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Experts ponder drug compounding law’s impact on ophthalmology

Issue: May 25, 2015

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In 2013, in the wake of infectious outbreaks traced to steroids and repackaged intravitreal Avastin produced at compounding pharmacies, Congress passed the Drug Quality and Security Act, which included the Compounding Quality Act. The law gives the FDA new authorities to regulate the activities of compounding pharmacies, drug repackagers and a new class of “outsourcing manufacturers.”

In subsequent guidance documents, the FDA clarified various requirements regarding the activities of traditional compounders, such as the need to receive a patient-specific prescription for each compounded drug. In a set of draft guidance documents issued in February, the FDA made recommendations on outsourcing facilities, mixing and repackaging, and interstate shipping. Some experts see some of the recommendations as a plus, while others have a less optimistic view.

Overall, the drug compounding law involves a “mixed bag” of upsides and downsides, according to Daniel A. Kracov, JD, OSN Regulatory/Legislative Board Member.

“At a high level, what I think ophthalmologists are going to see is somewhat less availability of certain products that they may have received from compounding facilities previously,” Kracov said. “The purpose of the act, in many respects, is to try to diminish the unlawful practice of compounding of large quantities of, particularly, injectable products in compounding pharmacies and to try to drive those activities into outsourcing facilities, which are subject to good manufacturing practices.”

Judy E. Kim, MD, OSN Retina/Vitreous Board Member, said that while she understands the need for improved oversight of compounding pharmacies for the safety of patients, these laws do not address the unique needs of ophthalmologists, particularly retina specialists, who use Avastin (bevacizumab, Genentech) to treat various ocular conditions, including age-related macular degeneration, diabetic retinopathy, vein occlusions, retinopathy of prematurity and neovascular glaucoma.

New compounding pharmacy regulations do not address unique needs of ophthalmologists, particularly retina specialists, according to Judy E. Kim, MD.

Image: Kim JE

“[Some of] these blanket policies are going to negatively impact the physicians and the patients,” Kim said. “In particular, the proposed beyond-use date of 5 days for repackaged biologics, which includes Avastin, is too restrictive and makes it practically impossible to use Avastin for most ophthalmologists. It mandates that we have only 5 days to use the drug from the time it was repackaged at an outsourcing facility, but it does not account for the time to order and ship the drug to our practices and does not account for the days needed for sterility testing of these drugs. Also, this 5-day period seems quite arbitrary, since the literature shows that Avastin remains stable and sterile beyond 5 days. Limiting the access to Avastin means we will be left to use more expensive drugs only, which will not only increase the health care costs, but also result in some patients declining needed treatments because they cannot afford more expensive drugs. FDA should hear different groups’ voices and make logical decisions and consider exceptions as we give them the appropriate biological and safety data. When access to these drugs impacts so many patients, this is a big issue.”

Barbara S. Fant

Pharmaceutical consultant Barbara S. Fant, PharmD, voiced support for oversight of compounding pharmacies in light of recent growth and change within the industry.

“I think the extent of compounding pharmacies has definitely increased over the past few years,” Fant said. “There needs to be some sort of oversight, more than there was in the past, because I think the laws and regulations that were passed back then [did not foresee] the extent to which compounding pharmacy facilities would expand into their current role. The regulatory changes need to strike a healthy balance between making compounded drugs available and assuring the safety and quality of the compounded products that are provided.”

Compounding Quality Act

Section 503A of the Federal Food, Drug and Cosmetic Act (FDCA) describes the conditions under which certain compounded drugs are entitled to exemptions from three sections of the FDCA that require compliance with current good manufacturing practices (CGMPs), labeling with adequate instructions for use and FDA approval prior to marketing.

The Compounding Quality Act also created section 503B under the FDCA, which allows a 503A compounding pharmacy to become an outsourcing facility. An outsourcing facility may qualify for exemptions from FDA approval and labeling requirements, but not from CGMPs.

Daniel A. Kracov

Kracov characterized the designation of 503B outsourcing facilities as a mechanism to shift compounding activities to more regulated settings.

“I think it’s very important in terms of being the mechanism that FDA wants to move the compounding of sterile injectables into an outsourcing facility CGMP environment rather than all over the country in various compounding pharmacies. I think they were quite concerned about that,” Kracov said.

Unlike traditional 503A compounders, outsourcing facilities may produce drugs without patient-specific prescriptions, he said.

