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Weak drug regulation and patient tragedies: We’ve seen this story before

Plenty of new drugs, but few that are truly innovative. Growing costs from their use. Physicians deemed “Dupes of Big Pharma” for their interactions with the pharmaceutical industry. A call to produce better information on which drugs work best. Finally, shoddy drug manufacturing is injuring and even killing patients. These stories could be lifted from today’s headlines — but they’re actually from 1962. Problems with the behavior of the pharmaceutical manufacturing industry, and our relationship with it, are not new. Nor are they restricted to one country. Every developed country’s health-care system is different, but one feature is near-universal: none have a public pharmaceutical industry. Ever nation relies on for-profit, private companies to supply its population with drug products.

Blog posts here can get pretty wonkish about health policy, as many of the substantial challenges to science-based medicine have their roots in regulation — whether it’s DSHEA which implemented a regulatory double-standard for supplements, or the state-by-state legislative alchemy that Jann Bellamy has documented, which transforms magical thinking and pseudoscientific practices into registered and regulated health practitioners. Federal food and drug regulations have also come under some scrutiny (and praise). The FDA’s under fire again; this time over its responsibility to oversee pharmaceutical manufacturing. But in this case, it’s not Big Pharma that’s the villan — it’s pharmacies.

Pharmacies rarely makes the headlines, and that’s probably a good thing. Safe and effective is boring. But my Google Alert for pharmacy news has been pinging me nonstop. The catastrophe of fungal meningitis that continues to emerge across America may be the worst drug manufacturing disaster since the 1930′s when the S.E. Massengill company inadvertently mixed the antibiotic sulfanilamide with antifreeze, killing over 100 people. It was the Massengill fatalities that led to the Food, Drugs and Cosmetics Act (1938). They were a good first start, focusing on the requirement to for manufacturers to document that their products were safe. But they didn’t go far enough.

From today’s perspective, the FD&C Act (1938) was pretty basic.  There was no requirement for manufacturers to demonstrate good manufacturing practices. And if the FDA didn’t move to block a sale within 60 days, a product could be sold. By the 1950′s, it was clear that the Act wasn’t fully effective. Concerns of excessive pricing and questionable evidence statements from manufacturers eventually led to hearings led by Senator Estes Kefauver. Over 18 months an array of new amendments emerged: efficacy claims would be reviewed and approved. Side effects must be reported. Drugs must be approved for sale before any sales could begin. Good drug manufacturing standards would be mandatory, and would be FDA-inspected. Advertising would be monitored. Drugs would have clear generic names, in addition to trade names. All of these proposals made it into the final wording. What’s pretty interesting is what they cut:

  • Compulsory licensing of generics after 3 years to allow competitive markets
  • Banning so-called “me-too” drugs — new drugs which failed to offer substantial improvements over existing drugs — would be forbidden, as well as minor modifications to existing chemicals that didn’t offer any therapeutic improvements (hello, Nexium)
  • Patent approval only where a new drug offered advantages over the current standard treatment — not just demonstrating superiority over placebo

Why did they get cut? As expected, there was strong opposition from pharmaceutical companies. But the American Medical Association also objected, particularly against a greater role for the FDA in evaluating efficacy. The bill was on life support until the thalidomide disaster in 1962 that secured its passage, now called the Kefauver-Harris Amendments to the Federal Food, Drug and Cosmetics Act. It effectively set the template for modern-day regulation which has been subsequently emulated around the world. Without these amendments, the requirements for pre-licensing clinical trials probably would not exist. Nor would longer patents, granted in 1984 based on appeals for longer patent protection due to the barriers established before drugs can be sold.

