable for a few days butit’s going to give them between 9 and 12 months of relief. Although this isn’t a perfect solution, we do not have an approved alternative to betadine at this time, so we’re trying to make the best of the situation.

I prefer this algorithm because we start with trying therapies that are least invasive and most cost-effective first, and then if these do not work, we move our way up. This process also increases adherence in patients who need injections to maintain their vision.

I like CAM because I know that, when I put it on, it is centered on the cornea. The problem with other amniotic membranes is that they may fold or not fit well, requiring a lot of logistics, which makes the process more complicated. Amniotic membranes are not something I do on a daily basis as a retina specialist, so using CAM makes the process much easier, even if it’s a bit more uncomfortable for some patients. CAM is easy and fast, and I know I’ve done it right. Retina clinicians are pretty busy, so anything to make the process easier with the least amount of hassle is better for me and my patients.

CAM is for patients who continue to complain about their OSD signs and who are symptomatic, even though they’re using drops and plugs. These are high-need, corneal-sensitive patients. CAM won’t change the IVT therapy patients undergo, but it will make it better.

Although we are not looking to replace the general ophthalmologist or cornea specialist in managing DED, once patients start with retina specialists, most don’t see their regular ophthalmologist routinely. Retina specialists should understand that what they do can contribute to worsening dry eye. At minimum, we can recommend artificial tears for all our patients, and if they have persistent signs and symptoms, we might continue moving up the algorithm I described. Of course, conferring with their referring eye care provider is very important, as different providers have varying views on who should manage these patients’ DED.

Retina specialists need to be more aware of OSD and what patients are going through. They also need to know that giving IVT shots can have unintended consequences. One of the secondary benefits of managing DED is that retina specialists will end up with higher patient adherence. One long-term issue with current therapies is that patient adherence wanes over time. Patients don’t want to come into the doctor’s office several times. If the process of getting an IVT injection is more comfortable, then we will have better patient adherence and better outcomes, which make our patients, their family, and our community better.

1. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and classification report. 

. 2017;15(3):276-283. doi:10.1016/j.jtos.2017.05.008

2. Bron AJ, de Paiva CS, Chauhan SK, et al. TFOS DEWS II pathophysiology report. 

. 2017;15(3):438-510. doi:10.1016/j.jtos.2017.05.011

3. John T, Tighe S, Sheha H, et al. Corneal nerve regeneration after self-retained cryopreserved amniotic membrane in dry eye disease. 

. 2017;2017:6404918. doi:10.1155/2017/6404918

4. Prokera. BioTissue. Accessed May 19, 2022. 

CAM encourages corneal healing in patients with ocular surface disease.

Exploring cryopreserved amniotic membrane following intravitreal injection

Growth in the clinical and commercial development of gene therapies for retinal degenerative diseases has been explosive over the past decade. The rapid expansion of the field has been led by dramatic vision restoration for virtually blind patients made possible by voretigene neparvovec-rzyl(Luxturna; Spark Therapeutics), which the FDA approved in December 2017. It is the first gene therapy for the eye or any inherited retinal disease to cross the regulatory finish line in the United States. Developed by gene therapy pioneer Jean Bennett, MD, PHD, for children and adults with Leber congenital amaurosis (LCA) or retinitis pigmentosa (RP) caused by biallelic RPE65 mutations, the therapy provided immediate and impressive vision improvements in a phase 1/2 clinical trial at Children’s Hospital of Philadelphia. Those initial results, reported in 2008, sent a strong signal to investigators and biotechnology companies that gene therapy could be a powerful modality for treating retinal diseases. 

Now, dozens of companies are in the retinal gene therapy development space and more than 20 clinical trials for genetic therapies are underway for patients with a broad range of retinal degenerative diseases. These include RP, LCA, choroideremia, achromatopsia, and the dry and wet forms of age-related macular degeneration (AMD).

The Foundation Fighting Blindness, the world’s leading private funder of retinal degenerative research, has played a pivotal role in advancing retinal gene therapies into clinical development. As an early funder of the modality for myriad retinal diseases, the foundation began investing in RPE65 gene therapy research back in the mid-1990s and ultimately invested $10 million in the research that eventually led to voretigene neparvovec.

“We were very early adopters, recognizing that the retina was an ideal gene therapy target. It’s a small, accessible piece of tissue, and many conditions that affect the retina are monogenic. We knew that if we could directly address the patient’s mutated gene by augmenting or modifying its activity, we had an excellent opportunity to save and restore vision,” said Benjamin Yerxa, PhD, chief executive officer at the foundation. “Furthermore, we see gene therapy’s potential for gene-agnostic applications such as neuroprotection and optogenetics to help a broad range of patients, regardless of the mutated gene causing their vision loss.”

