By Susan J. Matthees –  

In an interesting twist in a developing story on the importation of thiopental, a drug used to administer the death penalty by lethal injection, the attorney for Georgia death row inmate Andrew Grant DeYoung sent Attorney General Eric Holder a letter alleging that the Georgia Department of Corrections (“GDC”) appears to have violated the Controlled Substances Act (“CSA”) by failing to register as an importer of thiopental and file a declaration to import the drug.  As we previously reported, six inmates on death row are suing FDA over the importation by three states of allegedly adulterated and misbranded thiopental.  Mr. DeYoung, the Georgia inmate on death row, is not one of the plaintiffs in the suit against FDA.

Thiopental (sodium pentothal) is a Schedule III nonnarcotic controlled substance.  Under the CSA, a nonnarcotic controlled substance cannot be imported unless it “is imported for medical, scientific, or other legitimate uses, and is imported pursuant to such notification, or declaration, or . . . as the Attorney General may by regulation prescribe.”  21 U.S.C. § 952(b).  The Drug Enforcement Administration (“DEA”), as delegated by the Attorney General, has promulgated regulations requiring importers of such substances to be registered and file an import declaration. 

The letter alleges that Dream Pharma Ltd., a distributor in London, England, sold and shipped thiopental to the GDC in July 2010, but that the GDC is not authorized to posses thiopental because it is not registered with DEA.  When questioned, the GDC allegedly produced a DEA-issued registration to possess Schedule III narcotics, but not Schedule III nonnarcotic substances, such as thiopental.  Further, the letter alleges that GDC failed to declare its importation of thiopental as required by 21 U.S.C. § 954(2). 

Federal law and regulations provide some exceptions to registration requirements for the Department of Defense and federal Bureau of Prisons in the case of prescribing, dispensing, or administering controlled substances, but not to procure or purchase.  21 C.F.R. § 1301.22(a).  There is also an exemption for state officials engaged in enforcing state or local laws relating to controlled substances.  Id. § 1301.24(a)(2).  It does not appear that these exemptions would apply to this situation. 

The letter asks Attorney General Holder to direct DEA and/or other appropriate agencies to investigate the GDC’s actions. 

By Carrie S. Martin –

In a draft guidance issued on February 28, 2011, called “Medication Guides – Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Services (REMS),” FDA proposes:  (1) to implement a procedure that allows applicants with a REMS to request eliminating a Medication Guide (“Med Guide”) requirement from the REMS; and (2) to exercise enforcement discretion regarding incorrect distribution of Med Guides to healthcare providers (“HCPs”) and patients.

Eliminating Med Guides from REMS.  FDA’s Med Guide regulations (21 C.F.R. Part 208) were issued in 1998 and require the distribution of Med Guides for certain drugs and biological products that FDA determines pose a serious and significant public health concern.  The Food and Drug Amendments Act of 2007 (“FDAAA”) authorized FDA to require a REMS if the Agency determines that certain measures are necessary to ensure the benefits of a drug with a known or potential risk outweigh its risks.  Under FDAAA, a REMS can include a Med Guide, elements to ensure safe use (“ETASU”), such as limits on distribution, and a communication plan to HCPs.  Despite the two regulatory pathways to a Med Guide, all new Med Guides required by FDA since the enactment of FDAAA, as well as all safety changes to an existing Med Guide, have been part of a REMS.  As a result, the vast majority of the REMS are Med Guide-only REMS that do not include ETASU or communication plans.  Making the Med Guide as part of the REMS subjects the applicant to other requirements implemented by FDAAA that are not included in Part 208, such the creation of an assessment plan.     

With the draft guidance, FDA proposes to allow applicants with Med Guide-only REMS to submit a prior approval supplement (“PAS”) that “proposes a REMS modification to eliminate the REMS if [the applicant does] not believe that the REMS is necessary to ensure that the benefits of the drugs outweigh the risks.”  Similarly, if the REMS includes a Med Guide and a communication plan, the applicant may also submit a PAS to eliminate the Med Guide.  Of note, the draft guidance is silent as to whether an applicant with a REMS that includes a Med Guide and ETASU can similarly request elimination of a Med Guide.  Also of note, if FDA approves the PAS, the Med Guide will endure as labeling and must meet the requirements in Part 208 unless FDA approves a supplement that requests eliminating the Med Guide completely. 

Enforcement Discretion.  The Med Guide regulations in Part 208 are intended to apply primarily in an outpatient setting and require that the Med Guides be distributed directly to a patient via a pharmacist.  However, in many instances, the drug – and hence the Med Guide – is dispensed to an HCP who then gives the drug to the patient.  This often happens in hospital settings, for example.  This had created some confusion over whether the Med Guide needed to be provided to the patient each time the HCP administered the drug.  Under this draft guidance, FDA plans to exercise enforcement discretion when the drug is dispensed to an HCP for administration to a patient in an inpatient setting or an outpatient setting, such as in a clinic or dialysis center, with several exceptions.  FDA will not exercise enforcement discretion (i.e., a Med Guide must be distributed directly to patients) when:  (1) a patient requests a Med Guide; (2) the drug is given in an outpatient setting but will by used by the patient without supervision by an HCP; (3) when a HCP first gives a drug to the patient in an outpatient setting; or (4) when the HCP first dispenses a drug to patient after the Med Guide has been “materially changed.”

