By Kurt R. Karst –    

We’ve been wondering for a while now when FDA might be asked in a public forum to decide on the issue of whether a “first applicant” eligible for a period of 180-day generic drug marketing exclusivity has forfeited such eligibility if FDA tentatively approves the ANDA on the date that is 30 months from the date of application submission.  That day has come with Sandoz Inc.’s (“Sandoz’s”) June 19, 2012 citizen petition (Docket No. FDA-2012-P-0661) seeking FDA’s determination as to whether purported first applicant Ranbaxy, the sponsor of ANDA No. 077830 for a generic version of NEXIUM (esomeprazole magnesium) Delayed-release Capsules, 20 mg and 40 mg, forfeited 180-day exclusivity eligibility in connection with its ANDA as a result of FDA’s February 5, 2008 tentative approval of the application.  According to FDA’s Paragraph IV Certifications List, August 5, 2005 is the first date on which an ANDA was submitted to FDA containing a Paragraph IV certification to a patent listed in the Orange Book for NEXIUM (NDA No. 021153).

Under FDC Act § 505(j)(5)(D)(i)(IV), which is one of the six 180-day exclusivity forfeiture provisions added to the FDC Act by the 2003 Medicare Modernization Act, 180-day exclusivity eligibility is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed. [(Emphasis added)]

The 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which [FDA] received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .”  FDC Act § 505(q)(1)(G).  The FDA Safety and Innovation Act (“FDASIA”) (§ 1133), which is awaiting the President’s signature, would further clarify FDC Act § 505(j)(5)(D)(i)(IV) with respect to certain ANDAs by extending the period during which a first applicant must obtain tentative approval (or final approval if tentative approval is not warranted).  FDASIA § 1133 would not come into play in this case given the 2005 submission date of ANDA No. 077830.

According to Sandoz:

Based on the apparent date on which Ranbaxy’s ANDA was submitted to FDA and the date on which it received tentative approval, Ranbaxy has forfeited its 180-day exclusivity under forfeiture condition (IV), failure to receive tentative approval “within” 30 months after ANDA submission, because Ranbaxy did not obtain tentative approval until the first day of the 31st month and thus not “within” 30 months. (Emphasis in original)

An FDA forfeiture decision is warranted in this case, argues Sandoz, for several reasons.  First, applying common dictionary definitions of the word “within” means that, “‘[w]ithin 30 months’ must be inside that 30-month time period, not outside it” (emphasis in original).  Moreover, counting months – i.e., “the first month after submission of Ranbaxy‘s ANDA on August 5, 2005 ended on September 4, 2005, the second month ended on October 4, 2005, and so on” – means that “February 4, 2008 is the last day that is ‘within’ 30 months of August 5, 2005, ” and as such, “Ranbaxy‘s tentative approval date of February 5, 2008 is one day after expiration of the statutory 30-month period.”  Second, long-standing FDA interpretations and applications of 5-year New Chemical Entity (“NCE”) exclusivity and 7-year orphan drug exclusivity support a forfeiture determination in the case of ANDA No. 077830.  In particular, Sandoz argues with respect to NCE exclusivity that:

[T]the NCE statutory language provides that a Paragraph IV ANDA “may be submitted . . . after the expiration of four years from the date of the approval” of the reference product. . . .  Since FDA has long allowed Paragraph IV ANDAs in this situation to be submitted on the NCE-1 date (the fourth anniversary of the approval of the reference product), FDA must regard the NCE-1 date as the first day of the fifth year after the approval of the reference product.  The logical conclusion is that the last day of “four years from the date of the approval” of the reference product is the day before a Paragraph IV] ANDA may be filed on the NCE-1 date.  (Emphasis in original)

Similarly, Sandoz argues with respect to orphan drug exclusivity that:

Seven-year orphan drug exclusivity prohibits FDA from, in relevant part, approving a generic version of the drug “until the expiration of seven years from the date of the approval of the approved application.” . . .  Just as FDA cannot accept a Paragraph IV ANDA where the RLD is protected by five-year NCE exclusivity until after the expiration of four years from the date of approval of the RLD, FDA cannot approve a generic drug where the innovator product is protected by seven-year orphan drug exclusivity until after the expiration of seven years from the date of approval of the innovator product.  (Emphasis in original)

Finally, Sandoz says that its interpretation of FDC Act § 505(j)(5)(D)(i)(IV) “best serves the public health and the intent of the Hatch-Waxman Amendments,” becuase it “would potentially open the generic market much sooner.”

Interestingly, this is not the first time Sandoz has raised the “within 30 months” issue with FDA.  As we previously reported, back in 2010, Caraco Pharmaceutical Laboratories, Ltd. (“Caraco”), a subsidiary of Sun Pharmaceutical Industries Limited, issued a quarterly report stating with respect to 180-day exclusivity for generic PRANDIN (repaglinide) Tablets that:

The Company believes that it is the first to file an ANDA with a Paragraph IV certification for this drug product and it intends to defend this action vigorously to capitalize on the potential for obtaining 180 days exclusivity available for this product.  On May 26th, 2010, the Company received correspondence from the FDA forwarding a letter sent by Sandoz Inc. to the FDA challenging the Company’s 180 day exclusivity based on when the Company received tentative approval for its product.  The Company responded to the FDA on June 17, 2010.  On June 28th, 2010, Sandoz Inc. replied to the Company’s correspondence.  The Company issued a further letter to the FDA stating its position regarding the 180 day exclusivity on July 9, 2010.  The Company believes it received tentative approval timely, and that it has the potential to obtain 180 day exclusivity for this product.  It intends to defend that position vigorously.

