Drug Compounding: Many Considerations

The tug-of-war pitting patients against pharmaceutical companies against pharmacists selling competing compound drug mixtures to the public has lately gained greater urgency. Pharmaceuticals manufacturers contend that once their branded medications have been approved by the FDA, compounded concoctions that replicate them should not be permitted, as they are not subject to the same high safety standards and inspection requirements of the branded drugs. Consumers and pharmacists, among others, claim such arguments mask a different Big Pharma goal: the pursuit of high profits at the expense of patient access to affordable medications.

Now, a nationwide outbreak of fungal meningitis, likely caused by one component of a compounded drug, is altering the dialog. The suspect product in this instance is an injectable steroid, preservative-free methylprednisolone acetate (80mg/ml), which was produced by New England Compounding Center (NECC), in Framingham, MA. It was distributed across the country to pain clinics, which administered it to an estimated 13,000 patients. As of Oct. 9, 11 people who received these steroid injections had died of fungal meningitis, and 119 more had reportedly been sickened. Still more were anxiously waiting to see if they would develop symptoms of this non-contagious form of the disease.

Compounding Through the Years

Drug compounding has been in practice for centuries. Indeed, before modern pharmaceuticals operations came into being, people worldwide got their medications from pharmacists and others who combined medicinal ingredients, natural or synthetic, to create concoctions to treat heart disease, liver problems and other ailments. In some cultures, this is still the dominant means of obtaining medicine.

The developed world has migrated to the use of pre-made, mass-produced drug products, but its demand for compounded drugs has not gone away. These products are often much less costly than highly promoted name-brand drugs.
In addition, mass-produced pharmaceuticals sometimes are in short supply, requiring physicians to seek out alternatives for their patients. When this happens, compounding pharmacies can take up the slack.

Because drug formulation by pharmacists and doctors pre-dated the advent of federal oversight, the FDA does not exercise the same control over compounded drugs that it does over mass-produced pharmaceutical products. Such operations are, within reason, generally permitted to operate without federal supervision. Instead, the states oversee these facilities. The FDA does, however, have some authority. For example, it reserves the right to step in and stop drug compounding operations that, rather than dealing with small orders for specific patients, produce compounded drugs on a large scale for mass distribution. See FDA Compliance Policy Guidance, Sec. 460.200 Pharmacy Compounding.

FDA Refuses to Take Action

This year, prior to the meningitis outbreak, another drug compounding story was in the news, involving KV Pharmaceutical, compounding pharmacists and women at risk for pre-term births.

Getting a drug through the rigorous FDA approval process generally means that its maker can expect to reap large profits, preferably with market exclusivity. Medications containing patented components may achieve market exclusivity through means of the patent itself, which competitors may not breach with impunity. But when no patent is involved, market exclusivity may still be obtained in some cases through the Orphan Drug Act (Public Law 97-414, as amended). The Orphan Drug Act was enacted to encourage pharmaceuticals manufacturers to develop and sell drugs that treat uncommon illnesses and diseases. Because such ailments are suffered by a relatively small number of people, it would often be unprofitable for companies to invest in drugs to treat them. To encourage companies to finance and develop these less-demanded medications, the FDA grants orphan drug manufacturers who meet the Act's criteria seven years of market exclusivity.

This is the system the drug company KV Pharmaceutical used to receive FDA approval to market an anti-pre-term birth medication in February 2012. But, to the manufacturer's surprise, Makena (hydroxyprogesterone caproate) did not thereafter enjoy market exclusivity, even though it was the only FDA-approved form of hydroxyprogesterone caproate.

That is because the formulation was not patented, but was merely an officially approved version of a drug that has been made in pharmacies for years. In its non-branded form, commonly known as 17P, hydroxyprogesterone caproate generally costs consumers no more than $25 per week. KV Pharmaceutical originally set the price for Makena at more than $1,500 per week, causing an outcry from doctors and consumers. Even a later drastic reduction in the price did not appease KV Pharmaceutical's critics.