Submission of Comments.  FDA requests comments on the draft guidance be submitted by May 31, 2011.  Electronic comments can be submitted via the following website:  http://www.regulations.gov.  Written comments should go to the Division of Dockets Management (HFA-305), FDA, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

By David B. Clissold –

In a federal lawsuit filed on Friday, February 25, 2011 in the District of Columbia, Lorillard, Inc., Lorillard Tobacco Company, and R.J. Reynolds Tobacco Company sued the FDA, DHHS, Kathleen Sebelius, Margaret Hamburg, and Lawrence Deyton for declaratory and injunctive relief to bring the membership of the Tobacco Products Scientific Advisory Committee (“TPSAC”) and the membership of the Constituents Subcommittee of the TPSAC into compliance with the law, and to prevent the defendants from taking any action based on any report or advice provided by the TPSAC or the Constituents Subcommittee.  The complaint alleges that several members of these committees have financial interests and biases that potentially compromise their impartiality.  The plaintiffs state that these conflicts and biases stem from the members’ service as expert witnesses in litigation against tobacco-product manufacturers and their current or recent employment as consultants to the pharmaceutical industry regarding nicotine replacement therapy products and other smoking-cessation products. 

The TPSAC is currently drafting a report on menthol in cigarettes (due March 23, 2011) and will then consider dissolvable products, and the Constituents Subcommittee is currently preparing a report on constituents in cigarette smoke.  The complaint alleges that some of the TPSAC members have incentives to lead the TPSAC to develop a negative report on menthol in cigarettes, since “such a report would be of financial benefit to them in their roles as consultants to pharmaceutical companies that manufacture nicotine replacement therapy products” and “would enhance their value as paid expert witnesses in lawsuits against manufacturers of menthol cigarettes.”  The plaintiffs also touch upon the controversy within the public-health and tobacco-control communities over a possible role for smokeless tobacco products in reducing the harm from tobacco in the United States, thus potentially qualifying such products as a “modified risk tobacco product.” The complaint alleges that the non-voting members of the TPSAC have been excluded from the preparation of the TPSAC report on menthol in cigarettes, and that the defendants “probably will exclude them from important activities relating to dissolvable tobacco products and other subjects.”

As a prelude to the lawsuit, the complaint describes a flurry of correspondence regarding these potential conflicts between the plaintiffs and defendants from March 2010 through February 2011.  The complaint alleges violations of the Administrative Procedure Act, Food, Drug, and Cosmetic Act, and the Federal Advisory Committee Act.  The plaintiffs ask that the court prohibit the defendants from receiving or relying on any information or report issued by the TPSAC or the Constituents Subcommittee, enjoin the defendants from transmitting plaintiffs’ trade secret information to either committee, and require the participation of the non-voting members in matters that do not involve access to confidential information.

By Kurt R. Karst –      

In a win for compounding pharmacies and a loss for FDA, the U.S. Court of Appeals for the Fifth Circuit ruled last week in Med. Ctr. Pharmacy v. Holder that the U.S. District Court for the Western District of Texas violated the law-of-the-case waiver doctrine and that FDA forfeited its ability to argue that the Agency may conduct limited inspections of pharmacy records to determine if pharmacy-compounded drugs comply with FDC Act § 503A (pharmacy compounding) and § 512(a) (new animal drugs) when FDA failed to raise any objection to an initial district court decision on the issue.

The case was before the fifth Circuit for the second time.  In July 2008, the Court ruled in Med. Ctr. Pharmacy v. Mukasey, 536 F.3d 383 (5th Cir. 2008) (see our previous post here), that, although there are reasons to believe Congress did not intend to deem all compounded drugs unapproved “new drugs,” compounded drugs are not exempt from the “new drug” definition at FDC Act § 201(p), and that compounded veterinary drugs fall within the statutory definition of “new animal drug.”  Notwithstanding this determination, however, the Court said that compounded drugs are exempt from the FDC Act’s adulteration, misbranding, and new drug approval provisions if they comply with the conditions set forth in FDC Act §§ 503A and 512(a).

On remand to the Texas District Court, FDA argued that the Fifth Circuit’s July 2008 decision enlarged the Agency’s authority to inspect the records of compounding pharmacies under FDC Act § 704.  The district court agreed with FDA and declared that notwithstanding the pharmacy inspection exception at FDC Act § 704(a)(2)(A), the Agency may, consistent with FDC Act § 704(a)(1), conduct limited inspections of pharmacy records to determine if pharmacy-compounded drugs comply with the conditions set forth in FDC Act §§ 503A and 512(a).  (Previously, the Texas District Court had ruled that state law-compliant pharmacies are exempt from FDA records inspections under FDC Act § § 503A(a)(2)(A).)  The plaintiffs in the case, a group of ten compounding pharmacies, appealed the district court’s new inspection ruling and argued that FDA forfeited the inspection issue because the Agency did not appeal the original inspection ruling, and that the district court therefore erred by reopening the issue on remand.

In its February 25, 2011 decision vacating and remanding the case back to the district court, the Fifth Circuit agreed with the compounding pharmacies.  Under the so-called “waiver doctrine” of the “law-of-the-case doctrine,” an issue that a party could have raised in an earlier appeal in the case, but that was not raised, is barred from consideration (see United States v. Castillo, 179 F.3d 321 (5th Cir. 1999).  The Fifth Circuit ruled that “[t]he instant case . . . fits squarely within the waiver doctrine,” and that because “FDA failed to raise its objection to the district court’s original inspection declaration in the first appeal,” and indeed, “expressly disavowed any intent to raise the inspection issue,” the Agency “forfeited the inspection issue, and the district court erred by reversing its prior inspection ruling on remand.” 