The foundation currently funds a broad range of gene therapies and other treatment modalities at both early and late stages of development. Its RD (Retinal Degeneration) Fund, a venture philanthropy fund with nearly $120 million in commitments, was launched in 2018 to help investigators and start-up companies move their emerging therapies into and through early-stage clinical trials. The fund’s goal is to attract additional investments from pharmaceutical and biotechnology companies to fund the more expensive, late-stage trial phases. Furthermore, all returns on the fund’s investments are put back into the foundation to support additional research and investments. 

“The ultimate goal of the RD Fund is to get more treatments across the finish line and out to patients. We can’t afford to fund late-stage clinical research, which often costs a hundredmillion dollars or more, but we can afford the earlier-stage research to attract those major investments from biotechs and big pharma,” said Yerxa.

In fall 2021, the RD Fund took the bold step of launching its own company, Opus Genetics, to develop gene therapies for orphan retinal diseases, those rare conditions that weren’t being addressed by other companies. Opus’ $19 million in seed financing included investments from the Manning Family Foundation and Bios Partners. Its first 3 targets are for LCA caused by mutations in 

. The LCA5 and RDH12 therapies were developed preclinically by Opus cofounder Bennett and licensed from the University of Pennsylvania. The NMNAT1 treatment was developed in the laboratory by cofounder Eric A. Pierce, MD, PhD, and licensed from Harvard Medical School’s Massachusetts Eye and Ear. Opus plans to launch a clinical trial for 

 by the end of 2022. In April 2022, the company signed a collaboration agreement with Resilience to provide manufacturing services for its gene therapy pipeline.

In October 2020, the RD Fund realized its first financial win when Novartis acquired Vedere Bio for around $280 million. In 2019, the fund had helped launch Vedere Bio to advance an optogenetic therapy developed by its scientific cofounders John G. Flannery, PhD, and Ehud Isacoff, PhD, from the University of California, Berkeley. The investigators’ approach––a gene-agnostic gene therapy––provides potential vision restoration for patients who have lost all their photoreceptors to a condition such as RP by delivering a gene that expresses a light-sensing green cone opsin in surviving ganglion cells. In essence, the treatment enables ganglion cells to work like a back-up system for lost photoreceptors. The approach holds promise for restoring vision for patients who are completely or nearly blind, regardless of the mutation causing their disease. A new incarnation of the company, Vedere Bio II, was subsequently launched after the Novartis acquisition to continue development of other retinal gene therapies.

Also in 2020, the RD Fund invested in the gene therapy start-up Atsena Therapeutics, which reported early, encouraging vision improvements for 3 patients in a phase 1/2 clinical trial for its LCA (

 mutations) gene therapy. Cofounded by Shannon E. Boye, PhD, and Sanford L. Boye, MS, both of the University of Florida in Gainesville, Atsena also has preclinical gene therapy programs for X-linked retinoschisis and Usher syndrome type 1B.

SparingVision, another RD Fund investment, is planning to launch a clinical trial in 2022 for its gene-agnostic, cone-preserving therapy for patients with RP, Usher syndrome, and related conditions. Nearly 2 decades ago, José-Alain Sahel, MD, and Thierry Léveillard, PhD, investigators from the Institut de la Vision in Paris, France, identified a protein secreted by rod photoreceptors that is critical to the survival of cones. Aptly named rod-derived cone-viability factor, it is the protein expressed by SparingVision’s cone-preserving gene therapy. The company is also developing a gene therapy that restores light sensitivity to cones that have lost their ability to process light due to advanced forms of RP, Usher syndrome, and related diseases.

The RD Fund’s other gene-related therapy investments include SalioGen Therapeutics, whose Saliogase technology seamlessly inserts new DNA of any size (eg, the Stargardt disease gene 

) into precise, defined genomic locations. The fund also invests in ProQR Therapeutics, which has an RNA therapy in a phase 2/3 clinical trial for individuals with Usher syndrome 2A and nonsyndromic RP caused by mutations in exon 13 of the 

“We are off to a great start with our investments and working to continue to expand our portfolio with the strategy of investing in strong science being developed by well-managed companies,” said Yerxa. “I think our coinvestors recognize and appreciate our commitment to making every shot on goal really count.”

Foundation Fighting Blindness is a driving force in advancing retinal gene therapies into clinical trials.