So how did we end up with a meningitis outbreak this year? Through a loophole in the Act. The contamination of injectable steroids is one of a long string of medical harms caused by “compounding pharmacies” — pharmacies that skirt FDA regulations by acting as chameleons. To hospitals and physicians, they’re businesses selling drug products, just like any other pharmaceutical company. But to the FDA, they claim to be pharmacies, not pharmaceutical companies, which put them under the jurisdiction of state pharmacy regulators. Why the loophole? Until fairly recently, all pharmacies used to be compounding pharmacies. Each store made its own dosage forms like creams and capsules. Everything could be personalized. Today, compounding in the pharmacy has dwindled for most products, as Pharma can do it faster, cheaper, and more accurately.  But compounding is a legitimate part of pharmacy practice, and can fill real patient care needs. And in an era of regular drug shortages, they can manufacture drug product – but without any of the quality standards mandatory for pharmaceutical companies.  Unlike federal requirements which are uniform across the USA and around the world, regulations for pharmacies are determined at the state level, by pharmacy regulators. The same degree of oversight simply does not exist.

It should not be surprising that compounding pharmacies have fought all attempts by the FDA to impose more rigorous manufacturing standards, which would make it harder to sell products. To lawmakers, advocates position it as an access and “right to choose” argument especially for “natural” products like “bioidentical” hormones which are often made by compounding pharmacies. These are the same pharmacies preparing chelation infusions, and they used autistic children to argue for their right to continue to manufacture these products, despite the fact that they are clinically useless for autism. But they seem to work well as a lobbying tool. They’ve successfully killed legislation proposed in 1997, 2003 and again in 2007.  This lobbying success is remarkable given there have been no shortage of problems: Since 1990 the Institute for Safe Medication Practice has documented 22 significant pharmacy compounding errors involving 71 different drugs resulting in over 200 adverse events — some fatal.

But is FDA oversight required to keep fungal contamination out of injectable drugs? It shouldn’t be. The United States Pharmacopeia Chapter <797> establishes sterile manufacturing standards which are expected to be adhered to by pharmacies that make these products. Tightening of requirements <797> in 2008 had the effect of causing more outsourcing to larger pharmacies, as smaller centres could not meet the requirements.  Probably most concerning is that the requirement to follow <797> isn’t uniform across states — five boards don’t mandate it, and the others don’t audit consistently. That seems to be the case in Massachusetts , where the New England Compounding Center (NECC),  has now been closed permanently as it’s revealed that  basic safety and manufacturing standards, including <797> requirements were not being followed when it manufactured preservative-free methylprednisolone acetate. The two lots of drug contaminated with black mold have reached 14,000 patients in 23 states. This is no small operation. Furthermore, NECC was flouting state pharmacy law by failing to act as a pharmacy: it shipped product out without a prescription, or labelled for an individual patient.

Conclusion

Regulatory frameworks evolve over time. Regrettably, it sometimes takes a public health catastrophe to give lawmakers the motivation to ignore vested interests and act in the interest of public health. Like the Massengil deaths in the 1930′s, and the thalidomide birth defects in the 1960′s, the New England Compounding Centre may prove to be the impetus for the appropriate regulation of compounding pharmacies. Products manufactured by facilities like NECC should receive the same regulatory oversight, and meet the same manufacturing standards as any other bulk manufactured drug product. What’s clear is that this responsibility cannot be left to the pharmacy profession to manage itself. As I pointed out back in 2010, pharmacy regulators have repeatedly failed to act on the ethical and safety problems with compounding pharmacies. That their inertia has resulted in another public health tragedy is shameful to the profession of pharmacy, and patients across America are quite literally paying the price.

Posted in: Pharmaceuticals, Politics and Regulation

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20 thoughts on “Weak drug regulation and patient tragedies: We’ve seen this story before

  1. rork says:

    Perhaps on another day I could use spoon feeding on the bad/good of me-too drugs, and non-inferiority of new drugs.

  2. windriven says:

    “prove to be the impetus for the appropriate regulation of compounding pharmacies.”

    Scott, is the problem lack of regulation or the lack of enforcement? I’m not arguing a position here, I’m truly not clear on this.