Sandoz notes in the company’s June 2012 petition (footnote 17) that the arguments the company raises with respect to generic NEXIUM Delayed-release Capsules apply “with equal force to the same factual scenario as found for generic versions of PRANDIN® (repaglinide) Tablets.”

Making things even more interesting is speculation that Ranbaxy’s ANDA No. 077830 for generic NEXIUM Delayed-release Capsules is one of the unidentified ANDAs in the Consent Decree (see here and here) the United States filed against Ranbaxy earlier this year and for which Ranbaxy agreed to forfeit 180-day exclusivity.  Although the list of ANDAs subject to forfeiture has not been made public, we note that FDA’s most recent update to the Paragraph IV Certifications List shows that long-pending ANDAs for generic DEPAKOTE ER (divalproex sodium) Extended-release Tablets, 250 mg, and DETROL (tolterodine tartrate) Tablets, 1 mg and 2 mg, were withdrawn (and presumably resulted in a forfeiture of any associated 180-day exclusivity under FDC Act § 505(j)(5)(D)(i)(II)).  FDA tentatively approved Ranbaxy’s ANDA No. 076953 for generic DETROL Tablets, 1 mg and 2 mg, on September 15, 2005.  FDA tentatively approved Ranbaxy’s ANDA No. 077143 for generic DEPAKOTE ER Extended-release Tablets, 250 mg, on September 12, 2005.

By Kurt R. Karst –      

In a June 25th decision from Judge Amy Berman Jackson of the U.S. District Court for the District of Columbia, the court gave a mixed bag ruling on Cross-Motions for Summary Judgment (here and here) filed by FDA and Stat-Trade, Inc. (“Stat-Trade”) in a long-running dispute over FDA’s assessment of user fees under the Prescription Drug User Fee Act (“PDUFA”) in relation to the Stat-Trade’s NDA No. 020353 for NAPRELAN (naproxen sodium) controlled-release tablets, 375 mg, 500 mg, and 750 mg, and the Agency’s process for granting waivers for prescription drug user fees submitted by Stat-Trade.  Legal challenges to FDA’s interpretation and application of PDUFA have been rare over the almost 20-year existence of the statute.  In fact, the Stat-Trade decision is only the second court decision of which we are aware (see here). 

As we previously reported, Stat-Trade filed a Complaint and a Motion for Preliminary Injunction in October 2011 seeking to compel FDA to rule on the company’s PDUFA user fee exception and waiver requests.  Subsequently, Stat-Trade agreed to withdraw the company’s Motion for Preliminary Injunction after FDA agreed to rule on the company’s pending requests. 

Briefly, Stat-Trade alleged that for several years FDA incorrectly assessed fees for certain NAPRELAN strengths that are the subject of an approved ANDA listed in the discontinued section of the Orange Book.  FDC Act § 379h(a)(3)(B) excepts a “prescription drug product” from annual product fees if “such product is the same product as another product approved under an [ANDA].”  FDA and Stat-Trade disagreed as to whether this statutory exception applies in any situation where there is an FDA-approved generic equivalent (regardless of whether the product is listed in the active or discontinued section of the Orange Book), or whether it applies only when the generic is being actively marketed. 

Stat-Trade also submitted multiple requests to FDA seeking waivers of PDUFA fee assessments under the so-called Barrier to Innovtion (“BTI”) and Fees-Exceed-the-Costs (“FEC”) statutory provisions.  The BTI provision at 21 U.S.C. § 379h(d)(1)(B) requires FDA to grant a partial or complete waiver of fees to any company that can demonstrate that “the assessment of the fee would present a significant barrier to innovation because of limited resources available to such person or other circumstances.”  The FEC provision at 21 U.S.C. § 379h(d)(1)(C) requires a fee waiver if the fees “will exceed the anticipated present and future costs incurred by [FDA] in conducting the process for the review of human drug applications for such person.”  Under 21 U.S.C. § 379h(i), to qualify for consideration for a BTI or FEC waiver request “a person shall submit to [FDA] a written request for such waiver . . . not later than 180 days after such fee is due.”

In late October 2011, FDA denied Stat-Trade’s BTI requests for Fiscal Years 2009 to 2011, partially granted the company’s Fiscal Year 2009 and 2010 FEC requests, and refused to rule on Stat-Trade’s FEC request for Fiscal Year 2011 “on the grounds that it could not issue its final determination until it had calculated its standard costs for fiscal year 2011, which, it estimated, would not occur until June 2012 at the earliest.”  With respect to FDA’s interpretation of the “generic exception,” the Agency issued a formal decision affirming the Agency’s interpretation of FDC Act § 379h(a)(3)(B) that active marketing is necessary for the exception to apply.

In November 2011, Stat-Trade filed a two-count Second Amended Complaint alleging violations of the Administrative Procedure Act (“APA”).  Judge Jackson distilled the amended complaint down to the following in her decision:

Count I of the second amended complaint asks the Court to determine whether Stat-Trade is entitled to reimbursement of product fees it paid for the 375 and 500 mg strengths of Naprelan for fiscal years 2009–2012 as well as the amounts it paid to FDA in penalties, interest, and administrative charges for its late payment of product fees for fiscal years 2009–2011. This presents two distinct legal questions:

1)  Whether FDA exceeded its authority under the PDUFA by interpreting the generic exception provision to be limited to situations where the generic is not only “approved,” but also in active production; and

2)  If the Court finds that the exception should have applied, whether FDA abused its discretion and acted in excess of statutory authority by denying Stat-Trade’s request to correct the FY 2009–2011 invoices on the grounds that they were time barred by 21 U.S.C. § 379h(i).