The federal government was not deaf to these complaints, as it was its own drug approval system that had created what might become a monopoly in a heretofore price-moderating free-market system. The FDA therefore took the unusual step of announcing that it would not ban the sale of pharmacy-compounded 17P, as it generally would have done once an FDA-approved form of a traditionally pharmacist-blended medication gained approval. Unhappy with this decision, KV Pharmaceuticals provided the FDA with evidence that some of these compounded products might not be as pure or as potent as they should be. After conducting tests on the samples provided to it, the agency issued a June 15 release, proclaiming the samples essentially fine. However, the agency went on to state, “Although the analysis of this limited sample of compounded
hydroxyprogesterone caproate products ' did not identify any major safety
problems, approved drug products, such as Makena, provide a greater assurance of safety and effectiveness than do compounded products.”

KV Pharmaceuticals has now filed suit in federal court against the FDA and the U.S. Department of Health and Human Services (HHS) for failing to take action to curtail the sale of 17P. The company is seeking an injunction to compel the defendants to enforce the market exclusivity the Orphan Drug Act usually confers. It argues not only that it has been stripped of its own rights under the Act, but that the defendants have put millions of women at risk of receiving adulterated drugs because, although Makena is available and is the only FDA-approved form of hydroxyprogesterone caproate product on the market to prevent pre-term birth, Medicaid and other insurance programs continue to force at-risk mothers to use compounded drugs, made from ingredients of uncertain provenance, in order to save money.

In the meantime, having at least temporarily lost its market exclusivity dreams, the company this summer was compelled to file for Chapter 11 bankruptcy protection.

Balancing the Issues

It's a patient's right to access to necessary medications vs. a pharmaceuticals manufacturer's justified expectation of profits for taking a risk and investing in a drug. It's safety above all else vs. acceptance of a small risk to promote the greater good of affordable treatments.

The FDA specifically found the tested samples of the Makena look-alike, 17P, to be safe, but that does not mean that all such formulations will always be nontoxic. Certainly, the injectable steroids made by NEEC in the past were considered safe, as they were used without incident for years. Now, the massive outbreak of deadly meningitis is changing the dialog.

Consumer advocacy organization Public Citizen has blasted the FDA for failing to exert oversight of NEEC which, unlike a mom-and-pop compounding pharmacy, operated just like a large-scale drug manufacturer, introducing medications into interstate commerce. In an Oct. 9 release, the group called for a congressional investigation, and stated, “If current statutes and regulations provided the FDA with authority to prevent [the meningitis outbreak] disaster, senior FDA officials should be held accountable. If holes in the agency's existing legal authority are identified, Congress should act immediately to pass legislation to remedy the situation.” See www.citizen.org/pressroom/pressroomredirect.cfm?ID=3727.

Prompted by the meningitis crisis, Rep. Henry Waxman (D-CA), along with other signatories, sent a letter on Oct. 9 to the Chairmen of the Congressional committees with authority over this issue asking them to conduct an inquiry into what they termed “serious concerns about the scope of the practice of pharmacy compounding in the United States and the current patchwork of federal and state laws and systems that oversee this practice.” See http://democrats.energycommerce.house.gov/sites/default/files/documents/Upton%20Pitts%20Stearns%20Meningitis%202012%2010%209.pdf.

The International Academy of Compounding Pharmacists also issued a release in response to the meningitis outbreak, reminding the public that pharmaceutical compounding has a long history of providing quality products to patients in need, and that compounding pharmacies offer things that Big Pharma does not, such as medications with personally tailored strengths, or medications that do not contain ingredients to which particular patients are allergic. It also noted that the pharmacy profession has an accrediting body, the Pharmacy Compounding Accreditation Board (PCAB), and stated, “Pharmacies with PCAB accreditation status have demonstrated that their policies and processes meet the highest possible quality standards. New England Compounding Center is not a current PCAB accredited pharmacy.” (Emphasis in original). See www.prnewswire.com/news-releases/the-international-academy-of-compounding-pharmacists-responds-to-meningitis-outbreak-tied-to-compounding-pharmacy-172725431.html.

In an Oct. 5 release, the FDA made clear that had not yet conclusively determined that NECC's product was the cause of the outbreak of fungal meningitis across the country; however, it confirmed that the Centers for Disease Control's interim data showed that all the infected patients received an injection of NECC's product. Meanwhile, NECC has recalled all products produced at its Framingham, MA, facility, and has voluntarily shut down its operation.

Janice G. Inman is Editor-in-Chief of this newsletter.

