During the past few years, compounding pharmacies have received a lot of press. In 2012, a story involving a compounding pharmacy received national attention when as many as 14,000 people received contaminated injections of a steroid medication. A total of 751 patients contracted meningitis or other infections from the injections, and 64 people in 20 states died.1
A year before this nationwide outbreak, ophthalmologists at Bascom Palmer Eye Institute in Miami were treating patients who had received intraocular injections of tainted Avastin. As early as November 2011, Roger A. Goldberg, MD, MBA, reported a series of 12 patients who developed Streptococcus endophthalmitis after injection with intravitreal bevacizumab.2,3 These 12 patients presented to Bascom Palmer with severe intraocular infections one to six days after receiving an intravitreal injection of bevacizumab. The injections occurred at four different clinics in south Florida, but all doses of bevacizumab were prepared by the same compounding pharmacy in Broward County.
None of the patients received injections at Bascom Palmer, but nine patients presented to its tertiary-care ophthalmic emergency room for treatment, and three others were seen in consultation. Initially, all patients were treated with vitreous tap and injections, and eight patients later received a vitrectomy. Microbiology cultures for 10 patients were positive for Streptococcus mitis/oralis. Seven unused syringes of bevacizumab prepared by the compounding pharmacy at the same time as those prepared for the affected patients were also positive for S. mitis/oralis. After four months of follow-up, all but one patient had count fingers or worse visual acuity, and seven ultimately required evisceration or enucleation.
Dr. Goldberg, who is now in practice at Tufts New England Eye Center and Ophthalmic Consultants of Boston, explains that many of the patients in the Miami outbreak of endophthalmitis were part of the same health insurance group.
“They mandated the use of a specific compounding pharmacy for their patients, and this placed the contracted retinologists in a difficult situation,” says Dr. Goldberg. “They were told that they had to get their Avastin from a particular pharmacy for this subset of their patients. The syringes were labeled for each patient and were shipped to the doctor’s office in advance of the patient visit. One patient expected to only need an injection in one eye, so a syringe was sent for that patient. On exam, the patient had a new submacular hemorrhage in the other eye and required treatment in the fellow eye as well. The fellow eye received Avastin from another source, and this eye did not develop endophthalmitis, despite being treated on the same day. So, we know it wasn’t the doctor’s injection technique that caused the infection.”
In another practice, four patients from this medical group were no-shows for their appointment, and Dr. Goldberg and his colleagues were able to track down the four unused syringes, and they were culture-positive with the same bacteria. “We know that the bacteria came in the syringes. It was not introduced by the physicians,” he adds.
Reports in the media have increased awareness about compounding pharmacies and how they operate. “To be honest, I didn’t know much about the compounding process and the regulations and guidelines associated with it until this happened,” Dr. Goldberg says. “In ophthalmology, since the 12-case outbreak of endophthalmitis, we have seen several more small outbreaks associated not just with Avastin, but with triamcinolone and brilliant blue dye. Awareness of the issue has grown over the past few years, and more than a dozen compounding pharmacies have recalled Avastin syringes and other drugs due to sterility concerns.”
Compounding pharmacies are not all the same in terms of their size, their breadth and how many states they operate in. “The south Florida endophthalmitis outbreak originated from a relatively small pharmacy; the nationwide meningitis outbreak was a much larger pharmacy,” Dr. Goldberg says. “Both had problems with how they were handling drugs, inspecting equipment, maintaining sterility and ensuring sufficient documentation. One of the issues that the investigators in south Florida had was tracking down all of the syringes that were made at the time that these contaminated syringes were made. Because the documentation wasn’t in order, it made the Department of Health inspector’s job more difficult.”
He notes that Bascom Palmer has prepared nearly 100,000 Avastin syringes without any incidence of contamination, so they can be prepared safely. “The CATT trial compared the effectiveness of Avastin with Lucentis, and there were no more episodes of endophthalmitis with Avastin than there were with Lucentis,” he says. “Avastin would be more expensive if it was prepared in the way that the CATT trial prepared it, but still a lot less than $2,000, which is what Lucentis costs.”
On November 27, 2013, President Obama signed the Drug Quality and Security Act. The legislation was aimed at regulating compounding pharmacies and establishing a track-and-trace pedigree system for drugs.
Under the DQSA, a compounder can become an “outsourcing facility,” though this is not required. Outsourcing facilities must comply with current good manufacturing practices requirements; will be inspected by the Food and Drug Administration according to a risk-based schedule; and must meet certain other conditions, such as reporting adverse events and providing the FDA with certain information about the products they compound.
If compounders register with the FDA as outsourcing facilities, patients could be assured that drugs from those facilities were subject to CGMP requirements and federal oversight.
The FDA anticipates that state boards of pharmacy will continue their oversight and regulation of the practice of pharmacy, including traditional pharmacy compounding.
“It is too soon to tell what impact the law will have on patient safety,” says David G. Miller, RPh, executive vice president and CEO of the International Academy of Compounding Pharmacists. “There are components in the law that should help. First and foremost, the new outsourcing facility registrations are designed to give the FDA clear authority and knowledge about companies that are producing sterile medications/compounds and placing them into the marketplace throughout the country. From a regulatory oversight standpoint, that is one definite step in the direction to improve patient safety. There are new sections of the law that will require the FDA to create lists of medicines that should not be compounded because either they represent a safety issue to patients or because making the medications is so difficult that it presents a potential risk. These are clear steps forward in terms of protecting patient safety.”