Count II of the complaint asks the Court to determine whether Stat-Trade is entitled to reimbursement for the penalties, interest, and administrative fees that it paid to FDA for the late payment of fees that were eventually waived under the FEC waiver provision of PDUFA. This count also presents two distinct legal questions:

1)  Whether FDA’s decision to defer processing Stat-Trade’s 2011 FEC waiver request until it can determine standard costs for that year constitutes unreasonable delay and is arbitrary and capricious; and

2)  Whether it was arbitrary and capricious for FDA to refuse to review Stat- Trade’s 2009–2010 FEC waiver requests until Stat-Trade had abandoned or exhausted its appeals for its BTI waiver requests.

Judge Jackson addressed each issue in turn.  With respect to Count I, Judge Jackson, in applying the familiar Chevron analysis, found that the case can be resolved at Chevron Step One.  “Stat-Trade takes the position that the statute is unambiguous and so the obligation to defer to the department is not triggered in this case.  Looking at the text of the provision, the Court agrees; the exception plainly applies when there is an approved generic without further limitation,” wrote Judge Jackson in her 26-page opinion.  That win for Stat-Trade was short-lived, however.  As a result of the 180-day deadline for making PDUFA user fee refund requests, and Stat-Trade’s untimely filed refund requests for certain Fiscal Years, Judge Jackson ruled that Stat-Trade is not entitled to a refund of the fees for the untimely filed refund requests.  With respect to Fiscal Year 2012 product fees and Stat-Trade's timely request, however, Judge Jackson ordered FDA to refund the disputed fees.  Moreover, the decision is short-lived because Congress is poised to change PDUFA in a manner consistent with FDA's interpretation of the generic exception.  According to FDA, the change “will clarify FDA’s longstanding policy to use the active portion of the Prescription Drug Product List in the [Orange Book] to identify fee-eligible prescription drug products,” 

With respect to Count II, Judge Jackson found that FDA’s decision to defer processing Stat-Trade’s 2011 FEC waiver request until it can determine standard costs for that year does not constitute unreasonable delay and is not arbitrary and capricious under the APA.  “Since it is the statute, and not FDA policy, that requires waiver applicants to pay their fees before they receive the waiver, the Court cannot find FDA’s timetable to be unreasonable merely because the upfront payment imposes a burden on some companies.  Furthermore, FDA offers a reasonable justification for its method of calculating standard costs.”  As to the second issue under Count II, Judge Jackson said that the issue is moot as a result of FDA’s voluntary review of the waiver requests.

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By Kurt R. Karst –      

Nearly seven years after having received a citizen petition (FDA Docket No. FDA-2005-P-0120) requesting that FDA apply more stringent and unconventional bioequivalence requirements (and twice supplemented – here and here – along the way) before approving generic versions of ADDERALL XR (dextroamphetamine mixed salts of a single-entity amphetamine product) 5mg, 10mg, 15mg, 20mg, 25mg, and 30mg Capsules, FDA finally issued a decision to Shire Pharmaceuticals Group, plc (“Shire”) late last Friday granting in part and denying in part the October 17, 2005 petition.  On the same day, FDA also approved Actavis’ ANDA No. 077302 for generic ADDERALL XR. 

In responding to Shire’s petition, FDA, for only the third time, determined that generic applicants must, in addition to demonstrating bioequivalence using the traditional metrics of area under the plasma concentration versus time curve (“AUC”) – calculated to both the last measured concentration time (“AUC0-t”) and AUC extrapolated to infinity (“AUC0-inf”) – and maximum (i.e., “peak”) drug concentration (“Cmax”), demonstrate bioequivalence using certain partial AUC (“pAUC”) metrics.  As we previously reported, FDA has set out pAUC requirements for generic versions of RITALIN LA (methylphenidate HCl) Extended-Release Capsules and AMBIEN CR (zolpidem tartrate) Extended Release Tablets.  (Still pending are decisions on two 2004 citizen petitions requesting that FDA apply pAUC bioequivalence metrics to generic versions of METADATE CD (methylphenidate HCl) Extended-Release Capsules and CONCERTA (methylphenidate HCl) Extended-Release Tablets.)

FDA approved ADDERALL XR, a dopamine agonist amphedamine, on October 11, 2001 under NDA No. 021303 for the treatment of Attention Deficit Hyperactivity Disorder (“ADHD”) in children ages 6-12 years).  FDA later approved NDA supplements for ADDERALL XR the treatment of adult ADHD (August 11, 2004) and for the treatment of adolescent ADHD (July 21, 2005).  ADDERALL XR contains the neutral sulfate salts of dextroamphetamine (d-amphetamine) and amphetamine with the dextro isomer of amphetamine saccharate and d,levo (l)-amphetamine aspartate monohydrate in two types of drug-containing beads – immediate-release (“IR”) and delayed-release (“DR”) – designed to prolong the release of amphetamine from the drug product.  ADDERALL XR is listed in FDA’s Orange Book with four unexpired patents – U.S. Patent Nos. 6,322,819 (“the ‘819 patent), 6,605,300 (“the ‘300 patent”), RE41,148 (“the ‘148 patent”), and RE42,096 (“the ‘096 patent”) – that are all scheduled to expire on October 21, 2018, but that are each subject to a period of pediatric exclusivity that expires on April 21, 2019. 

