Cover Story

Stricter drug compounding regulations complicate ophthalmology care

In 2012, New England Compounding Center released a batch of methylprednisolone tainted with fungus that resulted in an outbreak of fungal meningitis. After it was confirmed that the outbreak was caused by the compounded drug, the FDA imposed new regulations on compounding pharmacies and how they produce drugs. According to some ophthalmologists and representatives in the pharmaceutical business, these regulations have made the procurement and production of several compounded drugs difficult. And that difficulty can affect practice.

In 2013, Congress passed the Drug Quality and Security Act, which included the Compounding Quality Act. The act included several requirements for traditional compounders, which included the creation of a new section under the Federal Food, Drug and Cosmetic Act, according to an FDA release. This section, 503B, allowed a traditional 503A compounding pharmacy to become an outsourcing facility and create compounded drugs without a patient-specific prescription.

An outsourcing facility, according to section 503B, is inspected by the FDA on a risk-based schedule, must report adverse events, must provide information about the products it compounds and must comply with current Good Manufacturing Practices (cGMP).

The compounding regulations are well intentioned but ‘do not reflect the practicalities of daily practice,’ according to John P. Berdahl, MD.

Source: John P. Berdahl, MD

Safety is paramount

Since then, no outbreak at the level of the New England Compounding Center incident has been seen, according to Abraham Gitterman, JD, an associate in the Life Sciences and Healthcare Regulatory practice of Arnold & Porter Kaye Scholer.

“I think one interesting data point on the patient safety side is we certainly haven’t heard of anything on the level of what happened in New England in 2012 since the law has been in place, though there have been a number of recalls. I think that’s a huge testament to the actual enforcement that the FDA has been doing. They have been doing dozens, if not hundreds, of inspections of state-licensed pharmacies that are engaged in compounding to ensure patient safety,” he said.

Abraham Gitterman

Nearly 50 to 60 outsourcing facilities have voluntarily registered with the FDA, Gitterman said, and “virtually all of them have been inspected.” Furthermore, the state boards of pharmacies and the pharmacists engaged in compounding now recognize there is “a lot of liability,” he said, citing the 9-year sentence handed to Barry Cadden, the owner and head pharmacist of New England Compounding Center, in connection with the 2012 outbreak.

In a June press release from the U.S. Department of Justice Office of Public Affairs announcing the sentence, FDA Commissioner Scott Gottlieb, MD, said, “Protecting Americans from unsafe and contaminated drugs is at the core of our mission. Patients should not have to worry about the safety and sterility of the drugs they are prescribed. Since this tragedy, Congress has given the FDA important new authorities, and the agency has implemented key policies, all to provide a greater assurance of safety over compounded medicines. As part of these efforts, we will continue to hold accountable those who violate the law and put patients at risk.”

Tougher regulations

The compounding regulations are designed to increase patient safety and are well intentioned, but they “do not reflect the practicalities of daily practice,” OSN Refractive Surgery Section Editor John P. Berdahl, MD, said.

Under the regulations, Berdahl said he can no longer stockpile certain compounded agents to have on hand when needed during cataract surgery.

“For example, we use a pledget with dilating medications prior to cataract surgery. It used to be that we could have a number of pledgets made before procedures. They would be ready for patients when they came in, and we didn’t have to have an individual prescription for those patients. They were all made under the same conditions in the same batch. Now we need to have an individual prescription for each one of those patients,” he said.

Similarly, intracameral phenylephrine with lidocaine is used to assist in dilation, but patients now need an individualized patient prescription before surgery. If the patient has never had a prior surgery, it is an unknown whether he or she would need the dilating assistance.

“Under these new regulations, you can’t have that medication on hand, which can make the surgery more challenging and less safe. I understand the regulations are set up with good intention to ensure that high-quality medications are getting to patients and to the right patient, but like so often the regulation has unintended consequences that can actually put patients at risk from having the best treatment possible,” he said.

Restrictions vs. availability

The balance of tighter restrictions and the availability of needed compounded medications has become increasingly important in the current environment, OSN Cornea/External Disease Section Editor Elizabeth Yeu, MD, said.

Compounded medications, in a global sense, provide access to medications that are not available commercially, which are critically important in fields such as pediatrics and eye care. However, supplies of compounded medications, such as certain topical drops or intraoperative moxifloxacin-dexamethasone, are being limited, Yeu said.

