I am sure everyone who reads these blogs on Bio Careers is familiar with the on-going story about the outbreak of fungal meningitis traced to contaminated compounded corticosteroids used to treat back pain. The index case was described in the New England Journal of Medicine (Nov 29,2012) as a man in his 50s who presented with headache and neck pain after receiving a spinal steroid injection to help with pain related to degenerative lumbar disk disease. Initially, he was diagnosed and treated for bacterial meningitis and discharged. But he was readmitted soon thereafter and followed a progressive downhill course, and died presumably due to brain aneurysm formation and infarcts caused by the fungal infection in his brain.
As of December 28th, 2012, the CVD reported 656 cases thus far related to the contaminated drugs, including 372 cases of meningitis, 250 paraspinal or spinal infections, 27 joint infections and 39 deaths to date.
The outbreak has been ascribed to 3 lots of preservative free methylprednisolone, a steroid, from New England Compounding Center. These three lots were used to load 17,000 vials distributed between May 21-September 26, 2012, with each vial representing a potential case. The lots reached 23 states, and case finding has had to rely on patients in those states who received steroid shots for back pain, etc. logging on the a site listing the treatment centers that received the contaminated material, to determine if they are at risk. There is no method in place to track and trace to link each vial to any one individual patient.
While symptoms generally occur within 1-6 weeks of exposure to the contaminated steroids, longer incubation intervals have been reported. In attempting to assuage anxiety, patients are being offered some screening with non invasive imaging and invasive tests like spinal taps. But no methodology can provide complete reassurance. Patients have been told to watch for signs of infection like headache, fever, stiff neck, paresthesia, slurred speech or signs of stroke.
The compounding pharmacy involved in this debacle has a long history of shoddy manufacturing practice, and poor regulatory compliance. Inspection after the outbreak revealed “objectionable” conditions. 83 out of 321 vials of methylprednisolone acetate “which purports to be a sterile drug … had a greenish black foreign material and a white filamentous material inside… Microscopic examination of these vials showed the presence of fungus. Additional testing of 50 of these unopened vials confirmed microbial contamination in all 50 vials.”
Yuk! The compounder failed to be able to demonstrate that it had an autoclave to sterilize vials of drugs formulated using non-sterile raw materials. There was also filth and grime all over the place.
Watch for a huge flurry (more like a blizzard) of litigation, coming to a courtroom near you in the not too distant future.
On January 4th, 2013, the Boston Globe reported that the pharmacy tried to deflect blame to their cleaning people, a service that came in for 90 minutes once a month to clean the “cleanroom.” 90 minutes a month! My kitchen gets cleaned every day, in an effort to try to avoid killing my trusting family members with salmonella or E. coli or some other pathogen which comes into all our houses regularly on chicken, eggs or ground beef (not to mention a brown recluse spider two years ago).
Compounding pharmacies are a niche in drug manufacturing, one that is rife with problems. Compounders are said to provide an “indispensible” service by producing and packaging or repackaging specific drugs for individual patient with specific special needs. A patient may need a liquid rather than a pill, a lower dose than standard available formulations, flavored products for kids, unique combination of drugs, lactose free pills, or other customized products. Each compounded product is supposed to be produced/manufactured “on-demand,” so to speak, for one specific individual person. These “valuable” designer therapeutics (which are expensive) are NEVER tested for dose, sterility, and do not provide evidence of safety or efficacy.
Rather than make one set of pills for one person, compounders flagrantly violate manufacturing laws by mass producing products that are in high demand like the steroids implicated in the current outbreak and, in my experience, estrogens and progestin for menopause. After the Women’s Health Intiative in 2002 found that the most commonly prescribed estrogen, Premarin, did not prevent heart disease and also carried a risk of breast cancer, compounders started promoting two other estrogens, estradiol and estriol, alone or in combination. They claimed that “natural” estrogens did not impose the same risk as Premarin, and even said that natural estrogens would lower the risk of breast cancer. And they mass manufactured fixed ratio pills with estradiol and estriol, had “counselors,” advocates and advisors tell doctors what to write on prescriptions for these combos, products that were not really prepped for one patient. Rather, they were at the ready, and simply pulled off the shelf and mailed off to patients.
In 2006, the FDA conducted a study of compounded drugs testing for potency and contamination. They found that 33% failed analytical testing for dose and uniformity. Potency ranged from 67.5% to 268.4% of the declared dose. State regulators also have assayed compounded products, with Missouri and Texas finding that up to 25% of randomly sampled compounded drugs failed potency tests.
Everyone is calling for enhanced regulation and enforcement now. This is not a new idea. According to NEJM editorial (Dec 20, 2012), a law was enacted in 1997 specifying oversight and enforcement, but the US Supreme Court overturned the statute, saying that it limited commercial free speech, weakening the FDA efforts substantially. New legislation – the Verifying Authority and Legality in Drug (VALID) Compounding Act 7 – seeks to give the FDA greater authority to move on compounders, particularly those who are mass manufacturing.
Think about the great range of expertise at work during an investigation of a disease outbreak like this. Take a look at the FDA and CDC sites for more information. These are jobs that provide incredible intellectual stimulation and challenge. From http://www.cdc.gov/employment/menu_topjobs.html:
Top Jobs at the CDC
There are exceptional careers for extraordinary people at CDC. We hire the best, the brightest, and the most committed people to help us carry out our mission. Click on the job title to learn more about the qualifications, duties, and responsibilities of our most common positions.
• Behavioral Scientists
• Biologists
• Emergency Response Specialists
• Epidemiologists
• Health Education Specialists
• Health Informatics Specialists
• Health Scientists
• Medical Officers
• Microbiologists
• Public Health Advisors
• Public Health Analysts
Other Mission Support Positions
• Communications Specialists
• Computer/Information Technology Analysis and Specialists
• Contracts/Grants Analysts and Managers
• Engineers
• Program Managers and Analysts
• Public Affairs Officers/Public Relations
• Safety and Occupational Health Specialists
• Statisticians
• Writers-Editors
