Medication shortage may create a “natural” clinical trial

Epinephrine has been part of the Advanced Cardiac Life Support (ACLS) guidelines since 1974. In the 2010 recommendations, the value of epinephrine use in cardiac arrest was described as:

“Despite the continued widespread use of epinephrine and increased use of vasopressin during resuscitation in some countries, there is no placebo-controlled study that shows that the routine use of any vasopressor during human cardiac arrest increases survival to hospital discharge.

“In adult patients in cardiac arrest ... does the use of vasopressors (epinephrine, norepinephrine, others) or combination of vasopressors, compared with not using drugs .... improve outcomes (eg, ROSC, survival)?”¹

Under any other circumstance, it would be difficult to get institutional approval for a placebo-controlled trial on out-of-hospital cardiac arrest patients in order to answer that question. However, given the industry-wide shortage of such commonly used resuscitation medications, an opportunity exists to conduct such a study - without having to obtain such approval.

Obtaining Patient Consent During CPR
The Resuscitation Outcomes Consortium (ROC) is a clinical trial network focusing on research in the area of pre-hospital cardiopulmonary arrest and severe traumatic injury. Eleven regional clinical centers assembled in 2006 to conduct experimental and observational studies.

Here is how the University of Washington described consent in a ROC cardiac arrest study:

“The studies are being done under ‘exception from consent’. This means subjects are enrolled in the study without their prior consent. Federal regulations usually do not allow patients to be enrolled in a study without their informed consent or without the consent of their next of kin. However, in certain limited situations, such as emergency medicine research, the U. S. Food and Drug Administration (FDA) does allow some studies to be conducted without prior consent.”²

The webpage describes nine consent-related features of the study, including institutional review board (IRB) approval and a process for notifying the legally authorized representative of the unconscious patient of enrollment in the study. Those wishing to opt-out of the study before their cardiac arrest can contact University of Washington and they will receive a bracelet that will be honored by the paramedics.

“We may finally determine if epinephrine makes a difference in cardiac arrest”
This was an observation made by Wake County EMS medical director R. Brent Myers as be began the “National Drug Shortage in EMS” presentation at the January 2013 annual meeting of the National Association of EMS Physicians.³ His concern was that epinephrine supplies may run out within the year.

While it sounds dire, an opportunity arises that would create a natural clinical trial. No cardiac arrest patient would receive epinephrine. Retrospective patient outcomes can compare the ROSC and survival rate of those that got received epinephrine and those resuscitated after the drug became unavailable.

How did we get here?
Three United States factories produce 90% of the generic drugs. The 2003 Medicare Modernization Act changed reimbursement from a wholesale to retail model, significantly reducing the ability of factories to maintain their existing profit model. Private insurers followed Medicare’s lead.

The first shortage of cardiac epinephrine and 50% dextrose occurred in 2010. It was unexpected. Medical directors were scrambling with just a thirty-day supply and no future deliveries were available.

Reimbursement, regulation and safety are the three drivers in this crisis. Private corporations will not make products that are unprofitable. Some of the substitution medications were ten times more expensive than the original.

Federal regulation of medication is amazingly complex, convoluted and slow. Centuries of federal fixes and policy responses to issues of patient safety and business practices built a multi-hump camel that is expected to function as a horse.

Narcotics fall under additional regulations. Adding the DEA’s narcotic and dangerous drug procedures has the effect of adding two legs to the multi-hump camel.

Corporate performance is uneven. A recent patient safety example is a multistate fungal outbreak from contaminated injectable steroid from a compounding pharmacy. A potential 13,534 patients were exposed.⁴ Centers for Disease Control and Prevention (CDC) reports 678 cases of infection in 19 states, including 44 deaths.

Information sources
There are several centers that contain information about drug shortages. For example, the FDA maintains a Current Drug Shortages Index. However, the information is provided voluntarily by manufacturers. According to their web site, the FDA cannot require firms to report the reason for shortage or duration of the shortage or any other information about shortages.” http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm

The American Society of Health-System Pharmacists provides a list of current shortages, resolved shortages and medications no longer available. http://www.ashp.org/menu/DrugShortages.aspx

While there has been recent significant efforts by the EMS community to address the complex federal process of approving drugs, finding equivalent medications and assuring patient safety, it remains a fact that EMS systems must be must be prepared for complete unavailability of certain drugs. In the mean time, there is an opportunity to make lemonade out of lemons, and further our understanding about certain practices in emergency medicine.

References

1. Morrison, L. J, Deakin, C. D., et al. Part 8: Advanced Life Support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2010;122:S345-S421. Accessed February 1, 2013 from http://circ.ahajournals.org/content/122/16_suppl_2/S345.full.pdf
2. University of Washington Medicine (2006) “Pre-Hospital Interventions in Cardiac Arrest – FAQs.” Translational Research – ROC Studies. Accessed February 1, 2013 from http://www.uwmedicine.org/Research/Clinical-Research/Translational-Research/ROC/Cardiac-Arrest/Pages/FAQ.aspx
3. Myers, J. B. and S. Braithwaite (2013). The National Drug Shortage in EMS. Annual Meeting National Association of EMS Physicians, Bonita Springs, FL. Handout accessed February 1, 2013 from http://www.naemsp.org/Documents/HANDOUT%202013%20Myers%20Drug%20Shortage.pdf
4. Smith, R. M., et al. for the Multistate Fungal Infection Outbreak Response Team. “Fungal Infections Associated with Contaminated Methylprednisolone Injections — Preliminary Report.” New England Journal of Medicine published December 19, 2012, at NEJM.org. Accessed February 1, 2013 from: http://www.nejm.org/doi/full/10.1056/NEJMoa1213978

Note: A detailed description of consent for resuscitation research can be found in:
Halperin, H. R. and D. Chamberlin (2007). The special problem of consent for resuscitation research. Cardiac Arrest: The Science and Practice of Resuscitation Medicine. 2nd edition. N. A. Paradis, H. R. Halperin, K. B. Kern, V. Wenzel and D. A. Chamberlain. Cambridge, UK, Cambridge University Press: 216 - 228.