Shire’s October 2005 citizen petition made several requests, including that FDA establish certain therapeutic equivalence requirements, such as AUCpR (i.e., area under concentration-time curve truncated at the population median “Tmax”, which is the time to reach peak concentration) in addition to traditional pharmacokinetic parameters, and pAUC measurements for each time point up to 4 hours (AUC0-l, AUC1-2, AUC2-3, and AUC3-4).  A recent petition supplement also requests that FDA apply a pAUC metric of 1.5 hours, or, alternatively, a pAUC metric of 3 hours, and that the pAUC metric be applied in bioequivalence testing under fasting, sprinkled, and fed conditions with appropriate adjustments to the pAUC intervals. 

FDA, in the Agency’s petition response, acknowledged that “it is important to use parial AUC for some specialized dosage forms, because our current acceptance criteria . . . may not be adequate for certain drugs formulated as multiphasic [modified-release] products.”  Moreover, wrote FDA, “because the mixed amphetamine salts [modified-release] dosage form (1) contains IR and DR components; (2) is designed to achieve both rapid onset of activity and sustained activity throughout the day; and (3) does not show unusual accumulation at steady state, the additional metrics may be appropriate to ensure that generic versions are therapeutically equivalent to the reference product.”  FDA was unwilling, however, to accept Shire’s proposed pAUC parameters.  Instead, FDA found:

that using two partial AUCs, AUC0-5h and AUC5h-t, would be sufficiently sensitive to determine the bioequivalence of generic mixed amphetamine [modified-release] formulations.  We would require these two partial AUC metrics, in addition to Cmax, and AUCo-inf, for both d- and l- amphetamines in fasting, fasting sprinkle-in-applesauce, and fed bioequivalence studies of generic mixed amphetamine salts [modified-release] products referencing Adderall XR.

FDA also denied other requests made by Shire in the company’s petition and supplements, including that FDA require generic versions of ADDERALL XR to have identical or superimposable plasma concentration-time profies, that ANDA sponsors perform a deconvolution study, that FDA seek the advice of an advisory committee regarding the pAUC metrics for generic ADDERALL XR, that ANDA sponsors bioequivalence in the pediatric population, and that FDA require ANDA  applicants to conduct clinical effcacy studies if they have not demonstrated an identical plasma concentration-time profile.

Still unclear is how FDA resolved another round of 180-day generic drug marketing exclusivity for generic ADDERALL XR.  180-day exclusivity for generic ADDERALL XR is governed by the pre-Medicare Modernization Act version of the FDC Act where exclusivity is patent-by-patent and product-by-product.  Exclusivity with respect to the ‘819 and the ‘300 patents (for all strengths) was apparently triggered for another ANDA sponsor with the marketing of an authorized generic (see here).  In April 2010, Actavis submitted a citizen petition (Docket No. FDA-2010-P-0188) to FDA requesting the Agency’s determination that Actavis is entitled to 180-day exclusivity with respect to the ‘148 patent.  We understand that the petition was withdrawn.  (The ‘096 patent, which issued on February 1, 2011, first appeared in the February 2011 Orange Book Cumulative Supplement, and presumably triggered a certification from sponsors with pending ANDAs.)

By Kurt R. Karst –      

We’re always interested in cases where things, at first glance, just don’t seem to add up.  If we cannot find an explanation, we may put the case to the side for a while, and wait until an explanation becomes available.  That’s what happened when we saw the June 23, 2011 approval letter for Lannett Holdings, Inc.’s (“Lannett’s”) NDA No. 201517 for Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg per mL), which was submitted pursuant to FDC Act § 505(b)(2).  The approval letter states that the NDA, dated February 26, 2010, was  received by (i.e., submitted to) FDA on March 1, 2010.  Shortly before FDA received Lannett’s NDA submission, the Agency, on January 25, 2010, approved a supplement to Roxane Laboratories, Inc.’s (“Roxane’s”) NDA No. 022195 (also submitted as a 505(b)(2) application) for Morphine Sulfate Oral Solution.  With that supplement, FDA approved a new strength: 100 mg per 5 mL (20 mg per mL).  What perplexed us is how FDA was able to accept Lannett’s application as a 505(b)(2) NDA in light of the Agency’s prior approval of the same drug product.  (Both drug products are approved for the same use: for the management of moderate to severe acute and chronic pain in opioid-tolerant patients.)  In other words, why didn’t FDA refuse to accept Lannett’s 505(b)(2) application and instead require that the application be submitted as an ANDA?

The premise of FDC Act § 505(j) is that an ANDA drug is a duplicate of the brand name drug (i.e., the Reference Listed Drug (“RLD”)).  Draft FDA guidance generally defines the term “duplicate” to mean:

drug products that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, in identical dosage forms, but not necessarily containing the same inactive ingredients, and that meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity disintegration times and/or dissolution rates. 

Elsewhere, FDA has stated that the word “duplicate” means “a product that is the same as the listed drug with respect to active ingredient, dosage form, route of administration, strength, and conditions of use, among other characteristics.”

FDA’s regulation at 21 C.F.R. § 314.101(d)(9) states that “FDA may refuse to file an application if . . . . [t]he application is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the act.”  21 C.F.R. § 314.101(d)(9).  FDA explained how the Agency interprets this regulation in a June 2004 response to a citizen petition (Docket No. FDA-2003-P-0338).  In that case, which concerned a then-pending 505(b)(2) application for Loratadine Tablets, 10 mg, FDA determined that an intervening NDA approval for the same drug product does not bar the Agency from approving a pending 505(b)(2) application.  Specifically, FDA ruled that 21 C.F.R. § 314.101(d)(9) “bars 505(b)(2) applications for products eligible for approval under section 505(j) of the Act only if the product described in a 505(b)(2) application may be approved via section 505(j) at the time of the application’s submission” (emphasis added).  A 505(b)(2) application submitted to FDA before the approval of another NDA – an intervening NDA – that would otherwise render the 505(b)(2) application drug product a duplicate of an approved drug is, according to FDA, unaffected by the intervening NDA approval. 