The Fifth Circuit’s ruling in Med. Ctr. Pharmacy v. Holder, although it really only applies to the ten compounding pharmacy plaintiffs in the case and does not match the same level of overall success compounders had in Thompson v. Western States Med. Ctr., 535 U.S. 357 (2002), is nevertheless a win for the plaintiffs on what is to them an important inspectional issue.

By Ricardo Carvajal –

FDA denied a citizen petition filed on behalf of OVOS Natural Health, Inc. (“OVOS”) that asked the agency to issue a regulation under FDC Act § 201(ff)(3)(B) or § 301(ll) acknowledging that marketing of homotaurine as a dietary ingredient in dietary supplements is permissible.  OVOS filed the citizen petition because OVOS had not marketed homotaurine as a dietary supplement or food before OVOS obtained authorization for an IND pursuant to which at least two substantial clinical investigations have been instituted and made public; thus, FDC Act § 201(ff)(3)(B) appeared to prohibit the marketing of homotaurine as a dietary supplement, and FDC Act § 301(ll) appeared to prohibit its addition to food.  However, both sections contain provisions that authorize FDA to issue a regulation that essentially waives their applicability to a particular substance.  

In its response, FDA concluded that the request to exercise its rulemaking authority under FDC Act § 201(ff)(3)(B) or § 301(ll) was moot because homotaurine is not a dietary ingredient within the meaning of FDC Act § 201(ff)(1)(A)-(F).  FDA determined that homotaurine is not an “amino acid” under FDC Act § 201(ff)(1)(D) because it is a gamma-amino sulfonic acid, and not an alpha-amino carboxylic acid or a constituent of proteins.  FDA also determined that OVOS’s homotaurine does not qualify as a botanical (or extract thereof) because it is made synthetically.  Further, FDA determined that there was no evidence that homotaurine “has ever been a dietary substance for use by man to increase the total dietary intake.”

FDA’s response is worth reading for its lengthy discussion of the agency’s interpretation of the term “amino acid” in the context of dietary supplement regulation.  The response also suggests that FDA can be expected to closely scrutinize the applicability of the definition of “dietary supplement” to synthetic substances that are not already part of the food supply.

By Kurt R. Karst –   

It was just yesterday that we commented on how folks in the Hatch-Waxman community have been patiently awaiting FDA’s decision on an October 2010 citizen petition (Docket No. FDA-2010-P-0545) requesting that the Agency not approve any ANDA for a generic version of XYZAL (levocetirizine dihydrochloride) that omits, via a “section viii” statement, information on seasonal and and perennial allergic rhinitis covered by U.S. Patent No. 5,698,558 (“the ‘558 patent”) – XYZAL’s so-called “primary indications.”  Earlier today, FDA responded.  FDA denied the petition and approved ANDAs with skinny labeling for chronic idiopathic urticaria – XYZAL’s so-called “secondary indication.”   The bottom line in FDA’s XYZAL petition decision is similar to many of the Agency’s previous labeling carve-out petitions:

permitting carve-outs for certain patent-protected indications for levocetirizine dihydrochloride would not require removal of safety information from the labeling or alteration of the labeling in such way that would render the drug products less safe or less effective than Xyzal for the remaining conditions of use.

The decision also gives us good reason to update our popular Generic Drug Labeling Carve-Out Citizen Petition Scorecard.  So here you go . . . .

Generic Drug Labeling Carve-Out Citizen Petition Scorecard

FDA Citizen Petition Responses Permitting a Labeling Carve-Out

• FDA Response, Docket Nos. 2001P-0495, 2002P-0191, 2002P-0252 (June 11, 2002) – ULTRAM (tramadol HCl)
• FDA Response, Docket No. 2001P-0495/PRC (Mar. 31, 2003) – ULTRAM (tramadol HCl)
• FDA Response, Docket No. FDA-2003-P-0074 (Apr. 6, 2004) – REBETOL (ribavirin)
• FDA Response, Docket No. FDA-2005-P-0368 (Dec. 1, 2006) – OXANDRIN (oxandrolone)
• FDA Response, Docket No. FDA-2006-P-0274 (Mar. 13, 2008) – ETHYOL (amifostine)
• FDA Response, Docket No. FDA-2007-P-0169 (Apr. 25, 2008) – MARINOL (dronabinol)
• FDA Response, Docket No. FDA-2008-P-0304 (June 18, 2008) – ALTACE (ramipril)
• FDA Response, Docket No. FDA-2008-P-0069 (July 28, 2008) – CAMPTOSAR (irinotecan HCl)
• FDA Response, Docket No. FDA-2006-P-0073 (Nov. 18, 2008) – PULMICORT Respules (budesonide inhalation suspension)
• FDA Response, Docket Nos. FDA-2008-P-0343 & FDA-2008-P-0411 (Dec. 4, 2008) – PRANDIN (repaglinide)
• FDA Response, Docket No. FDA-2008-P-0343/PRC and PSA & FDA-2008-P-0411 (June 16, 2009) – PRANDIN (repaglinide)
• FDA Response, Docket No. FDA-2009-P-0411 – ACTOS (pioglitazone HCl) & ACTOPLUS MET (March 15, 2010) (pioglitazone HCl; metformin HCl) 
•  FDA Response, Docket No. FDA-2009-P-0601 (June 17, 2010) – NAROPIN (ropivacaine HCl monohydrate)
• FDA Response, Docket No. FDA-2010-P-0087 (July 30, 2010) – LYRICA (pregabalin) 
• FDA Response, Docket No. FDA-2010-P-0545 (February 24, 2011) – XYZAL (levocetirizine dihydrochloride)

