There are many interesting aspects surrounding the issue of FDA approval of Non-Biologic Complex Drugs (NBCDs), not the least of which is the FDA’s pathway to predictably for follow-on products such as those now being prepared for glatiramer (Copaxone).
And the FDA issues have a crucial impact on patient care – specifically therapeutic interchangability. Payers are watching.
As the agency has stated (most recently in a response to a letter from Representative John Dingell):
FDA believes that it is possible for manufacturers to develop generic versions of complex large-molecule drugs that can be demonstrated to have the “same” active ingredient as the reference listed drug and meet the requirements for generic approval under section 505(j) of the FD&C Act and FDA regulations … FDA currently believes that it may be possible, with some complex products, for an applicant to demonstrate that its proposed drug product meets the standards for approval as a generic drug under section 505(j).
‘It is possible.” “May be possible.” Now that’s a real conditional response.
Importantly, the agency notes, “It is important to note that analytical methods, data analysis, and pharmaceutical manufacturing capability continue to evolve.”
As far as human trials are concerned, the FDA writes that, “in appropriate cases, FDA can ensure that a generic version of a complex large-molecule product approved under section 505(j) is therapeutically equivalent to the reference-listed drug without clinical safety or efficacy data because the product has been shown to satisfy the statutory sameness standard and other requirements of section 505(j).
Clearly not every case with every NBCD is identical (Lovenox certainly comes to mind), but greater clarity on how the agency review process is certainly needed. Each circumstance – although unique – cannot be forever de novo.
And the policy precedents for biosimilars are also important to consider.
On legal front, the FDA is being given chevron deference by the courts.
Per www.fdalawblog.net …
In a May 14, 2014 Order following a hearing earlier that day, Judge Ellen Segal Huvelle of the U.S. District Court for the District of Columbia granted on ripeness grounds FDA’s Motion to Dismiss a lawsuit brought by Teva Pharmaceutical Industries Ltd. and Teva Neuroscience, Inc. (collectively “Teva”) alleging that FDA’s May 2, 2014 denial “without comment” of a December 2013 Citizen Petition (Docket No. FDA-2013-P-1641) concerning COPAXONE (glatiramer acetate injection) violates the FDC Act and the Administrative Procedure Act. At the same time, Judge Huvelle denied as moot Teva’s Motion for a Preliminary Injunction.
As we previously reported, Teva filed the lawsuit seeking declaratory and injunctive relief after FDA denied “without comment” several citizen petitions Teva submitted to FDA since 2008 concerning the approval of ANDAs for generic COPAXONE and considered by FDA under the citizen petition procedures added to the FDC Act at Section 505(q). According to Teva, “FDA’s tactics make it virtually impossible for a court to provide aggrieved petitioners with meaningful relief before they are harmed irreparably.” Each patent listed in the Orange Book for the 20MG/ML strength of COPAXONE expired on Saturday, May 24, 2014. (After patent expiration, FDA can make ANDA approval decisions.)
The D.C. District Court almost immediately denied Teva’s Motion for a Temporary Restraining Order after it was filed, and scheduled a May 14th hearing on Teva’s Motion for a Preliminary Injunction. Teva pitched its requested relief as follows:
The relief Teva seeks could be structured in either of two ways. First, this Court could simply enjoin the FDA from approving any purported generic version of Copaxone® until the Court has conducted an expedited trial on the administrative record defined by Congress and ruled on the merits of Teva’s petitions. In the alternative, this Court could employ a variant of the procedure Judge Bates first crafted in the Hi-Tech case, permitting the Agency to finally offer its views on the issues Teva has raised on a negotiated timetable—though whatever views the Agency might offer would be, by the law’s plain terms, outside the administrative record and thus entitled to no deference—but enjoining the Agency from acting to approve any purported generic version of Copaxone® until this Court can provide meaningful judicial review of the critically important matters Teva has raised.