    Standards for sterile processing are well understood throughout the medical manufacturing industry. Even in cases where products are not sold sterile (devices now, not drugs), manufacturers pay close attention to bioburden.

    It may be that additional regulation is needed. But I’m always cautious about the impulse to add new laws and regulations where existing strictures are not being enforced. When people say, “there ought to be a law,” there often is. What there ought to be is good enforcement of existing law before we decide that we need new ones.

    1. Scott Gavura says:

      @windriven:
      We can generally categorize compounding into two type of practices. There’s individual prescription compounding, for which state/provincial regulations are designed. That’s the practice common to most pharmacies these days – making a suspension of a solid oral dosage form for someone with swallowing difficulties, for example. Then there’s the compounding by pharmacies like NECC which is essentially bulk manufacturing – call it Little Pharma. The scale and magnitude (and potential for harms) are much greater. Compounding pharmacies use the former to argue against regulation, which allows the latter to continue. Yet the oversight and enforcement framework is not comparable to the standards and expectations established by the FDA for manufacturers.

  3. windriven says:

    @Scott Gavura

    “which is essentially bulk manufacturing – call it Little Pharma”

    Bait and switch. Achieve licensure as a pharmacy but operate in fact as a manufacturer.

    There ought to be a law ;-)

  4. The Dave says:

    When our first child was born (2007), my wife got a prescription for Newman’s Nipple Ointment (because of an allergy to lanolin) that had to be filled by a compounding pharmacy. While there, the pharmacist handed us some propaganda pamphlets about how there were laws proposed that would severely limit the ability of compounding pharmacies to practice. They did a good job of making it sound like Big Pharma was persecuting the little guy, but a small red flag did go off in my head that something just didn’t seem right about it. Now I think I fully understand what was going on.

    Thank you, SG

  5. DugganSC says:

    I see a parallel to this and the issues of small food manufacturers. There have been a number of articles over the last year or two of small food purveyors (up to and including children operating lemonade stands, but primarily people making pies and such from their kitchen) being slapped with fines and threats of legal action for not operating under restaurant standards. Putting a new law into place may help to bind these huge companies that are claiming the ability to compound the medications, but may also suddenly restrict the ability of the drug store down the street to put your medication into a more palatable form. Would it be enough to require explicit labeling of medications that have been reprocessed much like how one can buy unpasteurized honey from the Amish fully knowing and accepting the risks?

    I speak, of course, as someone who was largely ignorant of this compounding issue prior to reading the article.

  6. lilady says:

    I’ve been following this outbreak of fungal meningitis intently on the CDC website, since it was first reported by media outlets.

    Here’s the latest from a Massachusetts TV media outlet, about the Massachusetts laws that govern compounding pharmacies. The compounding pharmacy that sent out thousands of vials to physicians, pain centers and hospitals to “stock supplies” of the injectable steroid, violated the Massachusetts law by failing to have individual patient prescriptions, before shipping the drug.

    http://www.cbsnews.com/8301-204_162-57539469/fungal-meningitis-outbreak-claims-24th-victim/

    “…..According to Massachusetts law, compounding pharmacies must have a prescription for every patient for each dose they send out. More than 17,000 vials of the suspect steroid went to clinics in 23 states. However, documents released Monday show that complaints against NECC for lack of individual prescriptions date back to 1999…..”

    I have been unable to find any demographics (age), of any of the patients who were infected/died (patient confidentiality)…but I’m willing to *bet* that many of these patients were NOT Medicare/Medicaid recipients. Did these physicians/pain centers/hospitals just go for the cheaper drug to keep costs down?

  7. The Dave says:

    I think I remember hearing early on that drug shortages from the big pharma manufacturers might have played a minor role, as well. Can anyone verify or refute that?

  8. Janet says:

    @windriven

    “There ought to be a law”

    Or perhaps a loophole being closed would suffice, since this seems to be the way the offending pharmacies got by with their practices. But, can a loophole be closed without creating new laws?

