Friday, November 16, 2012

Avastin/Lucentis Update 53: Latest Information on Contaminated Re-Packaged Avastin

Last Summer and Fall, I wrote two reports on the contaminated re-packaged Avastin that caused severe eye problems in some patients that received intravitreal injections for the treatment of their wet form of AMD (Avastin/Lucentis Updates 48 & 49).

This year, with all of the news about the meningitis outbreak, including several dozen deaths, caused by non-sterile compounding of a drug to treat back pain by a so-called compounding pharmacy, located in my home state of Massachusetts, and with a report presented at this year’s AAO Meeting about the contaminated Avastin from a Florida compounding facility that caused the loss of sight of several patients, I decided that an update was in order.

Here then is the report from MedPage Today by Kristina Fiore about the presentation made by  Roger Goldberg, MD, of the University of Miami, and colleagues, at the Retina Sub-Specialty Day, prior to this year’s AAO Meeting in Chicago, "Long-term outcomes of Streptococcus endophthalmitis outbreak after intravitreal injection of bevacizumab" AAO 2012; Abstract PA062.

By Kristina Fiore, Staff Writer, MedPage Today       
Published: November 15, 2012

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston

CHICAGO - All but one of 12 patients given injections of contaminated bevacizumab (Avastin) prepared by a compounding pharmacy in Florida permanently lost vision in the affected eye, researchers reported here.

Neither early nor late vitrectomy improved visual outcomes, and seven patients lost their eye completely in the endophthalmitis outbreak that occurred in Miami in July 2011, Roger Goldberg, MD, of the University of Miami, and colleagues reported at the American Academy of Ophthalmology meeting.

Ophthalmologists are "very reliant on compounding pharmacies, not just for Avastin but for all preservative-free formulations and intravitreal antibiotics," Goldberg said. "So to some extent we need to figure out ways to safely prepare these medications," he continued. "And it obviously begs the question that's been the main story here -- how to best ensure medications that pass through compounding pharmacies are safe."

Compounding pharmacies have come under increased scrutiny, including congressional hearings, with the ongoing meningitis outbreak -- 461 cases and 32 deaths -- caused by injections of contaminated methylprednisolone acetate made by a compounding pharmacy in Massachusetts.

Oversight of these entities currently falls to the states, but legislators have been calling for stronger federal regulation, including giving FDA clearer authority over compounders.

In the Miami endophthalmitis outbreak, Goldberg said 12 patients arrived in the ophthalmic emergency department within 6 days of getting an intravitreal injection of bevacizumab - nine of them arrived within 48 hours of having the shots. They'd all been treated by four community retina specialists in Miami-Dade and Broward counties over 4 days, and all of the bevacizumab syringes had been prepared by a single compounding pharmacy, Goldberg said.

Cultures for 10 patients came up positive for Streptococcus mitis or oralis, matching the strains in seven unused syringes prepared during the same time by the compounder.

An FDA investigation of the company revealed insufficient testing and monitoring of equipment, dirty lab equipment, a failure to maintain sterilization tools, and a leaking boiler near the clean room.

Compounders have been at the center of other contamination issues. Earlier this year, Franck's Compounding Lab in Ocala, Fla., was linked with 33 cases of fungal infections resulting from intravitreal injections of Brilliant Blue G dye and triamcinolone.

Goldberg told MedPage Today that with the rise of expensive, branded intravitreal anti-VEGF agents that come in appropriate doses, such as ranibizumab (Lucentis), the "need for Avastin syringes safely aliquoted from 4- or 16-ml vials into the tiny doses used in the eye has further increased our reliance on compounding pharmacies and the critical role they play in the care of our patients."

But therein lies the increased risk of contamination, according to Joel Zivot, MD, director of the cardiothoracic ICU at Emory University Hospital Midtown in Atlanta, who wasn't involved in the study. "Every time something that is sterile is handled, the opportunity for contamination increases. It would be impossible to get the contamination rate to zero," Zivot said. "Perhaps what will be needed are further safeguards on the prescribing side, including some testing to reduce the chance of delivering a contaminated product to the patient."

