The US Food and Drug Administration (FDA) has announced the approval of a generic version of a critical cancer drug that it has been allowing to be imported for almost a year under a rare exercise of its enforcement discretion intended to alleviate drug shortages.
In late 2011, regulators became aware of mounting drug shortages they said were caused by several factors, but most notably manufacturing problems found at a number of facilities that made sterile injectable drugs like Doxil (doxorubicin). Those problems caused the facilities to be shut down, creating difficulties for many patients and physicians who said they either could not find any supplies of the drug available, or did not have a sufficient amount of the drug to ensure a complete treatment regimen could be followed.
In the wake of mounting public outcry, FDA Commissioner Margaret Hamburg announced in February 2012 that the agency would be working with Sun Pharma FZE to allow for the limited import of a Doxil substitute, Lipodox, manufactured at an FDA-inspected facility in India.
"We are confident using regulatory discretion to ensure the safety and utility of this products," FDA Associate Director Valeria Jensen said. Jensen is the head of FDA's drug shortage program, which coordinated the import of the drug.
FDA called the import a "rare case," and press officials clarified to Regulatory Focus that it had only been used to alleviate drug shortages 8 times in the 18 months preceding the Lipdox announcement.
While Lipodox had not undergone bioequivalency or other laboratory testing, FDA spokeswoman Lisa Kubaska said the agency was confident that the two were interchangeable.
"We have every reason to believe that Lipodox has the same efficacy and safety as Doxil," said Kubaska in an email to Regulatory Focusat the time. "FDA evaluates the overseas drug to ensure that it is of adequate quality and that the drug does not pose significant risks for US patients."
"Sun Pharma markets Lipodox in other countries and has conducted studies that are reassuring to this effect." FDA sought out Sun Pharma to help ease the shortage, added Kubaska.
FDA officials would use the same tactic a month later to allow the import of a generic version of methotrexate, this time from an approved Hospira distributor in Canada.
That regulatory enforcement discretion has continued since February 2012. In October 2012, Regulatory Focus again reached out to FDA to determine if the agency planned to continue to exercise its regulatory discretion to allow for the import of Doxil in light of easing shortages and manufacturing facilities coming back online.
The 2011 shutdown of Bedford, Ohio-based Ben Venue laboratories, which manufactures Doxil for Johnson & Johnson, was a prominent cause of the drug's shortage. In October 2012, the facility announced that it had signed a consent decree with FDA and had resumed limited manufacturing operations on more than 100 drugs, including Doxil.
A 15 October 2012 letter from J&J subsidiary Jannsen, which markets Doxil, said the move was "restoring full access to Doxil in the US for physicians and the patients they serve."
"With this new full access, we are able to suspend the Doxil C.A.R.E.S. Physician Access Program," it continued, referring to the rationing program it had put in place to get Doxil to patients.
But even as shortages seemed likely to abate, FDA said it had no intention of stopping its allowance of Sun Pharma's Doxil substitute, Lipodox.
"FDA is continuing its exercise of enforcement discretion for the importation of Sun's liposomal doxorubicin product, Lipodox," said FDA spokeswoman Shelly Burgess in a statement exclusively to Focus. "Doxil remains in shortage. FDA continues to work closely with the manufacturer of Doxil as it works to resupply Doxil to the US market."
Burgess also said FDA plans to continue to use its enforcement discretion to allow for limited importation of unapproved drugs in the future to combat shortage situations. "FDA will continue to consider enforcement discretion for importation in appropriate cases. Temporary importation of foreign drugs is considered in rare cases when there is a shortage of an approved drug that is critical to patients and the shortage cannot be resolved in a timely fashion with FDA-approved drugs."
Burgess said the agency took measures to assess the product's safety and quality outside of bioequivalency testing. "Before exercising enforcement discretion for the temporary importation of a foreign drug to address a shortage, FDA evaluates the drug to ensure that it is of adequate quality and that the drug does not pose undue risks for US patients," she wrote.
Final Approval for Lipodox
But now Doxil patients will be able to have an easier time accessing the drug, granting approval to the Sun Pharma's Lipodox under its 505(j) generic drug pathway. That pathway requires more rigorous testing, including bioequivalence testing showing the drug is effectively identical to the reference listed drug (RLD).
"The agency is committed to doing everything we can to address drug shortages so that patients can get the medicines they need when they need them," said Jensen in a 4 February 2013 statement. "For the past year, the FDA has been working to ensure that supplies of doxorubicin HCl liposome injection were not interrupted."
FDA added that it will continue to allow the import of unapproved versions of Lipodox until the US-approved version is available in sufficient quantities to satisfy demand.
"Once supplies of Sun's generic doxorubicin hydrochloride liposome injection are sufficient to meet projected demand, FDA expects to stop exercising enforcement discretion for any unapproved doxorubicin HCl liposomal product," it said.
The approval is somewhat unusual because Doxil is protected by orphan drug status marketing exclusivity provisions until 17 May 2014. That protection, however, applies only to its indication for multiple myeloma. Its generic patent protections expired in 2009.
"FDA did not disregard any patents or exclusivities in approving Sun's ANDA," Sandy Walsh of FDA's Office of Public Affairs said in an email to Focus. "This indication will not be included in the Sun ANDA label because it is protected until May 2014. After this date Sun may include this indication in their label. The orphan drug exclusivity is for one indication, not for all of the indications that the drug is used for."