Elizabeth Yeu

“In my experience, compounding pharmacies that I trust for their quality of medications have had to limit what they are able to provide, in part due to tighter FDA restrictions. I certainly appreciate the need for stringent sterile technique and handling, as mishandling can lead to devastating complications. The other side to the story, unfortunately, is decreasing options and availability. In such a subspecialized field like ophthalmology, there are very obvious needs that our commercially available medications do not meet, and quality compounded medications to fill the treatment gaps are absolutely essential,” she said.

Quality control should always be top of mind. Drastic events, such as iatrogenic fungal meningitis and death, must lead to careful regulatory scrutiny, Yeu said.

“Unfortunately, overcaution can lead to missteps, too. In our current scenario, I do believe processes need to be in place to protect patients, but if limited access to proper care and treatments is the end result, then we all lose because patients suffer due to the lack of proper therapeutic management options,” she said.

Increased pharmaceutical scrutiny

It is a difficult landscape currently for compounding pharmacies, according to Charles W. Leiter,PharmD, former owner and current adviser to Leiter’s Compounding Pharmacy.

The designation split between 503A and 503B compounding pharmacy facilities has been difficult, and the additional regulations for compounding certain drugs have been a challenge. The 503B facilities must be up to code with cGMP, which is a costly proposition, Leiter said.

“In order to achieve cGMP, it’s a lot of documentation and it’s a ton of money. I bet the costs have gone up 5 to 10 times to make something with all these new regulations going in. The 503A, you have some of the same restrictions as far as the quality of the chemicals go, but if you’re going to put something with a higher expiration date on it, like 9 days or 14 days, you have to have it tested for that, too. Then you’re starting to fall into cGMP. They’re saying that you just can’t use high-performance liquid chromatography (HPLC) like the industry used to. We’d take a drug, we’d do an HPLC at timepoint one, two and three, and if it was within 90% to 110%, it was OK. Now they want us to do degradation studies and all this other stuff, so it can cost something like $100,000 to bring a drug to market,” he said.

Charles W. Leiter

Rising costs, decreased quantity

During his ownership of Leiter’s Compounding Pharmacy, Leiter said the company made about 1,800 drugs, all up to standards with USP general chapter 797, which ensures sterile preparation of the drugs to promote safety. Currently, he said, the compounding pharmacy produces only about 11 drugs.

It is not financially feasible to continue producing such a high number of drugs under the current restrictions, he said.

“All the doctors are having trouble. The cornea doctors are having a hard time treating their patients because they can’t find the medications. The retina docs are having problems with obtaining Avastin (bevacizumab, Genentech),” he said.

With such increased scrutiny on the field, compounding pharmacies need to be aware of their suppliers and how the products are manufactured, Leiter said. He suggested compounding pharmacies should audit all of their suppliers and shy away from the ones that resist the request.

Pharmacies need to be careful in this climate, he said. Outsourcing facilities have to test the drugs immediately when they come into their facilities for quality assurance. For this reason, quality assurance costs for compounding pharmacies have increased greatly over the past several years.

“Some compounding pharmacies have between 15 and 20 quality assurance staff employees now,” Leiter said. “That is 5% to 10% of their employees. The huge thing is that the cost has just gone up tremendously and the people who can’t afford the medications aren’t going to get them. To me, that’s the frustrating thing.”

Balance is necessary

The balance between compounding drug need and compounding drug cost is tough to find in this climate.

The primary concern for physicians is providing necessary medications for their patients, Berdahl said. However, with the current statutes and regulations in place, getting these patients the compounded medications they need has become increasingly difficult.

“We may not be able to get the individual medication that we need for our patient, and if we do and if we can, it becomes more expensive and thus puts more financial pressure on the health system. Finding a way to ensure that medications are going to be safe without decreasing access and increasing costs is crucial,” he said.

The individual prescription mandate for compounded drugs can be a challenge for traditional compounding pharmacies, Gitterman said. According to the FDA, a 503A compounding pharmacy can have a supply of a compounded product on hand based on the number of valid prescriptions that it received in a 30-day period over the past year. The compounding pharmacy cannot have more than a 30-day supply on hand at any time.