“The difference between the traditional compounding facility and a 503B facility is that, unlike a traditional compounding facility, an outsourcing manufacturer has the ability to produce without regard to whether there are actual prescriptions for each dose that goes out the door,” Kracov said. “They’re not allowed to make commercially available products, [but] they can repackage certain commercially available products.”

FDA guidance documents

The first draft guidance issued by the FDA in February covered entities considering whether to register as outsourcing facilities under section 503B of the FDCA. A facility that is only engaged in certain activities such as repackaging and compounding non-sterile drugs should not register as an outsourcing facility because its products would not qualify for the exemptions provided in section 503B, the document said.

The second guidance addressed repackaging of certain drugs by pharmacies and outsourcing facilities. Manipulation of a drug, such as reconstitution, mixing or combination with another ingredient, is not considered repackaging. Repackaged drugs are generally subject to the adulteration, misbranding and approval provisions of the FDCA.

FDA-approved drugs that are repackaged are assigned a beyond-use date (BUD) in accordance with various parameters, the document said.

The third guidance concerned mixing, diluting or repackaging biological products outside the scope of an approved biologics license application (BLA).

“The draft guidance notes that a biological product that is mixed, diluted or repackaged outside the scope of an approved BLA is an unlicensed biological product under section 351 of the [Public Health Service Act] and may not be legally marketed without an approved BLA,” the document said.

Biological products that are mixed, diluted or repackaged by a state-licensed pharmacy or federal facility are assigned a BUD that some experts believe will hinder the production and shipping of repackaged bevacizumab.

The fourth guidance addressed adverse event reporting for outsourcing facilities.

“Entities registered as outsourcing facilities are required to report adverse events to the FDA,” the document said. “We believe reporting all serious adverse events would provide important information about the potential product quality issues or public health risks associated with drug products compounded by outsourcing facilities.”

The fifth guidance concerned a memorandum of understanding (MOU) between a state and the FDA addressing the interstate distribution of “inordinate amounts” of compounded drugs by 503A compounders and the reporting of complaints related to compounded drug products distributed outside a state to the FDA.

“[A] pharmacist, pharmacy or physician has distributed an inordinate amount of compounded human drug products interstate if the number of units of compounded human drug products distributed interstate during any calendar month is equal to or greater than 30% of the number of units of compounded and non-compounded drug products distributed or dispensed both intrastate and interstate by such pharmacist, pharmacy or physician during that month,” the document said.

The fifth guidance has raised concerns about limits on the amount of a product that can be shipped across state lines by a facility in a state that does not have an MOU with the FDA.

Final guidances will be issued after the FDA receives comments and addresses stakeholders’ concerns.

Mixed feelings about guidances

“Basically, all of the guidances really could put a damper on things. I think much of this is a reaction to issues that we had with the New England Compounding Center and the contaminated steroids and whatnot. I think compounding pharmacies are doing a much better job of regulating themselves,” retina specialist John W. Kitchens, MD, said.

John W. Kitchens

Fant took a favorable view of the first guidance, pointing out that it provides some exemptions to FDCA regulations while requiring a certain degree of quality and willingness to undergo inspection by the FDA.

“It says right up front that you’re going to agree to abide by the CGMP regulations for compounding, so you’re not exempt from those manufacturing regulations,” Fant said. “But it also states that you’re agreeing to be inspected by the FDA. It creates an interim level in terms of a manufacturing process. You have the full pharmaceutical drug manufacturers, and then you have your local pharmacies that compound on a prescription basis. It creates this interim. It puts some important quality steps in place and puts some focus on the importance of that.”

Fant also noted that the first guidance ensures the purity of raw materials used in compounding.

“In other words, they’re agreeing that the products have to be manufactured from raw materials that meet the pharmacopeia requirements. So, I think that’s a good thing that it’s specified,” Fant said. “If there are no pharmacopeia requirements, there are other standards and such that they have to meet. I think that FDA is handling this in a reasonable way. I really like the fact that they’ve been working with the National Association of Boards of Pharmacy to try to come up with something that’s workable.”

According to Kracov, the third guidance is an important signal of the FDA’s thinking in terms of enforcement.

“I think FDA is going to be engaging in a lot more enforcement around the terms of what is repackaging vs. compounding or outsourcing facility manufactured. So, I think in some respects it remains to be seen how FDA is going to be enforcing this,” Kracov said.

Fant praised the fifth guidance as a means to maintain licensure and regulation at the state level.

“There are federal regulations that the government passes to pharmacies, but those responsibilities have always been at the state level,” Fant said. “Your license is at the state level. You’re bound by state regulations. So, I thought it was really key that the National Board [of Pharmacy] was able to negotiate with FDA that the primary jurisdiction still remains at the state level.”