FDA Citizen Petition Responses Not Permitting a Labeling Carve-Out

• FDA Response, Docket No. FDA-2003-P-0002 (Sept. 20, 2004) – RAPAMUNE (sirolimus)

Pending Labeling Carve-Out Citizen Petitions

• Docket No. FDA-2007-P-0294 – ACTOS (pioglitazone)
• Docket No. FDA-2007-P-0113 – THALOMID (thalidomide)
• Docket No. FDA-2009-P-0597 – Fluticasone Propionate and/or Salmeterol Xinafoate Products
• Docket No. FDA-2010-P-0403 – VAGIFEM (estradiol)
• Docket No. FDA-2010-P-0614 – COLCRYS (colchicine)

BPCA Section 11 Pediatric Labeling Citizen Petitions

• FDA Response, Docket No. FDA-2001-P-0053 (January 24, 2002) – BPCA Implementation
• FDA Response, Docket No. FDA-2002-P-0289 (May 21, 2003) – ALPHAGAN (brimonidine)
• FDA Response, Docket No. FDA-2010-P-0545 (February 24, 2011) – XYZAL (levocetirizine dihydrochloride) 

Withdrawn or “Dead” Labeling Carve-Out Citizen Petitions

• Docket Nos. FDA-2004-P-0426 & FDA-2003-P-0081; FDA Letter – SKELAXIN (metaxalone) (see our previous post here)
• Docket No. FDA-2001-P-0445 – NEURONTIN (gabapentin) Capsules

By Ricardo Carvajal –

In a letter directed to Attorney General Eric Holder, Senator Patrick Leahy (D-VT) asked the U.S. Department of Justice (“DOJ”) for an update on its investigation of the Peanut Corporation of America (“PCA”) and its president, Stewart Parnell.  According to the letter, FDA determined that PCA knowingly distributed potentially contaminated food, and evidence suggests that PCA shopped for a testing laboratory that would provide favorable results.  Sen. Leahy contends that “it is critical [for DOJ] to determine whether these actions rise to the level of criminal conduct.”  The letter also cites the recent pistachio recall and egg-related salmonella outbreak as evidence that “wrongdoers are disregarding the health and safety of American consumers by choosing to sell contaminated products.”  The letter closes by noting that Sen. Leahy has introduced legislation to impose tougher penalties for certain food safety violations, and asks whether DOJ “needs any additional tools to protect the American people.”

By Kurt R. Karst –      

As folks in the Hatch-Waxman community patiently await FDA’s decision on an October 2010 citizen petition (Docket No. FDA-2010-P-0545) requesting that the Agency not approve any ANDA for a generic version of XYZAL (levocetirizine dihydrochloride) with skinny labeling that omits, via a “section viii” statement, information on allergic rhinitis covered by U.S. Patent No. 5,698,558 (“the ‘558 patent”), we read with interest a decision from the U.S. District Court for the Eastern District of North Carolina (Western Division) on a related issue.

The North Carolina case stems from a May 2008 Paragraph IV patent certification Sandoz, Inc. made with respect to the ‘558 patent, and a timely filed patent infringement lawsuit triggering a 30-month stay of ANDA approval.  The ‘558 patent, which expires on September 24, 2012 and is subject to a period of pediatric exclusivity that expires on March 24, 2013, is listed in the Orange Book as a method-of-use patent with a U-812 patent use code defined as “RELIEF OF SYMPTOMS ASSOCIATED WITH SEASONAL AND PERENNIAL ALLERGIC RHINITIS.”  In February 2010, Sandoz allegedly revised its Paragraph IV certification to the ‘558 patent to a section viii statement, requesting approval for its proposed generic version of XYZAL for what the NDA holder has characterized in the above-referenced citizen petition as the “secondary indication,” chronic idiopathic urticaria, and that carves out the “primary indications,” namely seasonal and perennial allergic rhinitis.

Given the change from a Paragraph IV certification to a section viii statement, Sandoz filed a Motion to Dismiss arguing that the District Court no longer had subject matter jurisdiction over the litigation.  The plaintiffs in the case filed their own motion – a Motion to Extend Sandoz’s Thirty-Month Stay – arguing that Sandoz “has not reasonably cooperated in expediting this litigation.”  Naturally, Sandoz opposed the motion, and argued that it should be denied for at least three reasons: “(1) the Court lacks subject matter jurisdiction over Sandoz’s section viii ANDA filing, (2) the 30-month stay is inapplicable to ANDA applicants proceeding under section viii, and (3) Sandoz has not unreasonably delayed this action.”