Gene therapy: Where the action is for retinal diseases

A recent independent survey of retina specialists provides insights on their perspectives regarding the management of macular edema associated with noninfectious uveitis. The survey was conducted by 

The survey was prompted by the availability of triamcinolone acetonide injectable suspension (Xipere) for suprachoroidal use as a new modality for treating uveitic macular edema. The survey polled over 100 retina specialists across the United States, and the questions were designed primarily to assess clinicians’ views on the current standard of care for treating macular edema associated with noninfectious uveitis and retina specialists’ knowledge about alternative drug delivery methods, including suprachoroidal injections.

The results showed that the respondents overwhelmingly see a need for alternative options to treat the condition that represents the most common sight-threatening complication of noninfectious uveitis. In addition, the survey demonstrated the clinicians had strong interest in learning about drug delivery via the suprachoroidal space.

Overall, 90% of the retina specialists who participated in the survey agreed that there is a need for alternative treatments for patients with macular edema associated with noninfectious uveitis, and 94% of the respondents were interested in finding out more about drug delivery via the suprachoroidal space. Approximately one-third of the retinal specialists indicated they were “extremely interested” in learning more about suprachoroidal drug delivery, and 51% said they were “very interested”.

Responses to questions focusing specifically on the suprachoroidal route for drug delivery showed that 85% of the surveyed retina specialists consider it an option for treating macular edema associated with noninfectious uveitis. Almost half of the respondents (48%) agreed that this novel method of drug administration may facilitate targeted delivery of therapeutic agents to the retina and choroid.

The procedure for administering a suprachoroidal injection is distinctly different than the intravitreal injection procedure. Perhaps it is not surprising, therefore, 55% of respondents cited the need for training as an important factor for the integration of suprachoroidal administration into clinical care. Case studies and more information were identified as important factors for supporting adoption of the novel drug delivery approach by 39% and 33% of survey respondents, respectively. Patient access was noted to be an important factor by 29% of the retina specialists and 23% identified a need for patient education.

Eighty-nine percent of the retina specialists who participated in the survey were open to receiving training on the suprachoroidal injection technique. The survey results showed wide variation in their preferences for receiving the training. Although the retina specialists’ responses indicated significant interest in several different educational formats, they overall favored in-person programs.

Of the retina specialists who indicated interest in receiving training on suprachoroidal administration, the largest proportion (54%) preferred to receive it via in-person wet lab sessions, 45% preferred attending in-person workshops, 44% preferred in-person training demonstrations, and 29% favored live programs at conferences.

Nearly half of the respondents open to training expressed interest in online webinars with clinicians, 36% said they preferred virtual trainings, and 25% favored online workshops. Sizeable proportions of the retina specialists who were open to receiving training on suprachoroidal injection indicated preferences for at-home (nonweb-based) formats that could consist of using at-home study modules (38%); a demo kit providing answers to frequently asked questions, a brochure, and video (31%); or at-home training using materials received through the mail (27%).

Triamcinolone acetonide injectable suspension for suprachoroidal injection was approved by the FDA for the treatment of macular edema associated with uveitis in October. It is the first and only treatment approved for injection into the suprachoroidal space.

Free training on the suprachoroidal injection technique is available through Bausch + Lomb. Ophthalmologists interested in attending a Xipere training session can register online at 

https://www.xipere.com/hcp/xipere-training

Survey respondents point to a perceived gap in treatments for uveitic macular edema, document interest in suprachoroidal drug delivery. 

Survey: Retina specialists see need for alternative treatments for macular edema associated with noninfectious uveitis

I have been on the faculty at Bascom Palmer Eye Institute for nearly 6 years since completing my fellowship in 2016. I love being an academic retina specialist because it enables me to manage complex cases in a collaborative manner while also being involved in teaching and research at a level that might not always be feasible in a private practice setting. Regardless of practice type, the patients we see are similar—those with macular degeneration or diabetic retinopathy, for example, and those seeking surgical consultations. But in the university setting, we see more patients coming for third and fourth opinions, often from great distances. I thrive on that complexity and the opportunity to work with other specialists as well as trainees.

With medical students around, a lot of teaching is woven in with patient care. This requires some delicacy in the patient interaction and can slow things down a bit. But the reward is ongoing learning and access to the fresh perspective that students, residents, and fellows can bring. Additionally, we get to work alongside glaucoma, cornea, and other retina colleagues to manage complex cases.

