Experts report that the FDA’s slowness to approve new manufacturers or processes has dissuaded manufacturers from entering the market. To be precise: New manufacturers are entering the market, but not enough of them are.
At a November 2010 summit, which included the American Society of Health-System Pharmacists, the American Society of Anesthesiologists, the American Society of Clinical Oncology and the Institute for Safe Medication Practices, it was generally agreed that the FDA’s process for approvals for new generic drugs was too slow.
The Generic Pharmaceutical Association reports that there is now a backlog of about 1,400 unapproved filings for generics at the FDA. However, it does not specify how many of these are for sterile injectable drugs. Median review and approval times have slowed to nearly 21 months, far worse than the legislatively mandated six months. In 2005, the backlog was much smaller — only 891 applications — and the median time to approval was 16.3 months. The number of applications received that year was 766, increasing to 859 in 2009.
Furthermore, in 2006, the FDA for the first time required drugmakers to seek permission to make so-called “pre-1938” drugs. These drugs were already in use before 1938, when the FDA — without the benefit of Congress amending the law — imposed its monopoly on approving prescription drugs for distribution. Since 2006, manufacturers have had to submit a New Drug Application demonstrating safety and effectiveness for pre-1938 drugs, as if the companies wanted to launch a completely new product. This backlog means that it is increasingly difficult for competitors to enter the market if they anticipate a shortage developing.
It is unclear how frequently incumbent manufacturers stop production voluntarily and how frequently they do so in response to FDA orders when the agency perceives problems. When the FDA inspects a facility, it simply issues “Form 483” if it has questions or concerns not addressed during the inspection. Fewer than 640 Form 483s were issued in 2006, dropping to under 500 in 2008 and rising to about 650 in 2010. Unfortunately, these numbers themselves are not helpful: We don’t know how serious each issue was.
We do know that the FDA has increased inspections of injectable-drug manufacturing facilities. Experts assert that this increase in activity was largely caused by the 2008 recall of Chinese-sourced Heparin (a pre-1938 drug), which was associated with American patients’ deaths. However, the FDA had failed to inspect the deadly source because the agency had confused the names of the Chinese plants that supplied the pig intestines from which the active ingredient was extracted. So the FDA’s increase in inspections was caused not by an increase in dangerous activity at plants, but rather by the FDA’s own failure to maintain an accurate inspection schedule. We also know the FDA’s actions caused a facility in Canada to slow production, even though Canadian regulators thought it was safe.
The FDA’s warning letters are individually available, but it is not easy to digest them and understand the degree to which closing down of production lines is due solely to FDA action. Summary reports are few and far between. Even a March 2011 analysis by Bloomberg (reported from secondary sources) was merely able to conclude that 54 percent of manufacturing facilities inspected by the FDA in 2010 were cited for violations, up one-fifth from the low-water mark in 2007.[*] This analysis covered all manufacturing facilities, however, not just those for injectable drugs. In addition, a technical violation can result in a number of possible remedies short of ceasing production.
Furthermore, some of the drugs in shortage are also controlled substances, which are regulated by the Drug Enforcement Administration. If regulated by the DEA, the manufacturers cannot increase the quantity of the active pharmaceutical ingredient that they are making without seeking the DEA’s permission. However, there is no estimate of the relative importance of this factor.
While various supply-side factors may be contributing to the increase in shortages, there is reason to believe from the evidence discussed here that the FDA’s regulatory actions are a major source of the problem. Specifically, the agency’s slower generic drug approvals, newly instituted regulation of pre-1938 drugs and increased inspections of injectable-drug manufacturers all suggest that FDA over-regulation is an important contributor to the shortages of generic injectable sterile drugs.