“What does it mean to have a limited quantity based on established patient relationships and histories? Pharmacists generally will look at how much business they’ve done in the past few years, and they generally know their geographic patient population. So if a pharmacist is compounding 10%, 20%, 30% or 40% above that, FDA may consider that to be in excess of the ‘limited quantity’ requirement,” Gitterman said.

If it seems that there is not a justification for having a stock of a compounded product on hand, the FDA may get involved and issue a warning letter, he said.

Frustrations are not unanimous

However, frustrations are not completely widespread. Not all physicians are experiencing difficulties with the regulations, according to Sydney L. Tyson, MD, MPH, president of Eye Associates and SurgiCenter in New Jersey.

Tyson said he can procure proprietary compound formulations used for cataract surgery patients from the FDA-registered 503B pharmacy he uses.

Syndey L. Tyson

“As physicians, we welcome the FDA oversight and scrutiny of compounded medications. What’s important in selecting a compound drug supplier is ensuring the drugs are made by an FDA-registered 503B outsourcing facility. Products coming from these facilities are required to be made according to cGMP. For us, these standards are equivalent to major pharmaceutical drug production standards, so we can feel comfortable that the compounded products we prescribe for our patients are produced with the same or better standards,” Tyson said.

It is important for ophthalmologists to completely trust the provider they receive their compounded drugs from. Physicians should be extremely selective in whom they use as a supplier and should consider receiving compounded products only from FDA-registered laboratories that follow cGMP guidelines, he said.

Trust is key

The No. 1 concern physicians have in this climate is trust in a compounded drug for their patient. The main question physicians have for outside counsel or those who manage their practices is if a certain compounded medication can be trusted and safe for their patient, Gitterman said.

If a compounded drug causes a patient harm, he noted, the physician and the compounding facility may be liable.

“Can we trust it? Physicians and other providers can go on the FDA website to see if the pharmacy or outsourcing facility has a warning letter or a 483 from FDA. And FDA may eventually post a closeout letter that essentially means the FDA has been satisfied with the pharmacy’s corrections for whatever the issues or problems were. You’re hoping that means nothing further will be a problem. They implemented corrective and preventative actions, have hired a quality consultant in certain instances, they’ve taken care of it. But the problem is, it’s a continuous compounding world,” he said.

Anything can affect a compounding facility’s future compliance with compounding cGMP and cause an issue, Gitterman said. Adding a new drug, opening or updating a facility, moving to a new location — any of these factors can affect the final product or how a drug is compounded, even if the facility has addressed past FDA concerns or issues.

Competition is now limited

Competition has also become limited for compounding facilities. The local, smaller 503A compounding facilities may not have the financial means to produce and legally test the different kinds of compounded products manufactured by a 503B facility, Berdahl said.

“The only good solution I can think of or what I’m aware of are larger compounding pharmacies that are getting their products 503B certified. It’s an onerous process. It does limit competition because local compounders won’t be able to play in that arena, but it does ensure safety and it does allow us to get around some of the regulations that are applied to 503A pharmacies,” he said.

Compounded medications provide a solution for an ophthalmologist’s most vulnerable patients. Compounded medications are used in uncommon scenarios or disease states in which the market is typically not big enough for pharmaceutical companies to invest funding and provide a solution with a manufactured product, Berdahl noted.

This can make it difficult for an ophthalmologist to provide solutions and treatments for patients who do not have any other options, he said.

“It really makes it harder for some of our most vulnerable patients to get the care that they need from a regulatory standpoint but also from a reimbursement standpoint. It would be nice if compounded medications had an opportunity to be evaluated based on safety and efficacy to get reimbursed by insurance companies. That would increase competition in the drug space and hopefully end up providing more value to patients,” he said. – by Robert Linnehan

Disclosures: Berdahl reports he is a consultant for Imprimis, Novartis, Allergan and Bausch + Lomb. Leiter reports he is a consultant and stockholder with Leiter’s Compounding Pharmacy. Tyson reports he is a consultant for Alcon and Imprimis. Gitterman and Yeu report no relevant financial disclosures.

Click here to read the POINTCOUNTER, "Are the compounded drugs you used in your practice before 2013 equally accessible in 2017?"