Goldberg warned ophthalmologists to thoroughly check out a compounding pharmacy before they buy from it, doing their best to ensure the company is in compliance with USP-797, the current national standard of practice. He added that clinicians should also document all lots of the drug and syringes they buy, as well as keep accurate patient contact records in case they need to be notified quickly.

Wiley Chambers, MD, of the FDA, who was in the audience when the data were presented, noted that one patient had bilateral administration of bevacizumab, but one eye did not get infected. That's because only one of the syringes was from the contaminated compounder, Goldberg said. The other, a last-minute addition, came from a different compounding pharmacy.

"Perhaps the lesson," Wiley said, "is never use the same lot for bilateral injection."

Goldberg agreed, but noted that greater, coordinated oversight in terms of safety is the ultimate goal. "The most concerning feature to me is that compounding pharmacies are regulated by the state, and states have different rules, regulations, and commitments to oversight and enforcement," he told MedPage Today. "This introduces unwanted variation into the compounding process."

Goldberg reported no conflicts of interest.

Primary source: American Academy of Ophthalmology

In discussing this problem of obtaining sterile packages of drugs to be used in the eye with Ed Timm, President and CEO of Moibus Therapeutics, a commercial stage venture focused on supplying ophthalmic surgery solutions, including Mitosol®, a system for delivering antifibrotic agents in glaucoma, refractive, and corneal surgery, he suggested the following steps:

“In addition to insuring integrity of product sourced from compounders, it is my belief that two other things need to be done:

1. Pharma needs to stop only swinging for the fences and create sterile, approved formulations of standardized products currently prepared by compounders. Volumes are modest, so the resulting revenue will be equally modest. However, being part of this industry means that we embrace a certain inherent trust with respect to our obligations. We need to solve these problems, create sterile products that meet the highest standards, then do the heavy lifting to take them through FDA and then bring them to market.

2.  Compounders often speak of the essential triad to their mission: the physician, the patient, and the pharmacy. This continuum of care should in no way be interrupted. On the contrary, these specialty pharmacies should remain an integral part of this supply chain, thereby maintaining an efficient and expedient way of reaching these patients. Mobius currently utilizes two specialty pharmacies in such a manner, as they serve as our third party logistics. Both of these pharmacies also compound products for patients, but have embraced an expanded vision of the aforementioned triad.”

Tuesday, November 06, 2012

Gene Therapy in Ophthalmology Update 15: First Gene Therapy Treatment Approved!

As I first wrote back in July (Update 12: First Gene Therapy Approval on the Horizon), the first approval of a gene therapy application in medicine was expected soon. It has now been accomplished. On November 2nd, the European Medicines Agency gave final approval to a gene therapy approach to treat a rare genetic disease.

The therapy, given approval in Europe, called Glybera, was developed by uniQure, a Dutch company. It treats lipoprotein lipase deficiency (LPLD), a disease that affects only several hundred people in the European Union and a similar number in North America.

Glybera (alipogene tiparvovec), is a gene therapy treatment for patients with LPLD (also called familial hyperchylomicronemia). Patients with LPLD, a very rare, inherited disease, are unable to metabolize the fat particles carried in their blood, which leads to inflammation of the pancreas (pancreatitis), an extremely serious, painful, and potentially lethal condition. The approval makes Glybera the first gene therapy treatment approved by regulatory authorities in the Western world.

As I stated back in July, the reason I am noting this accomplishment in this space, where I normally write about treatments for ocular diseases is, because it brings “legitimacy” to the whole field of regenerative medicine. As readers of this online Journal are aware, my interest is in the field of ophthalmology. As you may be further aware, I am currently tracking twenty one clinical trials involving the use of stem cells (or cell threapy) to treat ophthalmic disorders and sixteen gene therapy clinical trials. Several of these are showing promising results and the above approval will bring increased attention to the whole of this field, including the ophthalmic trials.
The only drawback that I can see, is the potential cost of the above Glybera treatment.

As reported by Jeanne Whalen in her November 3rd writeup in the Wall Street Journal about the approval, Glybera is a one-time injection that could cost in the range of $1.6 million.