These challenging cases are gratifying because of the collaboration: a huge benefit of academic practice is having access to other specialties in the same institution, under one roof. In addition, ideally, this mode of care enables us to come up with the best treatment plan possible for these underserved patients.

If a treatment that addresses a retinal issue also exacerbates the patient’s glaucoma, for example, there may not be a straightforward solution, so close collaboration helps us ensure we have accurately weighed the risks and benefits. The best way to address these cases is through extensive communication, investing time even before or after clinic hours to talk to colleagues, send notes, and make sure everyone is on the same page. An advantage of being in the same building is that I can sometimes pick up the phone and walk a patient over to see a colleague in the cornea or glaucoma service.

For example, recently I took care of a patient with complex and rare polymicrobial delayed postoperative endophthalmitis and retinal detachment after cataract surgery. With multiple retinal surgeries, the infection has cleared and the retina is attached; however, the patient’s cornea has decompensated and I am now working with one of my cornea colleagues 2 floors up on a plan for partial corneal transplantation.

In academia, we deal with a certain level of bureaucracy that may not exist in a private practice setting, so we give up some degree of control in exchange for other positive aspects of academic practice. On the other hand, we do not have to worry as much about managing employees, office overhead, rent, and staffing as someone in private practice might. In addition, we often have more opportunities to attend and present at conferences and greater access to educational activities, whether as a teacher or learner.

The clinic workload may also be somewhat less in academic vs private practice settings. I am in my own private clinic 2 days per week on average, whereas those in private practice may be in clinic 4 to 5 days per week. On my clinic days, I typically have 50 to 60 patients scheduled, of whom about 90% show up. I operate on an average of 1 day a week, and I spend 1 full day staffing a resident retina clinic. Finally, I have an average of 1 “academic” day per week, which is typically filled with administrative responsibilities for our fellowship and residency programs, clinical research, add-on surgical cases, and lectures for medical students. 

My advice for those who may want to explore academic retina practice would be to think about the “why.” There are many advantages to being in private practice and some challenges inherent to the academic setting, so people who will thrive in academic retina are typically passionate about teaching, seeing complex and tertiary referral-type cases, and being involved in multidisciplinary care. We are fortunate as retinal specialists that research is possible in both the academic and private worlds; however, basic science and translational projects are typically easier to access in the university setting.

A window into the world of academic retina practice today.

Practice perspective: Academic retina 

Today, more than 50% of patients with wet age-related macular degeneration (AMD) are treated off-label with repackaged intravenous bevacizumab (Avastin) that was formulated and packaged for oncologic use. This anti-VEGF chemotherapy agent is approved for systemic administration in multiple cancers but has no approved indications in ophthalmology, despite its widespread use in treating a variety of retinal diseases. 

Other anti-VEGF therapies that are FDA approved specifically to treat retinal diseases—including ranibizumab (Lucentis), aflibercept (Eylea), brolucizumab-dbll (Beovu), and faricimab-svoa (Vabysmo)—are much more expensive than off-label bevacizumab. The result: Many clinicians are forced by insurance companies to use the much-less-costly systemic bevacizumab for many of their patients.

Because bevacizumab is not intended or packaged for intravitreal injection, it must be obtained from compounding pharmacies to be used in the eye. These pharmacies repackage very small quantities of oncologic bevacizumab into syringes for intravitreal injection for conditions such as wet AMD, diabetic macular edema, and branch retinal vein occlusion.

Although these repackaged bevacizumab syringes appear to satisfy an urgent clinical and financial need for patients with a variety of retinal disorders, they are known to be associated with considerable public health concerns due to the risks posed to patients from compounding pharmacies’ lack of compliance with a variety of FDA requirements. This article will examine some of the dynamics of repackaging bevacizumab into syringes for intravitreal use and suggest a way to eliminate these risks to allow physicians to continue to use bevacizumab for their patients.

What is repackaging, and why does the FDA allow it?

Pharmacy compounding, including repackaging, is permitted under FDA regulations when a physician prescribes medication for an individual patient that is unavailable commercially in the dosage and/or form needed by that individual patient. Examples of compounding include creating liquid formulations of medications that a baby or older patient cannot swallow in solid form. Bulk compounding of medications is not legal if the medication is commercially available (eg, FDA approved) in a form or dosage that is appropriate to treat the patient.

In the case of repackaged systemic bevacizumab, with no approved ophthalmic formulation, the only way for retina specialists to use the drug for intraocular injection is through off-label pharmacy repackaging. Compounding pharmacies aliquot small doses to create prefilled syringes of bevacizumab from a large vial for intraocular injection. Through this mechanism, retina physicians have relied on repackaged systemic bevacizumab for nearly 15 years to provide a cost-effective anti-VEGF therapy to their patients.