Under the FDC Act, a timely filed patent infringement lawsuit in response to a Paragraph IV certification means that “the [ANDA] approval shall be made effective upon the expiration of the [30-month stay] . . . or such shorter or longer period as the court may order because either party to the action failed to reasonably cooperate in expediting the action . . . .”  FDC Act § 505(j)(5)(B)(iii) (emphasis added).  Since the enactment of the Hatch-Waxman Amendments in 1984, it has been quite uncommon for a court to extend the statutory 30-month stay on ANDA approval.  In 2009, for example, the U.S. Court of Appeals for the Federal Circuit in Eli Lilly & Co. v. Teva Pharms. USA, Inc., 557 F.3d 1346 (Fed. Cir. 2009) affirmed a district court decision extending a 30-month stay with respect to an ANDA for a generic version of EVISTA (raloxifene HCL) Tablets.

Relying, in part, on a 2009 decision out of the U.S. District Court for the Eastern District of Wisconsin concerning an animal drug and the animal drug Hatch-Waxman counterpart, the Generic Animal Drug and Patent Term Restoration Act (Bayer Healthcare, LLC v. Norbrook Labs. Ltd., No. 08 C 0953, 2009 U.S. Dist. LEXIS 126929 (E.D. Wis. Sept. 24, 2009)), the North Carolina District Court denied Sandoz’s Motion to Dismiss.  The Court concluded that that was no evidence “to demonstrate that the FDA must or in fact has accepted the withdrawal of the Paragraph IV certification, or that the FDA will allow Sandoz to amend its application to include a section viii statement and ‘carve out’ information related to allergic rhinitis,” and that “Sandoz’s failure to cite any authority for the proposition that jurisdiction under section 271(e)(2) requires that an ANDA filer maintain a ‘Paragraph IV’ certification dooms its position” (internal quotation omitted; emphasis added).  As such the Court concluded that subject matter jurisdiction over the litigation is maintained. 

Given this conclusion, the Court rejected Sandoz’s arguments that an extension of the 30-month stay is inapplicable and proceeded to identify examples that the Court deemed sufficient to demonstrate that Sandoz failed to “reasonably cooperate in expediting the action” and that warranted an extension of the 30-month stay under FDC Act § 505(j)(5)(B)(iii) – namely failure to timely produce a privilege log and to comply with the Court’s discovery orders.  Accordingly, the Court extended the 30-month stay by 60 days, until January 27, 2011.

Now that the extended 30-month stay has ended, it would seem that the only block to an approval decision on any pending ANDAs containing a section viii statement to the ‘558 patent is FDA’s decision on the October 2010 citizen petition.  Although FDA has already approved one ANDA for generic XYZAL Tablets – ANDA No. 90-229 – that application contains a Paragraph IV certification to the ‘558 patent.  The sponsor qualified for 180-day exclusivity, which according to the most recent Orange Book Cumulative Supplement has not yet been triggered by commercial marketing, but that exclusivity would not prevent FDA from taking action on ANDAs containing a section viii statement to the ‘558 patent, just subsequent ANDAs containing a Paragraph IV certification to the patent.  Depending on (or perhaps regardless of) how FDA rules on the pending citizen petition, it is possible that the battle over generic XYZAL is far from over.

By Peter M. Jaensch –

United States Senator Charles Schumer (D-NY) recently introduced legislation that is intended to prevent sales of recalled biologics, drugs, medical devices, infant formula, and foods.  However, if that legislation is enacted it  may actually dissuade companies from undertaking voluntary recalls.

On February 14, 2011, Sen. Schumer introduced S. 330, the “Consumer Recall Protection Act of 2011,” which, if enacted, would prohibit sales “to a consumer of a covered product that is subject to a recall,” except  where the “defect was remedied” and the seller notifies the consumer of the “recall, defect, and remedy” prior to sale.  Among other products, the bill covers “[f]ood, drugs, devices, and cosmetics” as defined in the FDC Act.  The bill defines various triggers for when a product is considered to be subject to a recall.  Although specific triggers are provided for medical devices and infant formula, other products are considered subject to a recall whenever there is a “recall of the . . . product by the manufacturer or distributor in response to an advisory or other alert issued by the Commissioner of Food and Drugs that advises consumers to avoid the . . . product.”

The bill is at best ambiguous.  For example, what constitutes an “alert” or an “advisory,” and when is a recall considered to have begun “in response” to such notifications? Moreover, if enacted, S. 330 may actually reduce self-enforcement by companies.  As currently written, S.330 would appear to apply even when there is not a safety issue associated with the “recall.”  Under these and other circumstances, a manufacturer might well think twice about commencing a recall at all if the manufacturer will be prohibited from selling “recalled” products.

There is one particularly interesting bureaucratic feature in the legislation.  Even though the trigger for the prohibition of sales is largely tied to actions of the FDA, that agency would not enforce the legislation.  Instead, Sen. Schumer proposes that the Federal Trade Commission would enforce the legislation if it is enacted.

By Kurt R. Karst –      

Last week, substantively identical legislation was introduced in both the U.S. House of Representatives and in the U.S. Senate to amend the FDC Act to prohibit the manufacture, marketing, sale, or distribution of an authorized generic version of an NDA-approved drug until any period of 180-day exclusivity associated with an ANDA for a generic version of that NDA-approved drug has expired or has been forfeited.  The Senate version of the bill, S. 373, is titled the “Fair Prescription Drug Competition Act.”  The bill was introduced by Sen. John Rockefeller (D-WV), and is co-sponsored by Sens. Daniel Inouye (D-HI), Patrick Leahy (D-VT), Charles Schumer (D-NY), Jeanne Shaheen (D-NH), and Debbie Stabenow (D-MI).  The House version of the bill, H.R. 741, was introduced by Rep. Jo Ann Emerson (R-MO).  The bills introduced in the 112th Congress to ban authorized generics during the pendency of 180-day exclusivity are the latest iterations of legislation that dates back to at least the 110th Congress, when Rep. Emerson and Sen. Rockefeller introduced H.R. 806 and S. 438, respectively – see our previous post here.