Fant also pointed out that state boards of pharmacy must report complaints about products to the FDA.

“If they find any significant quality issues and such, they have to report those directly to FDA,” she said. “I think it’s a good use of resources. I think it’s a good cooperative agreement.”

Charles Leiter, PharmD, founder and vice president of Leiter’s Compounding Pharmacy, questioned the rationale behind the 30% cap on interstate shipment stipulated in the fifth guidance.

“If you don’t have a memorandum, you can send 5% out across state lines, or if you do have a memorandum of understanding with the FDA, you can send 30% across state lines,” Leiter said. “What are the pharmacies that are mail-order compounders going to do? If I was a 503A and I was sending 30% of my drugs across state lines and they were all the same drug, then I can see, OK, I’m probably a manufacturer. But I don’t understand where you’re a manufacturer if you’re doing patient-specific across state lines if [patients] can’t get it anywhere else.”

Kim noted the unintended consequences of a restriction on interstate shipping.

“Some states may not have 503B outsourcing pharmacies. With the 30% cap on interstate shipment, some practices may not be able to obtain the needed quantity of drugs from an out-of-state pharmacy. Potentially, the result may be that the medications are obtained from less than well-regulated in-state pharmacy, or the physician may be unable to obtain the desired medication to use,” Kim said. “The 30% cap may play a significant role in supply and demand of certain drugs, possibly the drug cost and sustainability of outsourcing pharmacies for some states.”

Limited access to bevacizumab

The guidances will have an adverse impact on the availability of bevacizumab, according to Kitchens.

“Because it’s the most commonly used intravitreal anti-VEGF injection, that would severely limit what we could do for some patients,” Kitchens said.

The law and draft guidances may hamper compounding pharmacies that only handle bevacizumab, Kitchens said.

“The compounding pharmacy we use is designed and actually run by retina specialists. It has a pharmacist who does the compounding. But it’s specifically so that they can better control the quality of the Avastin that they’re getting and have a more hands-on ability. So, if you start to limit the compounding pharmacies and say, ‘Look, 30% of your volume can’t be shipped out of state,’ that could inhibit some of those pharmacies,” he said.

In addition, Kitchens noted that restrictions on bevacizumab may conflict with some insurance companies’ requirement that bevacizumab be used as a first-line treatment.

“We could run into a very difficult scenario where we have limitations on our access to Avastin while still having demands from insurance companies that utilize Avastin first,” Kitchens said. “It could put us in a real tough bind. Hopefully, they will address these issues, amend the legislation or kill the legislation, and basically allow us to continue to have access to this really vital medication.”

Limitations on the availability of bevacizumab would affect patients with several indications, Kitchens said.

“Because we use it so frequently for common indications like wet macular degeneration, diabetic macular edema and retinal edema from vein occlusion, and a lot for orphan indications such as choroidal vascularization from ocular histoplasmosis syndrome and myopic vascularization, proliferative diabetic retinopathy and neovascular glaucoma, it would affect a lot of patients with these vision-threatening conditions that would be limited in what they could receive,” he said.

The 5-day BUD stipulated in the third guidance would severely curtail repackaging of bevacizumab by outsourcing facilities, according to Leiter. The current expiration period is 90 days.

“Personally, I think it’s a knee-jerk reaction. I think that it’s going to really affect the compounding industry in a huge way and affect patient and physician access to certain drugs not commercially available,” Leiter said. “For instance, they want to put a 5-day limit on Avastin if you’re an FDA outsourcing facility, which we are. That will kill Avastin.”

According to Kim, the 5-day BUD is “too restrictive” for ophthalmology and should be amended.

“It will be difficult to obtain Avastin within 5 days of repackaging. Even if we get the drug in time, if the practice doesn’t use these drugs within those 5 days, we have to throw them out and the practice will have to ‘eat the cost,’” she said. “These laws probably came with good intentions, but BUD of 5 days seems to have been picked out of thin air. For example, Avastin has been used safely beyond 5 days for nearly a decade. So, why make the cutoff at 5 days? We should do our best to let the lawmakers know that this mandate is troublesome for ophthalmology and detrimental to our patients.”

Potential economic impact

Leiter outlined administrative burdens and potential costs generated by the 5-day BUD for bevacizumab.