  9. lilady says:

    To clarify my comments above, about Medicare/Medicaid patients becoming infected through contaminated intrathecal injections, from compound pharmacies.

    I should have linked to Scott Gavura’s link at Bloomberg:

    http://www.bloomberg.com/news/2012-10-23/meningitis-outbreak-exposes-need-to-stop-drug-shortages.html

    “…..To get a sense of what might have happened, consider the forces that cause drug shortages. In most cases, the medicines in tight supply are, like the steroid involved in the meningitis outbreak, older generic injectables, the kind that are typically administered by a nurse, doctor or other health professional. They also include antibiotics and cancer and nutrition drugs.

    In an ordinary market, when one company’s production lines shut down, competitors step in to meet demand. The generic injectable drug business is different, however, in that it is greatly influenced by the practices of Medicare, the largest U.S. purchaser of health care. As a Bloomberg Government study points out, Medicare rules from 2005 prevent reimbursement to providers for injectables and other drugs that health-care workers administer from rising more than 6 percent above the average sales price. The cap has reduced suppliers’ incentive to expand capacity when shortages happen.”

    This price limit — well intended to prevent Medicare from overpaying for drugs — also puts pressure on generic drug makers to stint on quality control…..”

  10. windriven says:

    @Janet

    “But, can a loophole be closed without creating new laws?”

    I certainly hope so. If you follow the whole thread of my conversation with Scott, that was the point. New law may be required – but let’s enforce the old ones and close any loopholes before we succumb to legislative fever.

  11. TsuDhoNimh says:

    @DugganSC Putting a new law into place may help to bind these huge companies that are claiming the ability to compound the medications, but may also suddenly restrict the ability of the drug store down the street to put your medication into a more palatable form

    No, because it would be done by ONE prescription from ONE doctor for ONE patient of THAT pharmacy … the way the law now intends. Not batches of thousands of vials shipped over several states. Yes, the will and manpower to enforce the existing laws, and making it impossible for states to write laxer laws woudl be a start.

    My dad was a pharmacist from the early 1930s through the late 1970s, and he compounded many things, but always one at a time for a certain patient … and he would never have compounded anything for injection because he couldn’t keep things sterile. He knew how, but he didn’t have the facilities.

    He used to make my cough syrup too, because I can’t handle the taste of most of the commercial brands. You haven’t had a cold until you have on treated with terpin hydrate and codeine cough syrup, with REAL rum flavoring. :)

  12. mousethatroared says:

    Sorry if this has been mentioned and I missed it, but maybe it’s not so much the regulation but the funding mechanism for inspections and enforcement. Seems like this is an issue for enforcement. Should the tax payer pay for inspection and enforcement or should the party that profits from the product pay?

    Just a thought, I haven’t looked closely at the situation beyond thinking, ‘how very sad’.

  13. Calli Arcale says:

    I think more regulation is actually needed, but not a great deal more. Currently, compounding pharmacies are regulated primarily under state law — even if, like NECC, they are doing interstate trade. Now, states could certainly increase their enforcement so their regulations have some value, but since different states have very different standards, this doesn’t really solve the problem. I think the regulations should be federal, not state, at least for this, because there is such a potential for abuse, and the main loophole that I see is jurisdictional confusion.

    One compromise might be to say that if a pharmacy operates interstate, it is regulated federally. However, that would need to be done carefully, or it will create awkward situations in border cities.

  14. mho says:

    One thing I don’t understand: If there is supposed to be a prescription for each patient dose, aren’t the 23 clinics that ordered the drugs responsible?

  15. windriven says:

    @mho

    “aren’t the 23 clinics that ordered the drugs responsible?”

    As I understand it, no. The regulatory standard seems to be that compounding pharmacies may custom compound a preparation for a specific patient and at the direction of that patient’s physician. That is rather different from mass producing a more-or-less standard preparation and distributing it broadly. That, I believe, falls under the purview of FDA as a drug manufacturer with all of the regulatory burden (and assured quality and safety) that goes with it.