Both S. 373 and H.R. 741 would amend FDC Act § 505 to add new subsection (w) – “Prohibition of Authorized Generic Drugs” – to state:

(1) IN GENERAL- Notwithstanding any other provision of this Act, no holder of a new drug application approved under [FDC Act § 505(c)] shall manufacture, market, sell, or distribute an authorized generic drug, directly or indirectly, or authorize any other person to manufacture, market, sell, or distribute an authorized generic drug.

(2) AUTHORIZED GENERIC DRUG- For purposes of this subsection, the term ‘authorized generic drug’ –

(A) means any version of a listed drug (as such term is used in [FDC Act § 505(j)]) that the holder of the new drug application approved under FDC Act § 505(c)] for that listed drug seeks to commence marketing, selling, or distributing, directly or indirectly, after receipt of a notice sent pursuant to [FDC Act § 505(j)(2)(B)] with respect to that listed drug; and

(B) does not include any drug to be marketed, sold, or distributed –

(i) by an entity eligible for 180-day exclusivity with respect to such drug under [FDC Act § 505(j)(2)(B)(iv)]; or

(ii) after expiration or forfeiture of any 180-day exclusivity with respect to such drug under [FDC Act § 505(j)(5)(B)(iv)].

S. 373 would also make a technical, conforming change with respect to the applicability of the definition of “authorized generic drug” at FDC Act § 505(t)(3).  FDC Act § 505(t) – “Database for Authorized Generic Drugs” – was added to the law by Section 920 of the 2007 FDA Amendments Act and requires FDA to compile and publish a complete list of all authorized generic drugs identified in annual reports submitted to the Agency since January 1, 1999.  On July 28, 2009, FDA issued final regulations implementing FDC Act § 505(t) – see our previous post here.  FDA also maintains an online database of authorized generic drugs. 

According to Sen. Rockefeller, “the 180-day exclusivity incentive to launch a patent challenge [created by the Hatch-Waxman Act] is being widely undermined by authorized generics,” which are “becoming even more prevalent as patents on some of the best-selling brand name pharmaceuticals expire.”  Passage of the Fair Prescription Drug Competition Act would, according to Sen. Rockefeller, “revitalize and protect the true intent of the 180-day marketing exclusivity period created in the Hatch-Waxman Act.”

The issue of marketing an authorized generic during the pendency of an ANDA sponsor’s 180-day exclusivity has touched each branch of the federal government.  (See an article we published on the topic a few years ago in RAPS Focus.)  In July 2004, FDA denied two citizen petitions (Docket Nos. FDA-2004-P-0400 and FDA-2004-P-0146) challenging the marketing of authorized generics.  FDA concluded, in part, that “[t]he marketing of authorized generics during the 180-day exclusivity period is a long-standing, pro-competitive practice, permissible under the [FDC Act].”  FDA’s petition decisions were challenged in court, but the Agency ultimately prevailed.  (FDA has not yet substantively responded to a third petition – Docket No. FDA-2004-P-0401.)

In June 2009, the Federal Trade Commission (“FTC”) announced the publication of an interim report, titled “Authorized Generics: An Interim Report,” presenting the first set of results from an FTC study conducted at the request of several members of Congress to examine the short-term and long-term effects of authorized generics on competition in the prescription drug marketplace – see our previous post here.  According to the report, “drug prices are lower when authorized generics are marketed against a single generic drug than when they are not.”  The FTC has not yet issued a more comprehensive report on the topic. 

By Riëtte van Laack –

As previously reported, on Dec. 8, 2010, FDA published a proposal to amend the interim final rule ("IFR") governing health claims concerning the risk of cardiovascular heart disease and consumption of phytosterols (see 21 C.F.R. § 101.83).  FDA stated that, as of February 22, 2011, it intended to discontinue its policy of enforcement discretion that had been in effect since 2003 concerning certain health claims that go beyond the IFR.  Based on comments and petitions by industry contending that more than 75 days were needed to relabel and reformulate products (see our prior post here), FDA decided to extend the 2003 enforcement discretion policy until February 21, 2012.  FDA’s decision does not constitute a response to the petitions it received in response to the proposed rule. 

By Ricardo Carvajal –

Totally Wicked-E.Liquid (“TWI”), an importer and distributor of electronic cigarettes, filed suit to prevent FDA from regulating TWI’s electronic cigarettes as drugs, devices, or combination products, and from barring their importation into the U.S.  TWI claims that the nicotine in its product is derived from tobacco, and that the product is therefore subject to regulation as a tobacco product and not as a drug, device, or combination thereof – an issue that the D.C. Circuit Court of Appeals recently decided in industry’s favor.  TWI contends that “FDA’s actions in barring TWI’s imports, in addition to being ultra vires, are thus the very definition of ‘arbitrary and capricious.’”