The act also implements track and trace, which will be phased in. “This is the process by which we protect the entire drug supply system by having a formal reporting from the supplier of the raw ingredient to a manufacturer and from the drug manufacturer to a wholesaler and from the wholesaler to the pharmacy or the physician so that we can prevent the introduction of contaminated or counterfeit drugs into our drug supply system, so that’s a huge step forward for us as a country. The law is not just about compounds, it’s about all prescription drugs,” Dr. Miller adds.
A patient who presented at Bascom Palmer Eye Institute with endophthalmitis caused by an intraocular injection of tainted Avastin. |
Charles Leiter, PharmD, president of Leiter’s Compounding Pharmacy in San Jose, Calif., cites quality control as the most important issue in a compounding pharmacy. “Signing up for the FDA program is voluntary, and states have their own rules, so the 50 separate states will be doing 50 different things,” he says. “I don’t think this new legislation has a whole lot of teeth. It just adds another level of complexity. There is always going to be someone out there trying to sell more drug and make more money and cut more corners. We have actually increased our prices to cover our increasing testing of drugs and processes. The FDA really needs to crack down and make sure pharmacies are providing the best possible product that they can. It’s pretty obvious that there were people out there who didn’t know what they were doing.”
Dr. Goldberg agrees. “Different states have different degrees with which they mandate certain things from their compounding pharmacies, including the use of personal protective equipment and the frequency with which equipment has to be inspected, and there are striking differences. Perhaps this is a type of situation where there needs to be more consistency across state lines,” he adds.
He also notes that there is uncertainty regarding whether an individual patient-specific prescription will be required for each Avastin syringe. “Many states have put this requirement in place to keep compounding pharmacies from acting like manufacturers,” he says. “Each syringe produced has to be earmarked for a particular patient. The American Society of Retina Specialists has expressed concern that this will limit patient access to Avastin.”
In chronic disease conditions like macular degeneration, where patients sometimes need to be seen and receive injections every month, Dr. Goldberg says it’s not realistic to have them come in every month and then have them come back a week later for their injection. “It’s just too great of a burden on the patient and on the practice,” he says. “Complicating this issue is that several insurance companies in various states are saying that they will only reimburse the branded drugs if Avastin has been tried and doesn’t work. The [ASRS] is also fighting those policies. We want to have Avastin that is safe and readily available, but we don’t want to be mandated to use it. Ultimately, it is in the best interest of our patients if we are able to customize care for each patient.”
Do Your Homework
Even with the new act in place, it is up to physicians to determine which compounding pharmacies to use. “When evaluating a potential compounding pharmacy, use a checklist,” says IACP’s Dr. Miller. “For example, before you select a pharmacy, ask if the pharmacy is appropriately licensed. Is it accredited? Have there been any disciplinary actions? Make sure when you are entering into a relationship with a compounding pharmacy that you are focusing on who and what and how and not on where patients can get a drug at the lowest cost. You want physicians to have the same comfort level with their compounding pharmacy that they have with other physicians to whom they are referring patients. The decision should be based on knowledge, understanding, reputation and relationships, not based on price.”
In 2011, the IACP developed a new assessment questionnaire to assist hospitals and physicians in identifying and evaluating compounding pharmacies. This comprehensive checklist is based on United States Pharmacopeia standards and can be accessed online and printed out.4
Dr. Miller notes that everyone should be doing their homework whenever decisions are being made about a patient’s health care. “There are two ways to find out about disciplinary actions against pharmacies,” he says. “The first way is to ask them directly if there have been any disciplinary actions pertaining to their compounding practice. Additionally, as a consumer, you can access Board of Pharmacy records on disciplinary actions and the status of an individual pharmacist’s license by simply going online to the state board of pharmacy’s website. You can also check out your local pharmacy on the state board’s website. If your state board doesn’t have a website, you can call.”
Dr. Leiter recommends asking whether the pharmacy has a quality-control department. However, it should be noted that not all testing is the same. “When the pharmacy sends things out for testing,” he says, “what is it testing for? What size sampling does it test? For example, if it makes 100 vials, how many does it send out for testing? Testing is just one piece. The person who makes the drug and who does it day in and day out should be evaluated for his or her process and procedures. This needs to be done for every single drug. My pharmacy is basically becoming a manufacturer. I want to be doing this for a long time, and I want to be doing the best job that I can. I now have four people in my quality-control department, and that’s all they do. They analyze processes. If there is an error, they analyze that and come back with ideas on why, and they are completely independent from everyone else in the pharmacy. Doctors should call the pharmacy that they are using and quiz them. If they are close by, they should go visit, because if something happens they will get sued. They need to do their due diligence in finding a pharmacy. Many times, the phone calls I get are just about price. I just raised my prices because my cost went way up.”
Dr. Goldberg thinks that ophthalmologists across the country are becoming much more conscientious and cognizant of where their Avastin is coming from, and the amount of due diligence that is being done has increased because of these outbreaks and because of this awareness. “Treating physicians should be ensuring that their compounding pharmacy is in compliance with USP Chapter 797 and is certified by the Pharmacy Compounding Accreditation Board,” he says. “When a pharmacy voluntarily submits to this, certified compounding pharmacy inspectors come out and inspect the pharmacy and the processes that are in place to help ensure sterility.”
2. Goldberg RA, Flynn HW Jr, Isom RF, Miller D, Gonzalez S. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol 2012;153:204-208.
3. Goldberg RA, Flynn HW Jr, Miller D, Gonzalez S, Isom RF. Streptococcus endophthalmitis outbreak after intravitreal injection of bevacizumab: One-year outcomes and investigative results. Ophthalmology 2013;120:1448-1453.