“I have to validate when it leaves here and goes to a doctor’s office. We have to put a tracker in the box so that we can make sure the temperature remains the same,” Leiter said. “It takes my people a day to put it up. It is probably going to take a day to label and package it and everything, and then you’ve got to FedEx it overnight. So, the doctor only has 2 days. Then, what happens if a patient doesn’t show up? The doctor has to eat the price. I can’t take the drug back. Nobody gives credits on it. Once it’s gone, it’s gone.”

Operating as an outsourcing facility will dramatically increase costs, Leiter said.

“Costs are going way up. We have to validate every single product that we put out of this facility, and that could be anywhere from $2 to $20,000 a drug. … With our high-volume drugs, that’s not that big of a deal, but with the low-volume drugs where somebody needs something and you can send it to the doctor’s office, you’ve got to run those tests on it. It’s going to be prohibitive to do a one-off drug,” he said.

Leiter said that under the first draft guidance, 503A traditional compounders and 503B outsourcing facilities will have to be housed in different buildings.

“I’m 503A and 503B right now. So, if there’s a one-off that I need to do, I can do patient-specific and send it and not have to do all of that testing. But if this goes through, that’s done,” Leiter said.

Kim said that pharmacies may be taxed up to $15,000 per year to support oversight activities.

“Most likely, these ‘taxes’ for increased oversight are going to be handed down to us in the form of increased cost of the drug,” Kim said.

Kracov questioned the viability of markets to support outsourcing facility production of certain products.

“To the extent that ophthalmologists want to use a compounded product and have ready access to it for a large number of patients, it’s really going to be a question of whether there’s a sufficient market for those outsourcing facilities to produce that product or repackage a product under CGMP conditions,” Kracov said. – by Matt Hasson

How will beyond-use dates for repackaged Avastin impact your ability to care for patients?

Expiration date for outsourcing pharmacies is 5 days

Pravin U. Dugel

The idea is to allow physicians as much choice as possible. What has become clear is that there are some patients in whom one of the three drugs that we use for macular degeneration, diabetic macular edema and vein occlusion seems to work better than another drug. So, choices are made based on effectiveness sometimes, and there may be differences in safety. And there are certainly differences in price. And sometimes a drug may be effective for a while and another drug can be effective for a while.

Whatever is done to restrict those choices is a disservice to the patient because that decreases the proper patient care that we can give. Restricting Avastin at all is going to decrease the quality of patient care for the reasons that I mentioned. For the vast majority, care is provided by private practitioners who do not have access to university-based or hospital-based compounding pharmacies. For them to have barriers that they have to go through to obtain Avastin will simply lead to worse patient care. The majority of physicians who are in private practice need to obtain Avastin through a compounding pharmacy.

At the end of the day, the idea here is that, again, you want to have as much choice as possible. Restricting Avastin to 5 days, for instance, is very difficult for someone to say, “Look, I’m going to order just enough to last me 5 days but not too much so that it will expire, but not too little so that patients can’t get the drug when they need it.”

Pravin U. Dugel, MD, is an OSN Retina/Vitreous Board Member. Disclosure: Dugel reports he is a consultant for Genentech and Novartis.

Window for in-house pharmacies is 4 hours

Veeral S. Sheth

The FDA has issued draft guidance for the use of Avastin in our clinics. Speaking as a practice that utilizes an in-house pharmacy, the guidance would limit, if not eliminate, our ability to use Avastin. The FDA draft guidance suggests a 4-hour window for Avastin in in-house pharmacies. While you can draw multiple doses from a single sterile vial of Avastin, the 4-hour window makes it prohibitive to purchase a vial and hope that you are able to recoup the cost of the medication via reimbursement. For example, a vial costs, generally, more than $600, while Medicare reimburses a single dose at $45. So, you can see that if you are not able to use an entire vial or not at least recoup the cost, that is a losing proposition, and practices that rely on in-house pharmacies would certainly move away from Avastin and move toward more on-label use. The problem there is that we have patients who are not eligible for co-pay assistance. That means they are going to have higher co-pays, and some of them will not be able to afford it. So, at the end of the day, some of our patients will, as a result of this guidance, lose vision unnecessarily.

There are plenty of studies that show that Avastin has minimal degradation over 3 months. So, to have beyond-use dates at 4 hours or even 5 days is incongruous because we have plenty of evidence demonstrating that even up to 3 months, repackaged Avastin is efficacious and safe.

Veeral S. Sheth, MD, MBA, FACS, is director of scientific affairs, University Retina and Macula Associates, and clinical assistant professor, University of Chicago. Disclosure: Sheth reports no relevant financial disclosures.