More recently, FDA discussed the Agency’s intervening NDA approval policy as part of a May 17, 2012 decision granting a citizen petition to designate VELTIN (clindamycin phosphate and tretinoin) Gel, 1.2%/0.025% (NDA No. 050803) as a second RLD in the Orange Book.  A comment submitted to FDA contended, among other things, that VELTIN could have been submitted via an ANDA given the intervening approval of NDA No. 050802 for ZIANA (clindamycin phosphate and tretinoin) Gel, 1.2%/0.025%.  According to FDA, however:

Because there were no pharmaceutically equivalent products approved at the time that Veltin was submitted, it would not have been appropriate for the Veltin application to be submitted as a 505(j) application.  Although we approved the Ziana NDA while the Veltin application was under review, our policy is that we do not require applicants to withdraw and resubmit applications if another pharmaceutically equivalent drug product is subsequently approved.  Therefore, the 505(b)(2) NDA was an appropriate pathway for Veltin’s application.

(It should be noted that under somewhat analogous circumstances, FDA has decided – Docket No. FDA-2008-P-0329 – that the intervening approval of an NDA after the submission of an ANDA made pursuant to an approved suitability petition, and where the NDA approval renders the pending ANDA a duplicate of an approved drug, requires the generic applicant to submit a new ANDA citing the newly approved NDA drug product as the RLD.)

Given FDA’s regulation at 21 C.F.R. § 314.101(d)(9), we were hard pressed to come up with a simple explanation as to how FDA could have accepted Lannett’s application for Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg per mL), as a 505(b)(2) NDA given the previous approval of the same drug product under NDA No. 022195.  After all, FDA’s intervening NDA approval policy interpreting 21 C.F.R. § 314.101(d)(9) did not seem to fit the facts here.  Then, when FDA recently made available the Summary Basis of Approval for NDA No. 201517, an explanation was provided.  According to FDA’s Summary Review: 

The question of evaluating this application as a 505(b)(2) as opposed to an ANDA has been discussed.  The concentration of sorbitol contained in Lannett’s morphine sulfate 100 mg per 5 mL (20 mg per mL) product is high enough that there is a theoretical possibility that doses of morphine sulfate oral solution at or in excess of 300 mg total dose may result in a different relative morphine exposure than doses below 300 mg.  The potential effect of sorbitol on morphine sulfate absorption is based on the effects of sorbitol concentration on ranitidine, a [Biopharmaceutics Classification System (“BCS”)[ class 3 drug.  However, the BCS classification of morphine sulfate oral solution is not clear, and therefore, it is not clear if this concern is relevant for morphine sulfate.

One approach to determining whether there is an effect of the sorbitol concentration on the absorption of morphine would be to perform a pharmacokinetic [sic]. Performing such a study with a dose of 300 mg of immediate-release morphine, even with naltrexone blockade, poses an unacceptable level of risk for opioid toxicity.  Therefore, given that such a study is impracticable, at this time we do not believe that bioequivalence can be effectively investigated, nor can Lannett’s product be AB rated to Roxane’s morphine sulfate oral solution 100 mg per 5 mL (20 mg per mL).  Additionally, because such a bioequivalence study cannot be performed, this product is not appropriate as an ANDA; approval requires a clinical judgment on whether this drug is safe and effective for use.

Quite an interesting theory.  And FDA’s Summary Review for NDA No. 201517 appears to be the only documentation of this theory. 

Just as interesting is the history of Lannett’s efforts to market its Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg per mL), drug product without NDA approval.  As we previously reported, Lannett (along with Cody Laboratories, Inc.) sued FDA in July 2010 concerning the alleged grandfather status of Cody/Lannett’s marketed unapproved Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg per mL).  The lawsuit stems from FDA’s March 2009 Warning Letters to Cody and Lannett (among other companies) to stop manufacturing certain unapproved narcotic drugs, including morphine sulfate oral solutions. 

Cody/Lannett raised three issues in the litigation: (1) FDA’s alleged determination that Cody/Lannett’s product is a “new drug;” (2) FDA’s alleged failure to develop an administrative record for its determination that Cody/Lannett’s Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg per mL), product is a “new drug;” and (3) FDA’s alleged disparate treatment of Cody/Lannett’s standard review NDA compared to Roxane’s priority review NDA.  Ultimately, the U.S. Court of Appeals for the Tenth Circuit affirmed a November 2010 decision from the U.S. District Court for the District of Wyoming granting FDA’s Motion to Dismiss the case.  The Tenth Circuit also dismissed as moot Cody/Lannett’s claim of disparate treatment at FDA concerning the same drug submitted under an NDA.  One has to wonder whether or not there is any relationship between FDA’s decision discussed above concerning the basis for submission and approval of NDA No. 201517 and the litigation. 

Following that court battle, and perhaps in an effort to obtain final agency action to file a new lawsuit, Lannett petitioned FDA (Docket No. FDA-2012-P-0053), requesting that the Agency affirm, pursuant to the 1938 “grandfather clause” of the FDC Act, the grandfather status of morphine sulfate (see our previous post here).  Another Lannett petition (Docket No. FDA-2012-P-0189), seeks a similar determination with respect to certain Oxycodone HCl and Cocaine HCl drug products.  Both petitions are pending at FDA. 