In 2012, New England Compounding Center released a batch of methylprednisolone tainted with fungus that resulted in an outbreak of fungal meningitis. After it was confirmed that the outbreak was caused by the compounded drug, the FDA imposed new regulations on compounding pharmacies and how they produce drugs. According to some ophthalmologists and representatives in the pharmaceutical business, these regulations have made the procurement and production of several compounded drugs difficult. And that difficulty can affect practice.

In 2013, Congress passed the Drug Quality and Security Act, which included the Compounding Quality Act. The act included several requirements for traditional compounders, which included the creation of a new section under the Federal Food, Drug and Cosmetic Act, according to an FDA release. This section, 503B, allowed a traditional 503A compounding pharmacy to become an outsourcing facility and create compounded drugs without a patient-specific prescription.

An outsourcing facility, according to section 503B, is inspected by the FDA on a risk-based schedule, must report adverse events, must provide information about the products it compounds and must comply with current Good Manufacturing Practices (cGMP).

The compounding regulations are well intentioned but ‘do not reflect the practicalities of daily practice,’ according to John P. Berdahl, MD.

Source: John P. Berdahl, MD

Safety is paramount

Since then, no outbreak at the level of the New England Compounding Center incident has been seen, according to Abraham Gitterman, JD, an associate in the Life Sciences and Healthcare Regulatory practice of Arnold & Porter Kaye Scholer.

“I think one interesting data point on the patient safety side is we certainly haven’t heard of anything on the level of what happened in New England in 2012 since the law has been in place, though there have been a number of recalls. I think that’s a huge testament to the actual enforcement that the FDA has been doing. They have been doing dozens, if not hundreds, of inspections of state-licensed pharmacies that are engaged in compounding to ensure patient safety,” he said.

Abraham Gitterman

Nearly 50 to 60 outsourcing facilities have voluntarily registered with the FDA, Gitterman said, and “virtually all of them have been inspected.” Furthermore, the state boards of pharmacies and the pharmacists engaged in compounding now recognize there is “a lot of liability,” he said, citing the 9-year sentence handed to Barry Cadden, the owner and head pharmacist of New England Compounding Center, in connection with the 2012 outbreak.

PAGE BREAK

In a June press release from the U.S. Department of Justice Office of Public Affairs announcing the sentence, FDA Commissioner Scott Gottlieb, MD, said, “Protecting Americans from unsafe and contaminated drugs is at the core of our mission. Patients should not have to worry about the safety and sterility of the drugs they are prescribed. Since this tragedy, Congress has given the FDA important new authorities, and the agency has implemented key policies, all to provide a greater assurance of safety over compounded medicines. As part of these efforts, we will continue to hold accountable those who violate the law and put patients at risk.”

Tougher regulations

The compounding regulations are designed to increase patient safety and are well intentioned, but they “do not reflect the practicalities of daily practice,” OSN Refractive Surgery Section Editor John P. Berdahl, MD, said.

Under the regulations, Berdahl said he can no longer stockpile certain compounded agents to have on hand when needed during cataract surgery.

“For example, we use a pledget with dilating medications prior to cataract surgery. It used to be that we could have a number of pledgets made before procedures. They would be ready for patients when they came in, and we didn’t have to have an individual prescription for those patients. They were all made under the same conditions in the same batch. Now we need to have an individual prescription for each one of those patients,” he said.

Similarly, intracameral phenylephrine with lidocaine is used to assist in dilation, but patients now need an individualized patient prescription before surgery. If the patient has never had a prior surgery, it is an unknown whether he or she would need the dilating assistance.

“Under these new regulations, you can’t have that medication on hand, which can make the surgery more challenging and less safe. I understand the regulations are set up with good intention to ensure that high-quality medications are getting to patients and to the right patient, but like so often the regulation has unintended consequences that can actually put patients at risk from having the best treatment possible,” he said.

Restrictions vs. availability

The balance of tighter restrictions and the availability of needed compounded medications has become increasingly important in the current environment, OSN Cornea/External Disease Section Editor Elizabeth Yeu, MD, said.

Compounded medications, in a global sense, provide access to medications that are not available commercially, which are critically important in fields such as pediatrics and eye care. However, supplies of compounded medications, such as certain topical drops or intraoperative moxifloxacin-dexamethasone, are being limited, Yeu said.