As further noted in Ms. Whalen’s article, “The drug's approval is a huge step forward for the field because it's the first time a genetic medicine has been licensed," said Len Seymour, a professor of gene therapy at Oxford University who is unaffiliated with the drug's development. “It begins to exemplify what genetically coded medicines can do."

 “A one-time injection will carry an eye-popping price in the range of £1.25 million ($1.6 million), according to a company spokesman. National insurers in Europe are likely to pay the tab. In some markets, UniQure may collect payment in installments over five years,”

In an interview, UniQure chief executive Jorn Aldag said the high price is justified in part because the company will have a very small market: only about one or two people per million have the extremely rare disease that the drug treats. That amounts to several hundred people in the European Union. Other drugs for such rare disorders, called "orphan diseases," also carry high prices of up to $300,000 a year, a phenomenon that has drawn criticism from some insurers.

The European approval of Glybera gives a fillip to a field that has had "fits and starts" since gene therapy research began several decades ago, said Ellen Feigal, vice president for research and development at the California Institute for Regenerative Medicine (CIRM).

The most marked setback was the death of one teenager in a gene-therapy study in 1999. Later, several children in two separate gene-therapy trials in Europe came down with leukemia. The results prompted the U.S. Food and Drug Administration to place a temporary halt on certain gene-therapy trials. In April 2003, it eased the ban.

Recent results have proved more promising, including a gene therapy that successfully treated children suffering from a genetic illness that causes blindness. (Editors Note: As shown in my writeups  – see Update 8, about those trials for Leber’s Congential Amaurosis.)

Last year, researchers at University College London and St. Jude Children's Research Hospital in the U.S. successfully used gene therapy to treat six patients from hemophilia B, a blood-clotting disease.

I hope that this is just the first of many approvals in the regenerative medicine field in the near future.

Editors Note: According to a knowledgeable source (Alexey Bersenev, and his Stem Cell Assays blog), this approval is actually the fourth gene therapy approval in the world. There have been two previous approvals in China in the field of oncology, and one approval in Russia for peripheral arterial disease. To read further about these, please follow this link.

Thursday, November 01, 2012

New Vitamin Regimen Could Extend Useful Vision for Up to 20 Years for Sufferers of Retinitis Pigmentosa and Certain Types of Usher Syndrome (Types 2&3)

The Foundation Fighting Blindness has updated its information on the combined treatment regimen of vitamin A palmitate, oily fish (DHA) and lutein, which may slow vision loss in people with retinitis pigmentosa (RP) and Usher syndrome types 2 and 3. The new information replaces the Vitamin A Packet previously provided by the Foundation.

The treatment regimen is based on three peer-reviewed, Foundation-funded clinical studies conducted by Dr. Eliot Berson and his colleagues at the Massachusetts Eye and Ear Infirmary. Dr. Berson reported that the combined regimen may provide up to 20 additional years of useful vision for people with typical forms of RP.

The new information includes:

  • Research on lutein supplementation for slowing loss of mid-peripheral visual field
  • Research on oily fish consumption, or DHA supplementation, for slowing loss of visual acuity
  • Diseases for which vitamin A palmitate supplementation could be harmful
The new information can be downloaded from the Foundation's website. Printed copies may be obtained by contacting the Foundation's Information and Referral Department at 1-800-683-5555 or

Editors Note: The Foundation-funded clinical research studies conducted by Dr. Eliot Berson and his co-workers at the Harvard Medical School, Massachusetts Eye and Ear Infirmary, demonstrated that the combined treatment regimen of vitamin A palmitate, oily fish and lutein may provide an additional 20 years of useful vision for people who were between 18 and 60 years of age with typical forms of retinitis pigmentosa (RP) or Usher syndrome types 2 or 3.

These participants also began the study with best-corrected visual acuity of 20/100 or better.

This document is an update to the information on the treatment regimen previously provided by the Foundation Fighting Blindness.

Dr. Berson’s recommended treatment regimen is not appropriate for everyone with a retinal disease, and the decision to take it should only be made between the patient and his or her doctor.