Hyman, Phelps & McNamara, P.C. Director Douglas B. Farquhar is a key presenter at the Food and Drug Law Institute’s (“FDLI’s”) upcoming conference in São Paulo, Brazil.  The conference, which is scheduled for September 10-11, 2012, is titled “U.S. & Brazil: Navigating New Frontiers in Pharmaceutical, Medical Device & Food Law & Regulation,” and will focus on business opportunities and policy challenges of producing safe products and promoting public health.  Mr. Farquhar, who will discuss FDA enforcement activities relating to imported medical devices, will be joined by government officials and other internationally renowned experts who will discuss pharmaceutical, medical device and food law, regulation, and policy in the United States and Brazil.  A copy of the conference agenda is available here.

Brazil, one of the so-called “BRICS” countries, is rapidly emerging as a world leader in innovation and development in the pharmaceutical, medical device, and food industries.  Stakeholders ranging from multinational companies to small startups are staking a foothold in the region.  FDA and the Brazilian National Health Surveillance Agency (“ANVISA”) are working together to safeguard the integrity of the products being exchanged between the two countries, and, by extension, across the globe.  Understanding the current legal, regulatory, and economic environment for the development and sale of pharmaceuticals, medical devices, and foods in in the United States and Brazil is imperative for anyone doing business, or working with clients who are doing business, between the two countries. 

FDA Law Blog readers can receive a 15% discount off the conference registration price.  To receive the discount, use the following promotional code: BRAZIL2012.  To register for the event click here.

By Kurt R. Karst –      

Over the past year or so, we’ve seen a change in FDA policy concerning what approvals the sponsor of a 505(b)(2) NDA can cite in an application; that is, what previous FDA approvals a 505(b)(2) sponsor can rely on for the aproval of its drug product.  This change has not come about by rulemaking or by formal FDA guidance, but rather, has been communicated to potential 505(b)(2) applicants in general FDA correspondence.  As such, we thought the larger food and drug community would benefit from bringing this issue to light. 

FDC Act § 505(b)(2) describes a 505(b)(2) NDA as “[a]n application submitted under [FDC Act § 505(b)(1)] for a drug for which the investigations described in clause (A) of [FDC Act § 505(b)(1)] and relied upon by the applicant for approval of the application were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted. . . .”  Draft FDA guidance distills this statutory description down to “an application that contains full reports of investigations of safety and effectiveness but where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference.” 

FDA’s regulations implementing FDC Act § 505(b)(2) provide that one component of a 505(b)(2) application is the “[i]dentification of the listed drug for which FDA has made a finding of safety and effectiveness and on which finding the applicant relies in seeking approval of its proposed drug product by established name, if any, proprietary name, dosage form, strength, route of administration, name of listed drug's application holder, and listed drug’s approved application number.”  21 C.F.R. § 314.54(a)(1)(iii) (emphasis added).  FDA’s regulations (21 C.F.R. § 314.3) further define the term “listed drug” to mean:

a new drug product that has an effective approval under [FDC Act § 505(c)] for safety and effectiveness or under [FDA Act § 505(j)], which has not been withdrawn or suspended under [FDC Act §§ 505(e)(1) through (e)(5) or FDC Act § 505(j)(5)], and which has not been withdrawn from sale for what FDA has determined are reasons of safety or effectiveness.  Listed drug status is evidenced by the drug product’s identification as a drug with an effective approval in the current edition of FDA’s [Orange Book] or any current supplement thereto, as a drug with an effective approval.  A drug product is deemed to be a listed drug on the date of effective approval of the application or abbreviated application for that drug product.

For years, FDA has permitted sponsors of 505(b)(2) applications to cite products approved under an ANDA as a “listed drug” in their application.  In most cases, this occurred when the brand name drug product was discontinued and FDA designated a therapeutic equivalent approved under an ANDA as the Reference Listed Drug (“RLD”).  In other cases, FDA approved an ANDA under a suitability petition, or approved an ANDA pre-Hatch-Waxman pursuant to a finding under the Drug Efficacy Study Implementaion (“DESI”) program, and designated the ANDA product as the RLD. 

Under FDA’s evolving thinking around 505(b)(2) applications, however, an ANDA can no longer be cited as a listed drug in a 505(b)(2) application.  According to recent guidance from FDA on this issue to would-be 505(b)(2) applicants:

If you intend to rely on the Agency’s finding of safety and/or effectiveness for a listed drug(s) or published literature describing a listed drug(s) (which we consider to be reliance on FDA’s finding of safety and/or effectiveness for the listed drug(s)), you should identify the listed drug(s) in accordance with the Agency’s regulations at 21 CFR 314.54.  It should be noted that 21 CFR 314.54 requires identification of the “listed drug for which FDA has made a finding of safety and effectiveness,” and thus an applicant may only rely upon a listed drug that is the subject of an NDA approved under section 505(c) of the FD&C Act (in other words, an application approved under section 505(j) of the Act (i.e., ANDA, generic drug) may not be cited as a listed drug).  The regulatory requirements for a 505(b)(2) application (including, but not limited to, an appropriate patent certification or statement) apply to each listed drug upon which a sponsor relies.

If you choose to rely on FDA’s finding of safety and/or effectiveness for a listed drug(s) and you intend to use your proposed comparative clinical trial to establish a bridge between your proposed drug product and the specified listed drug(s), then you should use the specified listed drug(s) (rather than a bioequivalent ANDA product) as the comparator.

In other words, the 505(b)(2) pathway, according to FDA, contemplates a 505(b)(2) applicant’s reliance on the Agency’s finding of safety and effectiveness that is contained in an NDA; and because an ANDA does not contain this finding, it cannot serve as a “listed drug for which FDA has made a finding of safety and effectiveness.” 