By Peter M. Jaensch & John A. Gilbert –

Since the passage of the federal Combat Methamphetamine Epidemic Act in 2005 and state legislation adopted in most states around the same time, retail sales of over-the-counter (“OTC”) cold and allergy products containing pseudoephedrine (“PSE”) have been subject to strict controls.    These restrictions include daily and monthly purchase and sale gram limits, logbook requirements and other security measures such as requiring that the products be sold from “behind the counter.”   Two states, however – Oregon and Mississippi – have further restricted sales of these products by requiring they be dispensed only pursuant to a prescription and scheduling them as controlled substances under the states’ controlled substance laws.  Because of the continued concern about diversion of OTC PSE products, a number of states in this legislative season are contemplating taking similar action. 

Last year, Georgia, Illinois, Missouri, and Washington introduced similar bills requiring prescription-only purchases and scheduling the products as controlled substances – most did not emerge from committee review.  This year, in what seems to be a trend towards increased state regulation, the legislatures in Hawaii, Indiana, Kentucky, Tennessee and Virginia also recently introduced bills to schedule these substances and to require prescriptions in order to purchase products containing pseudoephedrine or other methamphetamine precursors.

These bills are similar in that they generally propose to schedule or reschedule all PSE products as controlled substances (e.g., Schedule III), thus requiring that the products only be dispensed pursuant to a prescription.  For example, in Hawaii, a senate bill introduced on January 20, 2011, adds “any material, compound, mixture, or preparation which contains any quantity of [pseudoephedrine]” to the list of substances classified as Schedule III controlled substances, and amends existing laws to eliminate provisions relating to the procedures for OTC sales of pseudoephedrine products.  In Indiana, Senate Bill 474 similarly classifies any “material, compound, mixture, or preparation that contains a quantity of  [ephedrine or pseudoephedrine]” as a Schedule III controlled substance, thus available only by prescription.  The bill was introduced on January 13, 2011, and to date has not been subject to a vote.

Of the new legislation we have reviewed to date, proposed legislation in Kentucky appears to be the most aggressive.  One bill would require that methamphetamine precursors such as ephedrine, pseudoephedrine, or phenylpropanolamine be classified as Schedule IV controlled substances, available only by prescription.  The proposed law would also prohibit any practitioner from dispensing more than 9 grams of such products to any one patient over a 30-day period and limits refills over a 30-day period.  In a competing bill, another Kentucky senator has introduced legislation that would create a registry of individuals convicted of felonies related to illicit use of precursor chemicals or methamphetamine.  Such individuals would be prohibited from purchasing PSE OTC products; however, the current draft of the legislation would exempt individuals who received the product by prescription.  This is similar to the current law in Oklahoma, which also has established a registry to block certain individuals from purchasing PSE.    

In Nevada, a state senator submitted a “Bill Draft Request” calling for a bill that would, “Require[]… products containing ephedrine, pseudoephedrine and phenylpropanolamine to be dispensed by prescription only unless the product is formulated to prevent conversion to methamphetamine.”  The Nevada legislature convened on February 7, 2011, and we are advised that a bill will be forthcoming.

The introduction of these state bills reflects a perception among the states that the current federal and state restrictions are not sufficient to prevent the diversion of PSE cold and allergy products.  It is unclear, however, whether requiring a prescription or scheduling the drug will make a difference in preventing diversion of PSE.  Such action will make it more difficult and costly for individuals to obtain these medicines for legitimate use.  We will continue to follow these and other similar state bills, and report on significant developments including whether there is any federal legislation introduced along these same lines.

By Kurt R. Karst –      

The tome that is the President’s Budget for Fiscal Year 2012 is chock-full of new proposals that, if implemented, would significantly affect both brand-name and generic drug manufacturers. 

What first caught our attention were some statements in an overview of the proposed FY 2012 budget for the Department of Health and Human Services that:

The Administration will accelerate access to more affordable pharmaceuticals that will lead to cost savings for consumers and health programs across the Federal Government.  The President’s Budget includes two proposals to increase availability of generic drugs by providing the Federal Trade Commission [(“FTC”)] authority to stop drug companies from entering into anticompetitive agreements intended to block consumer access to safe and effective generics, and hastening availability of generic biologics while retaining the appropriate incentives for research and development for the innovation of breakthrough products.

Another budget document, titled “Terminations, Reductions, and Savings” provides a little more detail on these proposals.  Both of these issues were topics discussed in President Obama’s 2009 10-year budget proposal.

With respect to patent settlement agreements, which opponents refer to as pay-for-delay agreements, the President’s Budget says that “[t]he Administration proposal would give the [FTC] the authority to prohibit pay-for-delay agreements in order to facilitate access to lower-cost generics.”  This is authority the FTC has craved for years now, and that according to President Obama’s budget proposal would yield savings of $8,790,000,000 between 2012 and 2021.  As we recently reported, in January, Senator Herb Kohl (D-WI), along with several other Senators, introduced S. 27, the Preserve Access to Affordable Generics Act.  The bill, like its predecessor versions introduced, amended, and debated in the 111th Congress, would amend the Federal Trade Commission Act to permit the FTC to “initiate a proceeding to enforce the provisions of [new Sec. 28] against the parties to any agreement resolving or settling, on a final or interim basis, a patent infringement claim, in connection with the sale of a drug product.”  Such agreements, if challenged, would be presumptively anticompetitive and unlawful unless it can be demonstrated “by clear and convincing evidence that the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement.” 