The tug-of-war pitting patients against pharmaceutical companies against pharmacists selling competing compound drug mixtures to the public has lately gained greater urgency. Pharmaceuticals manufacturers contend that once their branded medications have been approved by the FDA, compounded concoctions that replicate them should not be permitted, as they are not subject to the same high safety standards and inspection requirements of the branded drugs. Consumers and pharmacists, among others, claim such arguments mask a different Big Pharma goal: the pursuit of high profits at the expense of patient access to affordable medications.

Now, a nationwide outbreak of fungal meningitis, likely caused by one component of a compounded drug, is altering the dialog. The suspect product in this instance is an injectable steroid, preservative-free methylprednisolone acetate (80mg/ml), which was produced by New England Compounding Center (NECC), in Framingham, MA. It was distributed across the country to pain clinics, which administered it to an estimated 13,000 patients. As of Oct. 9, 11 people who received these steroid injections had died of fungal meningitis, and 119 more had reportedly been sickened. Still more were anxiously waiting to see if they would develop symptoms of this non-contagious form of the disease.

Compounding Through the Years

Drug compounding has been in practice for centuries. Indeed, before modern pharmaceuticals operations came into being, people worldwide got their medications from pharmacists and others who combined medicinal ingredients, natural or synthetic, to create concoctions to treat heart disease, liver problems and other ailments. In some cultures, this is still the dominant means of obtaining medicine.

The developed world has migrated to the use of pre-made, mass-produced drug products, but its demand for compounded drugs has not gone away. These products are often much less costly than highly promoted name-brand drugs.
In addition, mass-produced pharmaceuticals sometimes are in short supply, requiring physicians to seek out alternatives for their patients. When this happens, compounding pharmacies can take up the slack.

Because drug formulation by pharmacists and doctors pre-dated the advent of federal oversight, the FDA does not exercise the same control over compounded drugs that it does over mass-produced pharmaceutical products. Such operations are, within reason, generally permitted to operate without federal supervision. Instead, the states oversee these facilities. The FDA does, however, have some authority. For example, it reserves the right to step in and stop drug compounding operations that, rather than dealing with small orders for specific patients, produce compounded drugs on a large scale for mass distribution. See FDA Compliance Policy Guidance, Sec. 460.200 Pharmacy Compounding.

FDA Refuses to Take Action

This year, prior to the meningitis outbreak, another drug compounding story was in the news, involving KV Pharmaceutical, compounding pharmacists and women at risk for pre-term births.

Getting a drug through the rigorous FDA approval process generally means that its maker can expect to reap large profits, preferably with market exclusivity. Medications containing patented components may achieve market exclusivity through means of the patent itself, which competitors may not breach with impunity. But when no patent is involved, market exclusivity may still be obtained in some cases through the Orphan Drug Act (Public Law 97-414, as amended). The Orphan Drug Act was enacted to encourage pharmaceuticals manufacturers to develop and sell drugs that treat uncommon illnesses and diseases. Because such ailments are suffered by a relatively small number of people, it would often be unprofitable for companies to invest in drugs to treat them. To encourage companies to finance and develop these less-demanded medications, the FDA grants orphan drug manufacturers who meet the Act's criteria seven years of market exclusivity.

This is the system the drug company KV Pharmaceutical used to receive FDA approval to market an anti-pre-term birth medication in February 2012. But, to the manufacturer's surprise, Makena (hydroxyprogesterone caproate) did not thereafter enjoy market exclusivity, even though it was the only FDA-approved form of hydroxyprogesterone caproate.

That is because the formulation was not patented, but was merely an officially approved version of a drug that has been made in pharmacies for years. In its non-branded form, commonly known as 17P, hydroxyprogesterone caproate generally costs consumers no more than $25 per week. KV Pharmaceutical originally set the price for Makena at more than $1,500 per week, causing an outcry from doctors and consumers. Even a later drastic reduction in the price did not appease KV Pharmaceutical's critics.