    A similar standard exists for medical devices. A physician may prescribe a custom device or prosthetic and generally a manufacturer can fabricate and deliver that device without going through either the PMA or the 510(k) process. But as soon as that manufacturer decides to make multiple copies and sell them for general use – even if a physician’s prescription is required – the manufacturer must submit to the regulatory process.

    The difference is uniqueness. The loophole exists so that unusual requirements can be met on a timely basis and at a cost that doesn’t include massive regulatory overburden (even a simple PMA can cost tens of thousands of dollars to file and prosecute).

  16. lilady says:

    Here’s the latest on the New England Compounding Pharmacy investigation…

    http://www.reuters.com/article/2012/10/26/usa-health-meningitis-fda-idUSL1E8LQCRX20121026

    “….The FDA’s report adds to an emerging picture of sanitary conditions at NECC, a matter of interest to U.S. and state investigators trying to determine why the pharmacy was allowed to operate despite problems going as far back as 2002.

    Massachusetts health regulators said earlier this week that they had found evidence of problematic procedures, record-keeping and work conditions inside the pharmacy facility.

    FDA CITES COMPANY RECORDS

    According to the FDA report, company records showed more than four dozen instances of bacterial or mold contamination that exceeded acceptable levels over an eight-month period. Some of the contamination occurred inside two “clean rooms.”

    The report quoted NECC personnel as saying the firm shut off clean room air-conditioning each night at 8 p.m., a routine that FDA officials said was not typical for a facility that needs to be kept at a steady temperature.

    A number of instances involved “over-growths,” or blooms of bacteria or mold visible to the naked eye.

    The FDA said the discoveries were not investigated, the contaminants were not identified, and sterile products made on the days when samples were taken were not inspected. NECC had no evidence that corrective actions were taken, according to the report said.

    In a teleconference with reporters, FDA officials strictly limited their remarks to the observations contained in the report. They acknowledged that companies are responsible for correcting contamination that exceeds “action levels.”

    “Manufacturers and compounding firms know what to do,” said Steven Lynn, director of the FDA’s Office of Manufacturing and Product Quality.

    “They have the responsibility to manufacturer quality drugs and to have processes in place to ensure that there’s no breakdown in the supply or the processes that would cause contamination,” he told reporters in a teleconference.

    The FDA said its own inspections found “greenish black foreign matter” and other contaminants in an injectable steroid, 17 vials of steroids containing a “white filamentous material.”

    According to the report, officials found microbial growth in 50 of 50 vials tested, tarnished discoloration on the internal services of sterilizing equipment and yellow residue on equipment used to weigh ingredients and other raw materials used to create sterile drugs.

    The FDA said the production site abuts a recycling facility that handles mattresses and plastics, where excavators and freight trucks produce dust about 100 feet from rooftop units that serve NECC’s heating, ventilation and air conditioning system.”

  17. The Dave says:

    This is a vent more than anything but I recently saw this posted on the fb page for the main campus of the pharmacy school I go to:

    “There is a field trip to (redacted) Pharmacy on WEDNESDAY, at 6:30 pm. This means we get the owner’s complete focus and the pharmacy all to ourselves. This is a great opportunity to see a pharmacy focused on non-sterile compounding available for a possible P1 summer rotation or P3 rotation! They specialize in bio-identical hormone replacement, but also do veterinary and pediatrics. Additionally, they offer consultations for their HRT patients.”

    Part of me wants to speak out about the lack of scientific evidence supporting BHT, but the other part of me doesn’t want to rock the boat and flare tempers. I personally think compounding pharmacies potentially have an important role in the care of patients, and would possibly be interested in doing a rotation at one, but I think I’m going to have to pass on it because I don’t want to be put in the ethical dilemma of performing a service that I don’t believe in.

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