With respect to the 12-year period of reference product exclusivity created by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), President Obama’s FY 2012 budget says that:

Under current law, innovator brand biologics have 12 years of exclusivity and broad “evergreening” authority, whereby innovator manufacturers are able to make relatively minor changes to the “potency, purity, and safety” of their products to receive an additional 12 years of exclusivity. 

Under the Administration proposal, beginning in 2012, innovator brand biologic manufacturers would have 7 years of exclusivity and would be prohibited from receiving additional exclusivity by “evergreening” their products. 

The Obama Administration estimates that the change in reference product exclusivity  would yield savings of $2,340,000,000 between 2012 and 2021.

The issue of so-called “evergreening,” which is the practice of obtaining additional periods of exclusivity for product modifications, along with the period of reference product exclusivity were hotly debated during consideration of what ultimately became the BPCIA.  According to a December 21, 2010 letter signed by the three principal authors of the BPCIA, evergreening is not a concern because the BPCIA “is clear that no product, under any circumstances, can be granted ‘bonus’ years of data exclusivity for mere improvements on a product.”  The letter goes on to note, however, that “if a ‘next generation’ product is approved by the FDA as a new product (significant changes in safety, purity, or potency) then that new biologic will receive its own 12-year period of data exclusivity.”

The President’s FY 2012 Budget (here beginning on page 227, and here beginning on page 437) also proposes the creation of new user fees. 

The first new fee is the much-ballyhooed generic drug user fee.  Under the President’s proposal, the generic drug user fee charge would be an amount not to exceed $40,122,000 and “would be used to improve review times and reduce the current backlog of applications.”  As we recently reported, the ANDA backlog in FDA’s Office of Generic Drugs (“OGD”) continued to grow unabated in 2010, for a grand total of 2,361 original ANDAs pending at the close of 2010, and with an estimated median approval time of 31 months.  (According to the latest OGD statistics, the ANDA review backlog dipped slightly in January 2011 to 2,356 original ANDAs; however, the number of ANDAs pending more than 180 days continued to grow, from 1,816 ANDAs to 1,836 ANDAs.)

The President’s FY 2012 Budget would also create a new “reinspection fee for medical products” in an amount not to exceed $14,108,000.  According to the proposal, “FDA conducts post-market inspections of manufacturers of human drugs, biologics, animal drugs, and medical devices to assess their compliance with Good Manufacturing Practice and other regulatory requirements. The Budget includes a proposal to enable FDA to assess fees for follow-up reinspections that are required when violations are found during initial inspections.”  President Bush made a similar proposal in his FY 2009 budget request. 

Finally, the Obama Administration’s budget proposal includes a new “international courier user fee” in an amount not to exceed $5,338,000.  According to the budget proposal, “[t]he volume of imports, predominantly medical products, being brought into the United States by international couriers is growing substantially. To ensure the safety of these FDA regulated products through increased surveillance efforts, the Budget includes a new user charge to international couriers.”

Each of the user fee proposals is contingent upon the enactment of authorizing legislation.  Generic drug user fees, along with generic drug labeling preemption, may be among the most talked about topics at the GPhA Annual Conference taking place in Orlando later this week.

By Jeffrey K. Shapiro –

FDA’s Center for Devices and Radiological Health (“CDRH”) has proposed the “Innovation Pathway Program” for breakthrough medical devices.  CDRH says it will review these products in 150 days or less, which the agency claims is nearly half the review time of most premarket approval (“PMA”) applications.  The first product in the program is from the Defense Advanced Research Projects Agency (“DARPA”).  It is a brain-controlled, upper-extremity prosthetic device, which uses a microchip implanted on the surface of the brain to restore near-natural arm, hand, and finger function to patients suffering from spinal cord injury, stroke, or amputation.

Color us skeptical.  Not about the DARPA product.  We’re talking about the Innovation Pathway Program.

First of all, this program even at its best will affect probably just one or two products each year.  In other words, it is a very narrowly focused program.

Second, for many years, CDRH has had an Expedited Review procedure in place to speed approval of “breakthrough technology.”  Even CDRH has admitted it has not very worked well. 

The Innovation Pathway apparently is intended to improve CDRH’s track record with innovative products.  It would work like this:  CDRH will issue an Innovation Pathway Memorandum with a proposed roadmap and timeline for the development, clinical assessment, and regulatory review of the device.  The product would be assigned a case manager and reviewed by the Center Science Council, which is a new oversight body being developed within CDRH.  The Council will consist of senior managers and experienced scientists. 

As with the Expedited Review program, enrollment in the Innovation Pathway Program would not change the scientific or regulatory standards that CDRH uses to review submissions and authorize products for marketing.

As we said, color us skeptical.  The DARPA brain controlled prosthetic obviously has amazing potential, and FDA likely would have rushed it through in any event.  We’ll know if this new program has any value if additional products actually start speeding down the Innovation Pathway.

It already looks like that won’t happen any time soon.  CDRH said it will now seek comments from the public on this pathway before it is used again.  CDRH will host a public meeting on the Innovation Pathway program on March 15, 2011 at FDA’s White Oak campus.

This public outreach suggests the program announcement has been designed around the single DARPA product, and is not ready for prime time.  There will be a delay just to hold a public meeting and then digest the comments and further revise the program.

All of which suggests that it will be quite some time before another product is so lucky as to be allowed to speed down the Innovation Pathway.

We would prefer that CDRH work on significantly reducing the review times for all products, for both innovative and same-old, same-old technology.  That would be an innovation CDRH could be proud of.