PAGE BREAK
Elizabeth Yeu

“In my experience, compounding pharmacies that I trust for their quality of medications have had to limit what they are able to provide, in part due to tighter FDA restrictions. I certainly appreciate the need for stringent sterile technique and handling, as mishandling can lead to devastating complications. The other side to the story, unfortunately, is decreasing options and availability. In such a subspecialized field like ophthalmology, there are very obvious needs that our commercially available medications do not meet, and quality compounded medications to fill the treatment gaps are absolutely essential,” she said.

Quality control should always be top of mind. Drastic events, such as iatrogenic fungal meningitis and death, must lead to careful regulatory scrutiny, Yeu said.

“Unfortunately, overcaution can lead to missteps, too. In our current scenario, I do believe processes need to be in place to protect patients, but if limited access to proper care and treatments is the end result, then we all lose because patients suffer due to the lack of proper therapeutic management options,” she said.

Increased pharmaceutical scrutiny

It is a difficult landscape currently for compounding pharmacies, according to Charles W. Leiter,PharmD, former owner and current adviser to Leiter’s Compounding Pharmacy.

The designation split between 503A and 503B compounding pharmacy facilities has been difficult, and the additional regulations for compounding certain drugs have been a challenge. The 503B facilities must be up to code with cGMP, which is a costly proposition, Leiter said.

PAGE BREAK

“In order to achieve cGMP, it’s a lot of documentation and it’s a ton of money. I bet the costs have gone up 5 to 10 times to make something with all these new regulations going in. The 503A, you have some of the same restrictions as far as the quality of the chemicals go, but if you’re going to put something with a higher expiration date on it, like 9 days or 14 days, you have to have it tested for that, too. Then you’re starting to fall into cGMP. They’re saying that you just can’t use high-performance liquid chromatography (HPLC) like the industry used to. We’d take a drug, we’d do an HPLC at timepoint one, two and three, and if it was within 90% to 110%, it was OK. Now they want us to do degradation studies and all this other stuff, so it can cost something like $100,000 to bring a drug to market,” he said.

Charles W. Leiter

Rising costs, decreased quantity

During his ownership of Leiter’s Compounding Pharmacy, Leiter said the company made about 1,800 drugs, all up to standards with USP general chapter 797, which ensures sterile preparation of the drugs to promote safety. Currently, he said, the compounding pharmacy produces only about 11 drugs.

It is not financially feasible to continue producing such a high number of drugs under the current restrictions, he said.

“All the doctors are having trouble. The cornea doctors are having a hard time treating their patients because they can’t find the medications. The retina docs are having problems with obtaining Avastin (bevacizumab, Genentech),” he said.

With such increased scrutiny on the field, compounding pharmacies need to be aware of their suppliers and how the products are manufactured, Leiter said. He suggested compounding pharmacies should audit all of their suppliers and shy away from the ones that resist the request.

Pharmacies need to be careful in this climate, he said. Outsourcing facilities have to test the drugs immediately when they come into their facilities for quality assurance. For this reason, quality assurance costs for compounding pharmacies have increased greatly over the past several years.

“Some compounding pharmacies have between 15 and 20 quality assurance staff employees now,” Leiter said. “That is 5% to 10% of their employees. The huge thing is that the cost has just gone up tremendously and the people who can’t afford the medications aren’t going to get them. To me, that’s the frustrating thing.”

PAGE BREAK

Balance is necessary

The balance between compounding drug need and compounding drug cost is tough to find in this climate.

The primary concern for physicians is providing necessary medications for their patients, Berdahl said. However, with the current statutes and regulations in place, getting these patients the compounded medications they need has become increasingly difficult.

“We may not be able to get the individual medication that we need for our patient, and if we do and if we can, it becomes more expensive and thus puts more financial pressure on the health system. Finding a way to ensure that medications are going to be safe without decreasing access and increasing costs is crucial,” he said.

The individual prescription mandate for compounded drugs can be a challenge for traditional compounding pharmacies, Gitterman said. According to the FDA, a 503A compounding pharmacy can have a supply of a compounded product on hand based on the number of valid prescriptions that it received in a 30-day period over the past year. The compounding pharmacy cannot have more than a 30-day supply on hand at any time.

