The number of drug shortages has been rising steadily over the last five years, nearly tripling from 61 in 2005 to 178 in 2010. In 2011, FDA tracked over 250 drug shortages. The drugs in shortage are mostly generic injectable medications, many of which have been on the market for decades. FDA earlier this year issued Guidance to industry regarding notification of drug shortages.
In June, the House Committee on Oversight and Government Reform issued a report, which attributed drug shortages to some of the enforcement activity the Food and Drug Administration (FDA) has taken.
Committee Chairman Darrell Issa (R-CA) said the Committee had learned that FDA regulatory activity has effectively shut down 30% of the total manufacturing capacity at four of the country’s largest producers of generic injectable medications. In response to FDA action, companies that produce generic injectable drugs have taken their manufacturing off-line simultaneous to other generic competitors doing the same. Of the 219 drugs listed on the American Society of Health System Pharmacists (ASHSP) shortage list as of February 21, 2012, at least 128 – 58% of the drugs on the shortage list – were produced by at least one facility undergoing FDA remediation.
One month later, Jeanne Ireland, Assistant Commissioner for Legislation at FDA, responded to Ranking Member of the Committee, Representative Elijah Cummings (D-MD). In her letter, Ireland asserted that FDA is “not the root cause” of the shortages. Instead, she noted that more than half of all drug shortages are related to manufacturing product problems, including quality-related issues and delays. The remainder was caused by business decisions to discontinue certain products, difficulty obtaining raw materials, loss of manufacturing sites, increased demand, and component problems.
Ireland recognized that FDA has the authority to exercise “regulatory flexibility” to prevent or mitigate a drug shortage, such as by expediting inspections or review of manufacturing supplements to facilitate production changes. She explained that when FDA finds manufacturing problems or unsatisfactory manufacturing conditions, manufacturers generally must stop production to resolve the problem before resuming manufacturing and distribution.
Ireland also pointed to the recently enacted Food and Drug Administration Safety and Innovation Act (FDASIA) (Pub. Law 112-144), which provides the Agency with new tools to help resolve and prevent drug shortages. We previously provided an in depth summary of the new drug shortage provisions.
She reiterated the fact that in 2011, early notification by manufacturers allowed the FDA to help prevent shortages of 195 drugs, including 86 drugs produced by one company. In 2012, FDA has already helped avert 90 shortages. Much of this success was attributed to President Obama’s October 2011 Executive Order.
Responses to House Committee Questions
First, FDA responded to the Committee’s questions on Waning Letters. Ireland explained that Warning Letters may be issued when manufacturers fail to meet those standards, detailing the violations and the steps the manufacturer must take to come into compliance. Before issuing a Warning Letter, the Office of Compliance in the Center for Drug Evaluation and Research (CDER) consults with CDER’s Drug Shortage Program staff to discuss potential consequences of issuing the Warning Letter. Ireland said that these offices, and other parts of the Agency, balance the risks of a potential drug shortage “against the risk posed by the quality issues the manufacturer is experiencing.”
“The majority of the Warning Letters or other regulatory actions” cited by the Committee, “were related to deficiencies in manufacturing processes and product quality that posed a safety risk to patients. FDA noted that these risks (e.g. endotoxin contamination or the presence of metal particles in sterile drugs) warranted issuing a Warning Letter.
Ireland also clarified that for the cases referenced in the Committee’s report, “it was the manufacturers who made the determination to stop producing drugs. FDA did not require the firms to shut down and even worked with each of them to try to avoid a shutdown, offering assistance to help assess and address manufacturing and quality concerns. The letter describes in detail some of the serious manufacturing or quality problems found at the four firms cited in the Committees report that led to the Form 483s (FDA’s form to note a manufacturing violation or issue) and/or Warning Letters.
FDA next addressed what the Agency believes to be the “primary causes” behind both current and recent increases in drug shortages. FDA explained that there have been now recent changes in current good manufacturing practices (cGMP), and “no evidence of excessive enforcement actions related to manufacturing issues that could cause drug shortages.”
The letter also discussed Field Alert Reports (FARs), which manufacturers are supposed to submit to FDA within three days of becoming aware of quality-related problems with their approved drugs. The letter also addressed reports of product quality problems and adverse events from the public through FDA’s MedWatch website. FDA, however, indicated that both FARS and MedWatch reports “are often not the best indicator.”
Instead, FDA uses the data captured in these systems “to identify signals for follow up.” One instance where adverse events led to a product recall was in July 2009, when a total of 41 reported patients had post-operative chills and flu-like symptoms associated with Teva’s propofol. FDA also noted several Class 1 recalls of drug products, which indicated a potential serious risk to public health. FDA receives a FAR report in connection with a product recall.
Next, FDA noted that the 156% increase in Warning Letters cited by the Committee’s report between 2010 and 2011 was “unrelated to drug shortages; it was due primarily to the actions of the relatively new Center for Tobacco Products (CTP). In 2011, CTP issued 60% of all Warning Letters.
Finally, FDA noted that there have been no recent changes to the cGMP standards or inspection process that “would substantially impact compliance for product manufacturing, including manufacture of sterile injectibles.” Ireland noted that drug shortages began increasing years before the period highlighted in the report (2004-2011), and there has not been a radical increase in relevant Warning Letters.
She maintained that “FDA inspections do not cause firms to have manufacturing or quality problems, which are the root cause of many shutdowns.” She noted how FDA often conducts inspections to follow up on reports from manufacturers, after the manufacturer has identified manufacturing or quality problems or has received reports from practitioners and patients regarding quality issues with a drug.
Conclusion
Ultimately, as FDA begins drafting regulations to implement the drug shortage provisions of FDASIA, the Agency and Congress will likely continue pressing on these issues. It will be necessary for all stakeholders—industry and FDA—to work together to resolve these issues and to prevent future shortages from occurring. Transparency and predictability will enable firms to meet FDA standards so that patients can continue receiving their treatments.
FDA’s enforcement actions run in concert with the current political environment in Washington. Hamburg is perhaps the worst ever at FDA, posing for photo ops with groups like Public Citizen. Since I know this won’t get posted here’s some thoughts to connect – both Teva and Sandoz ceased the manufacture if methylprednisolone acetate injectable due to regulatory scrutiny. What do you suppose created the demand for the compounded product and how many deaths do you suppose would ever be linked to their products?