The federal government was not deaf to these complaints, as it was its own drug approval system that had created what might become a monopoly in a heretofore price-moderating free-market system. The FDA therefore took the unusual step of announcing that it would not ban the sale of pharmacy-compounded 17P, as it generally would have done once an FDA-approved form of a traditionally pharmacist-blended medication gained approval. Unhappy with this decision, KV Pharmaceuticals provided the FDA with evidence that some of these compounded products might not be as pure or as potent as they should be. After conducting tests on the samples provided to it, the agency issued a June 15 release, proclaiming the samples essentially fine. However, the agency went on to state, “Although the analysis of this limited sample of compounded
hydroxyprogesterone caproate products ' did not identify any major safety
problems, approved drug products, such as Makena, provide a greater assurance of safety and effectiveness than do compounded products.”

KV Pharmaceuticals has now filed suit in federal court against the FDA and the U.S. Department of Health and Human Services (HHS) for failing to take action to curtail the sale of 17P. The company is seeking an injunction to compel the defendants to enforce the market exclusivity the Orphan Drug Act usually confers. It argues not only that it has been stripped of its own rights under the Act, but that the defendants have put millions of women at risk of receiving adulterated drugs because, although Makena is available and is the only FDA-approved form of hydroxyprogesterone caproate product on the market to prevent pre-term birth, Medicaid and other insurance programs continue to force at-risk mothers to use compounded drugs, made from ingredients of uncertain provenance, in order to save money.

In the meantime, having at least temporarily lost its market exclusivity dreams, the company this summer was compelled to file for Chapter 11 bankruptcy protection.

Balancing the Issues

It's a patient's right to access to necessary medications vs. a pharmaceuticals manufacturer's justified expectation of profits for taking a risk and investing in a drug. It's safety above all else vs. acceptance of a small risk to promote the greater good of affordable treatments.

The FDA specifically found the tested samples of the Makena look-alike, 17P, to be safe, but that does not mean that all such formulations will always be nontoxic. Certainly, the injectable steroids made by NEEC in the past were considered safe, as they were used without incident for years. Now, the massive outbreak of deadly meningitis is changing the dialog.

Consumer advocacy organization Public Citizen has blasted the FDA for failing to exert oversight of NEEC which, unlike a mom-and-pop compounding pharmacy, operated just like a large-scale drug manufacturer, introducing medications into interstate commerce. In an Oct. 9 release, the group called for a congressional investigation, and stated, “If current statutes and regulations provided the FDA with authority to prevent [the meningitis outbreak] disaster, senior FDA officials should be held accountable. If holes in the agency's existing legal authority are identified, Congress should act immediately to pass legislation to remedy the situation.” See www.citizen.org/pressroom/pressroomredirect.cfm?ID=3727.

Prompted by the meningitis crisis, Rep. Henry Waxman (D-CA), along with other signatories, sent a letter on Oct. 9 to the Chairmen of the Congressional committees with authority over this issue asking them to conduct an inquiry into what they termed “serious concerns about the scope of the practice of pharmacy compounding in the United States and the current patchwork of federal and state laws and systems that oversee this practice.” See http://democrats.energycommerce.house.gov/sites/default/files/documents/Upton%20Pitts%20Stearns%20Meningitis%202012%2010%209.pdf.

The International Academy of Compounding Pharmacists also issued a release in response to the meningitis outbreak, reminding the public that pharmaceutical compounding has a long history of providing quality products to patients in need, and that compounding pharmacies offer things that Big Pharma does not, such as medications with personally tailored strengths, or medications that do not contain ingredients to which particular patients are allergic. It also noted that the pharmacy profession has an accrediting body, the Pharmacy Compounding Accreditation Board (PCAB), and stated, “Pharmacies with PCAB accreditation status have demonstrated that their policies and processes meet the highest possible quality standards. New England Compounding Center is not a current PCAB accredited pharmacy.” (Emphasis in original). See www.prnewswire.com/news-releases/the-international-academy-of-compounding-pharmacists-responds-to-meningitis-outbreak-tied-to-compounding-pharmacy-172725431.html.

In an Oct. 5 release, the FDA made clear that had not yet conclusively determined that NECC's product was the cause of the outbreak of fungal meningitis across the country; however, it confirmed that the Centers for Disease Control's interim data showed that all the infected patients received an injection of NECC's product. Meanwhile, NECC has recalled all products produced at its Framingham, MA, facility, and has voluntarily shut down its operation.

Janice G. Inman is Editor-in-Chief of this newsletter.