It is unclear whether FDA’s new policy is a one-size-fits-all policy, or whether there are exceptions.  For example, there might be some unique cases where FDA would permit a 505(b)(2) sponsor to cite an ANDA approved pursuant to a DESI proceeding as as a listed drug.  And what about an ANDA approved pursuant to a suitability petition that FDA has designated as a RLD – can a 505(b)(2) sponsor cite such a drug as a listed drug?  Perhaps FDA’s long-awaited proposed regulations implementing the Medicare Modernization Act will address these issues in greater detail. 

By Ricardo Carvajal –

In a relatively rare example of a request for regulatory action intended to benefit a specific racial or ethnic group, a coalition of businesses and nonprofits submitted a food additive petition (see here and here) asking FDA to amend the food additive regulation for folic acid to permit its addition to corn masa flour – a staple among populations of Latin American descent.  Since the late 1990’s, standards of identity for several grain-based foods have required the addition of folic acid.  According to the petition, that requirement is credited with decreasing the prevalence of neural tube defects among Hispanics and non-Hispanics.  However, Hispanic women continue to have a higher rate of neural tube defects, and fewer of them consume folic acid from fortified foods.  The petition contends that “[f]ortification of corn masa flour presents a clear opportunity to improve intake in those who consume corn masa flour products as a significant portion of their diet,” and could potentially decrease neural tube defects among Hispanic women. 

The observation that diet-related risk factors for certain diseases may vary among racial and ethnic groups is not novel (see, e.g., CDC’s estimation of disparate rates of obesity for Whites, Blacks, and Hispanics).  Nonetheless, it is not clear that a systematic approach to these issues has emerged in relation to food, as it has for drugs.  A 1995 FDA guidance document geared to drug and biologics developers provides recommendations for the collection of race and ethnicity data in clinical trials, in recognition of the fact that numerous “[d]ifferences in response to medical products have already been observed in racially and ethnically distinct subgroups of the U.S. population.”  That same year, FDA approved the first drug to treat a disease in patients identified by race (BiDil, for heart failure in Black patients). 

Although perhaps difficult to estimate, the potential cost savings associated with dietary interventions that reduce the risk of disease could be significant, particularly in relation to the cost of the intervention.  The corn masa petition estimates that the addition of folic acid to corn masa could prevent 40 cases of neural tube defects annually, each of which could generate direct lifetime costs of a half-million dollars.

By Kurt R. Karst –      

A new article, titled “Citizen Petitions: An Empirical Study,” analyzes citizen petitions submitted to FDA between 2001 and 2010 and concludes that petitions submitted to FDA concerning drug products are on the rise and show no signs of abating.  The paper, which is co-authored by Michael Carrier, a professor at the Rutgers School of Law-Camden, and Daryl Wander (currently a Law Clerk to the Hon. Francine Axelrad, P.J.A.D. of the Superior Court of New Jersey, Appellate Division) and that will be published in the Cardozo Law Review, also concludes that FDC Act § 505(q), which was added to the law by Section 914 of the FDA Amendments Act of 2007 (“FDAAA”), Pub. L. No. 110-85 (2007), as amended by § 301 of Pub. L. No. 110-316 (2008), and that is intended to prevent the citizen petition process from being used to delay approval of ANDAs and 505(b)(2) applications, “has not been successful in reducing the number of petitions.”  (Under FDC Act § 505(q), “[FDA] shall take final agency action on a petition not later than 180 days after the date on which the petition is submitted.”  As we previously reported (here and here), pending legislation would shave 30 days off of FDA’s response timeframe, from 180 days to 150 days.)

The authors culled information from Regulations.gov on citizen petitions submitted to FDA between 2001 and 2010 concerning human drugs (excluding citizen petitions that are suitability petitions) and cross-referenced their results with the FDA Law Blog 505(q) Citizen Petition Tracker for post-FDAAA petitions containing a 505(q) certification to come up with a universe of 258 petitions for the analysis.  The authors classified FDA petition responses (177 of them) as “granted,” “denied,” or “mixed.”  For those petition decisions (51 one of them) in which FDA issued a “mixed” decision (i.e., granted in part and denied in part), the authors analyzed each response and determined that the petition was either essentially granted (24%), essentially denied (45%), or was truly a mixed decision (31%). 

Using the universe of citizen petitions and FDA petition decisions, Carrier and Wander then drilled down on the data and performed several broad and sub-group analyses.  For example, their analysis shows (Table 1 below) an increase in the average number of petition submissions pre- and post-FDAAA from 27 to 34 in the three years before and after enactment of FDC Act § 505(q), respectively.

These data comport with data FDA reported on in the Agency’s Annual Reports On Delays In Approvals Of Applications Related To Citizen Petitions And Petitions For Stay Of Agency Action (see our previous posts here, here, and here).  We are eagerly awaiting the release of FDA’s fourth annual report on FDC Act § 505(q) petitions later this year.

In terms of citizen petition success rate, Carrier and Wander looked at the number of petitions decision FDA granted and denied between 2001 and 2010 (161 of them, which does not include 16 mixed decisions and 81 petitions for which a response was not located) and found, as depicted in Figure 1 below, that FDA granted 19% (31 petitions) and denied 81% (130 petitions).  (FDA is currently in the process of clearing the backlog of old petitions that may no longer be timely – see here.)  The success rate for petitions submitted by or on behalf of brand companies (which submit 68% of petitions) is 19%, compared to a success rate of 28% for petitions submitted by or on behalf of generic companies. 

