Posted 05 March 2014
By Alexander Gaffney, RAC
Drug shortages have been a recurring problem in the US thanks to a combination of market factors, regulatory decisions made by the US Food and Drug Administration (FDA) and manufacturing problems experienced by companies.
So in 2012, when Johnson & Johnson's oncology drug Doxil (doxorubicin hydrochloride liposome injection, NDA #050718) started experiencing shortages, FDA unveiled an unusual plan. It would allow a similar drug, Lipodox (ANDA #203263), made by Indian manufacturer Sun Pharma, into the country to help ease the shortages.
Background: Shortage of Doxil
As noted by Focus, the solution was not without some red flags, including FDA's admission that the drug had not undergone bioequivalence testing before being allowed into the US. Ordinarily, such testing is required to make sure the drug is substitutable for the other drug. However, in light of serious and ongoing shortages of Doxil, this concern was largely brushed aside.
FDA also issued assurances at the time regarding the drugs' safety, efficacy and quality.
"We are confident using regulatory discretion to ensure the safety and utility of this product," FDA Associate Director Valeria Jensen, head of FDA's drug shortage program, said.
"We have every reason to believe that Lipodox has the same efficacy and safety as Doxil," said FDA spokeswoman Lisa Kubaska in an email to Regulatory Focus. "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."
In a statement, FDA also said that it "evaluates the foreign-approved drug to ensure that it is of adequate quality and that the drug does not pose significant risks for US patients." Which is not, of course, the same as being bioequivalent.
Still, Kubaska said that the drug's sponsor, Sun Pharma, marketed the drug in other countries and had "conducted studies that are reassuring to this effect."
Background: Full Approval for Lipodox
FDA's "enforcement discretion" policy was intended to be temporary, but it remained in effect for a year until FDA ultimately granted the drug full approval in February 2013.
The agency granted full approval to Lipodox under FDA's 505(j) generic drug pathway, which requires bioequivalence testing to show that the drug is identical to the reference listed drug (RLD), in this case Doxil.
FDA added that it would 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.
Citizen Petition: What's Generic to What?
But according to a new Citizen Petition filed with FDA in February 2014, FDA's approval created new problems for future generic approvals.
As the petition explains, when FDA approved the Lipodox (#203263) ANDA, it also made it the RLD for doxorubicin, meaning that future generic versions of Doxil would need to show equivalence not to Doxil, but to Sun's Lipodox instead.
The petition, authored by Paul Braier of the law firm Greenblum & Bernstein, PLC, argues that FDA had erred in maintaining this policy. To begin with, FDA made the change "without an opportunity for public comment" and without subjecting the product to the "full array of clinical trials required for NDA approval."
While that was done to alleviate drug shortages-the petition observed that "since October 2013, Sun seems to meeting the entire US demand for the product"-it raised serious issues regarding the safety of future generic products, the petition says.
"FDA's action raises serious safety issues, because proving bioequivalence to Sun's product does not demonstrate bioequivalence to Doxil," which was subject to the full array of clinical tests, it said. That could result in a future generic product potentially being significantly different than the original Doxil formulation.
"Myriad variations actually exist between Doxil and Sun's product," the petition adds, citing a scientific report submitted in tandem with the filing. Those differences could harm patients, the petition says, noting the wide array of serious risks associated with use of the drug.
The petition notes a 2013 draft guidance on Doxorubicin HCl, which contains fairly extensive bioequivalence requirements for companies wishing to get generic versions of the drug approved, as evidence of the complexity of testing required for the product.
The petition goes on to ask that FDA "re-list Doxil as the RLD for doxorubicin HCL," or alternatively to "request that any ANDA or 505(b)(2) application referencing Sun's product be required to prove bioequivalence with enhanced statistical confidence to ensure that any product bioequivalent to Sun's product also will be bioequivalent to Doxil."