Although repackaged bevacizumab has helped millions of patients maintain and even improve vision for a variety of previously blinding retinal disorders, the approach may, nonetheless, unavoidably put patients at risk. This situation is largely due to the process of drawing up multiple syringes from a single vial, as well as to the fact that bevacizumab—developed and packaged for oncologic use—is not formulated to meet the FDA’s specific standards for ophthalmic injectables. The agency’s chemistry manufacturing and controls standards are an integral part of the FDA requirements for any drug approval, and the syringes that contain aliquoted bevacizumab have not undergone this rigorous review and vetting.

Typically, 70 to 80 separate aliquots are taken from one bevacizumab vial and repacked for intraocular use. This repetitive process opens the door to contamination; one of the most serious risks from contamination is bacterial endophthalmitis. Unfortunately, cases of endophthalmitis caused by repackaging of bevacizumab have been reported.

Other problems can also present. The repackaging process relies on human judgment as to the quantity of drug aliquoted into each syringe, and given that only a tiny amount is needed, even a small variation due to human error can significantly affect the actual dosage that a retina patient eventually receives. Studies

 have shown that prefilled syringes vary in terms of how much bevacizumab is provided, with underdosing being common; the impact of underdosing, of course, is that patients may appear not to be responding appropriately to treatment, when in fact they simply may be receiving a subtherapeutic dose of the anti-VEGF medication. Other risks derive from lack of FDA-reviewed analytical methods, specifications, drug stability data, unknown quantities of particulates or bacterial endotoxins, unverified FDA-approved pH levels, or even the temperatures at which the syringes are filled, stored, and shipped. Faulty performance along any of these dimensions can damage the molecule and compromise its safety and efficacy.

The syringes used to draw up an aliquot of bevacizumab can also introduce problems, including precipitating agglomerations of the molecule’s proteins such that the osmolarity of the drug solution in the aliquoted vial is compromised.

 Moreover, the prefilled syringes themselves often do not meet the FDA’s standards for ophthalmic injectables, may contain silicone lubricant that can be expelled into the eye and cause permanent visual obstruction and increases in intraocular pressure,

 or are not ophthalmic syringes at all but rather ones created for other uses (such as insulin injection). There are no standards or guidelines for the syringes containing repackaged bevacizumab.

When the FDA approves a drug for commercial marketing, in addition to establishing safety and efficacy, it also reviews and regulates the actual manufacturing process, the specific manufacturing equipment employed, and the packaging that will be used for the finished drug product. Current Good Manufacturing Process, or cGMP, is the global gold standard for pharmaceutical manufacturing and a threshold that must be met to secure FDA approval. The FDA demands that manufacturers of approved medications comply with all cGMP protocols. Repackaging pharmacies may not abide by cGMP standards when individual syringes are drawn for intraocular use.

In the interests of providing their patients with a proven anti-VEGF therapy at a more workable price point than is possible with the currently approved anti-VEGF retinal therapies, physicians have long relied on repackaged bevacizumabfrom compounding pharmacies—and indeed the molecule has proven itself a valuable therapy for many years. But a solution to the risks that repackaging entails, as delineated above, would be a bevacizumab molecule that is specifically developed and optimized to meet all the FDA’s rigorous requirements for an ophthalmic injectable, manufactured in a cGMP facility, packaged with a vial or syringe specifically designed for ophthalmic use, and introduced into the market via the established supply chain.

Such a product would bring retina physicians and their patients a safe and effective FDA-approved option, using a trusted and well-understood molecule, that mitigates the risks they currently face from repackaged bevacizumab from compounding pharmacies.

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http://www.fda.gov/NewsEvents /Newsroom/PressAnnouncements/ucm345019

3. US Food and Drug Administration. Drugs: FDA alerts health care professionals of infection risk from repackaged Avastin intravitreal injections. 

http://www.fda.gov/Drugs/Drugsafety/ucm270296

4. Sheyman AT, Cohen BZ, Friedman AH, Ackert JM. An outbreak of fungal endophthalmitis after intravitreal injection of compounded combined bevacizumab and triamcinolone. 

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Although off-label repackaged bevacizumab syringes appear to satisfy an urgent clinical and financial need for patients with a variety of retinal disorders, they are known to be associated with considerable public health concerns due to the risks posed to patients from compounding pharmacies’ lack of compliance with a variety of FDA requirements.