The so-called “Bates procedure” in Hi-Tech Pharmacal Co. v. FDA, Case No. 08-cv-1495, was established by Judge John D. Bates, who has been particularly critical of FDA’s handling of exclusivity decisions, to give the parties (i.e., FDA and a drug manufacturer) a chance to sit down in court where FDA would reveal an exclusivity decision, thereby allowing a potentially aggrieved generic manufacturer the opportunity to challenge that decision (see our previous post here).
FDA, in the Agency’s Motion to Dismiss, argued that Teva’s lawsuit should be dismissed for a litany of reasons. According to FDA:
Not only are Teva’s claims unripe and unjusticiable for want of standing, but Teva has not established that it will suffer certain, great, and irreparable injury in the absence of a preliminary injunction. If Teva ever suffers the loss that it claims it will here, such loss will be a small percentage of its multibillion dollar portfolio of generic and brand drugs, and thus would not threaten or even seriously injure the business. And finally, the balance of harms weighs against the entry of preliminary relief because Teva’s desire to further delay generic competition does not outweigh FDA’s interest in the thoughtful and careful exercise of its generic approval decisions without premature judicial interference.
FDA’s efforts to get Teva’s lawsuit tossed were backed by briefs (here and here) filed by Intervenor-Defendants Mylan Pharmaceuticals Inc., Sandoz Inc., and Momenta Pharmaceuticals, Inc., which reportedly have ANDAs pending at FDA for generic COPAXONE.
After a hearing that went on for over three hours, Judge Huvelle rendered her decision: granting FDA’s Motion to Dismiss and denying Teva’s Motion for a Preliminary Injunction. Her decision was grounded in previous decisions in Pfizer Inc. v. Shalala, 182 F.3d 975, 980 (D.C. Cir. 1999), AstraZeneca Pharmaceuticals v. FDA, 850 F. Supp. 2d 230 (D.D.C. 2012), and Mylan Pharmaceuticals Inc. v. FDA, 789 F. Supp. 2d 1 (D.D.C. 2011), where ripeness was a central issue to deciding the cases. Judge Huvelle also refused to employ the “Bates procedure;” however, she did ask for a 24-hour “heads-up” from FDA on ANDA action. According to Judge Huvelle at the May 14th hearing:
What we have here is a fact-specific complicated, complex scientific issue that has to be determined; and it hasn’t been determined yet. To force them to decide the really difficult scientific issues at this time, I don’t have the power to do so, and it has to wait until there is a concrete application of the requirements for bioequivalency and sameness. When that is determined, then Teva has the right to have a review of the administrative record and a speedy decision, and they can fight at that point about whether they’re entitled to a preliminary injunction. That is the only protective-window ability the court has. Although if, in fact, we have an approval of an ANDA and this case comes back to this Court, I can assure you the FDA will have a matter of days to get together the administrative record because that is the only thing that holds us up. . . .
Your right here is to get a final agency action. That doesn’t mean that it has to be the final agency action on what you want. They have said that we need to take it up in the context of a specific ANDA. That is an action. We haven’t got to that point yet. You cannot force us to take a premature action on this.
The Court rests on jurisdictional grounds and will grant the motion to dismiss, deny the [Preliminary Injunction]. To the extent that anything is going to happen, I am requiring the FDA . . . to give the Court notice so that we’re available to decide the difficult issues that come up here. I’m not in the position of doing what Judge Bates did because you don’t have a deadline, you’re not in that position, but I certainly think that as a courtesy to all people, you should give us 24 hours’ notice before if you’re going to issue anything . . . just to let us know.
The 24-hour notice from FDA is apparently intended to allow the Court to adequately prepare and schedule for what may be the next Teva lawsuit – this time challenging an FDA decision to approve ANDAs for generic COPAXONE.
For a more detailed look at the various briefs, here are some useful inks:
Supreme Court Docket:
Aug. 11 Brief of Respondents’ from Sandoz/Momenta and Mylan/Natco
Brief of Petitioners from Teva
Teva filed an earlier reply of applicant brief to the court on April 17, 2014, which can be found here, and a reply of petitioners brief on February 26, 2014, which can be found here.
Stay tuned.