“What does it mean to have a limited quantity based on established patient relationships and histories? Pharmacists generally will look at how much business they’ve done in the past few years, and they generally know their geographic patient population. So if a pharmacist is compounding 10%, 20%, 30% or 40% above that, FDA may consider that to be in excess of the ‘limited quantity’ requirement,” Gitterman said.

If it seems that there is not a justification for having a stock of a compounded product on hand, the FDA may get involved and issue a warning letter, he said.

Frustrations are not unanimous

However, frustrations are not completely widespread. Not all physicians are experiencing difficulties with the regulations, according to Sydney L. Tyson, MD, MPH, president of Eye Associates and SurgiCenter in New Jersey.

PAGE BREAK

Tyson said he can procure proprietary compound formulations used for cataract surgery patients from the FDA-registered 503B pharmacy he uses.

Syndey L. Tyson

“As physicians, we welcome the FDA oversight and scrutiny of compounded medications. What’s important in selecting a compound drug supplier is ensuring the drugs are made by an FDA-registered 503B outsourcing facility. Products coming from these facilities are required to be made according to cGMP. For us, these standards are equivalent to major pharmaceutical drug production standards, so we can feel comfortable that the compounded products we prescribe for our patients are produced with the same or better standards,” Tyson said.

It is important for ophthalmologists to completely trust the provider they receive their compounded drugs from. Physicians should be extremely selective in whom they use as a supplier and should consider receiving compounded products only from FDA-registered laboratories that follow cGMP guidelines, he said.

Trust is key

The No. 1 concern physicians have in this climate is trust in a compounded drug for their patient. The main question physicians have for outside counsel or those who manage their practices is if a certain compounded medication can be trusted and safe for their patient, Gitterman said.

If a compounded drug causes a patient harm, he noted, the physician and the compounding facility may be liable.

“Can we trust it? Physicians and other providers can go on the FDA website to see if the pharmacy or outsourcing facility has a warning letter or a 483 from FDA. And FDA may eventually post a closeout letter that essentially means the FDA has been satisfied with the pharmacy’s corrections for whatever the issues or problems were. You’re hoping that means nothing further will be a problem. They implemented corrective and preventative actions, have hired a quality consultant in certain instances, they’ve taken care of it. But the problem is, it’s a continuous compounding world,” he said.

PAGE BREAK

Anything can affect a compounding facility’s future compliance with compounding cGMP and cause an issue, Gitterman said. Adding a new drug, opening or updating a facility, moving to a new location — any of these factors can affect the final product or how a drug is compounded, even if the facility has addressed past FDA concerns or issues.

Competition is now limited

Competition has also become limited for compounding facilities. The local, smaller 503A compounding facilities may not have the financial means to produce and legally test the different kinds of compounded products manufactured by a 503B facility, Berdahl said.

“The only good solution I can think of or what I’m aware of are larger compounding pharmacies that are getting their products 503B certified. It’s an onerous process. It does limit competition because local compounders won’t be able to play in that arena, but it does ensure safety and it does allow us to get around some of the regulations that are applied to 503A pharmacies,” he said.

Compounded medications provide a solution for an ophthalmologist’s most vulnerable patients. Compounded medications are used in uncommon scenarios or disease states in which the market is typically not big enough for pharmaceutical companies to invest funding and provide a solution with a manufactured product, Berdahl noted.

This can make it difficult for an ophthalmologist to provide solutions and treatments for patients who do not have any other options, he said.

“It really makes it harder for some of our most vulnerable patients to get the care that they need from a regulatory standpoint but also from a reimbursement standpoint. It would be nice if compounded medications had an opportunity to be evaluated based on safety and efficacy to get reimbursed by insurance companies. That would increase competition in the drug space and hopefully end up providing more value to patients,” he said. – by Robert Linnehan

Disclosures: Berdahl reports he is a consultant for Imprimis, Novartis, Allergan and Bausch + Lomb. Leiter reports he is a consultant and stockholder with Leiter’s Compounding Pharmacy. Tyson reports he is a consultant for Alcon and Imprimis. Gitterman and Yeu report no relevant financial disclosures.

Click here to read the POINTCOUNTER, "Are the compounded drugs you used in your practice before 2013 equally accessible in 2017?"