Among other things, Carrier and Wander conclude that FDC Act § 505(q) “has not been successful in reducing the number of citizen petitions.”  This conclusion seems to jibe with a concern that FDA expressed in the Agency’s third annual report on 505(q) petitions that the provision “may not be discouraging the submission of petitions that do not raise valid scientific issues and are intended primarily to delay the approval of competitive drug products.” 

By our count, FDA has already received 17 petitions in Fiscal Year 2012 containing a 505(q) certification – several in recent months.  But it is too early to tell whether or not the Fiscal Year 2012 numbers will be on par with the numbers from previous years.  FDA may ultimately determine that not all of the petitions meet the criteria for consideration as a 505(q) petition.  For petitions submitted to FDA in Fiscal Year 2012, the Agency has issued three responses (two denials and one mixed decision).  A couple of the petitions are “duplicates” insofar as the petitions were withdrawn and resubmitted (and assigned a different docket number). 

Hyman, Phelps & McNamara P.C. invites you to register for our webinar, “Garbage Runs, Fake Identities, and Surprise Home Visits: Strategies to Deal With FDA's Nontraditional Investigative Tools,” which is scheduled to take place on Wednesday, June 20, 2012 from 12:30 – 2:00 p.m. ET. 

From routine on-site inspection to rummaging through trash bins outside your facility, FDA and other government agents have shown increasing willingness to obtain information outside of just conducting regulatory inspections of company facilities.  This webinar will provide an overview of popular, and not so well-known, tactics that the government uses, followed by a discussion of strategies to help your company to prepare for, and if necessary, respond to them.  Participants will gain an understanding of how to deal with the government's demands for information, directed to the company, its current employees, and even former employees, while protecting the company's interests.

The webinar will feature HP&M attorneys Doug Farquhar, John Fleder, and Anne Walsh, who bring the full perspective of experience in government enforcement, including a former Assistant U.S. Attorney, the former Director of DOJ's Office of Consumer Litigation, and a former Associate Chief Counsel at FDA.  They will:

• Share insights from their experiences in the government; 
• Describe trends on government enforcement efforts using these investigative techniques; 
• Analyze publicly disclosed cases; 
• Provide strategies for preparing your company before the government even begins its scrutiny, and responding when the government arrives;
• Explain how government investigative methods have been used against large as well as small corporations; and
• Answer participants' questions during the webinar

You can register for this free webinar here.  Please contact Lisa Harrington (lharrington@hpm.com) with any questions.

By Anne Marie Murphy & Benjamin K. Wolf* –

On June 12, 2012, FDA announced the availability of a draft guidance, titled “Considerations When Transferring Clinical Investigation Oversight to Another IRB” (“FDA Draft Guidance”).  This is the first time FDA has provided through guidance specific direction to the entities (including the original and receiving institutional review boards, or IRBs, the sponsor of the clinical investigation, and the clinical investigator) involved in the transfer of a study from one IRB to another.  Generally, the same IRB (a group formally designated by an institution to review, approve the initiation of, and to conduct periodic review of biomedical research of human subjects) maintains continued oversight of clinical trials at a research site.  However, an IRB or study sponsor may need to transfer a clinical trial for reasons including institutional reassessment or reorganization, natural disaster, or disqualification of the IRB. 

The Office for Human Research Protections (“OHRP”) made available its own draft guidance, titled “Considerations in Transferring a Previously Approved Research Project to a New IRB or Research Institution” (“OHRP Draft Guidance”), which, despite some minor variations from the FDA Draft Guidance, is meant to harmonize with the FDA Draft Guidance.  The Federal Register notice announcing the OHRP Draft Guidance can be found here.

The Agency suggests a non-exhaustive list of eight steps that should be addressed, as appropriate, prior to IRB transfer.  They are:

1. Identifying those studies for which IRB oversight is being transferred; 
2. Ensuring the availability and retention of pertinent records; 
3. Establishing an effective date for transfer of oversight, including records, for the clinical investigation(s); 
4. Conducting a review of the study(ies) by the receiving IRB, where appropriate, before it accepts responsibility for the study(ies);
5. Confirming or establishing the date for the next continuing review; 
6. Determining whether the consent form needs to be revised; 
7. Notifying the key parties; and
8. Updating IRB registration information.

Each of these steps is designed to ensure a smooth transition between IRBs and the continued observance of all regulations pertaining to IRB oversight—including continuous oversight by an IRB, document retention, and providing contact information for the IRB to FDA.

FDA is accepting comments on the Draft Guidance until August 13, 2012.

*  Summer Associate

REMINDER:  HP&M is hosting a webinar, Garbage Runs, Fake Identities, and Surprise Home Visits; Strategies to Deal With FDA's Nontraditional Investigative Tools, on Wednesday, June 20, 2012 from 12:30 – 2:00 p.m. ET.  Click here to register.

By Riëtte van Laack –

As we previously reported, the United States District Court for the Southern District of Florida denied the Federal Trade Commission’s (“FTC’s”) motion to hold Garden of Life and its founder, Jordan S. Rubin (collectively “GOL”) in contempt for allegedly violating a court-issued Consent Decree.  The Court held that a disagreement between FTC’s and GOL’s experts did not constitute evidence that GOL violated the Consent Decree which requires that GOL possess “competent and reliable scientific evidence” to support its claims. 

In an effort to tighten the screws regarding what GOL will contend in the future constitutes competent and reliable scientific evidence supporting GOL’s claims, the FTC moved to modify the Consent Decree.  The proposed modifications sought to redefine competent and reliable scientific evidence to mean two adequate and well-controlled human clinical studies for claims regarding bone and cognitive health benefits of GOL’s products and FDA approval for disease treatment and cure claims for GOL’s products. 

The Court rejected the FTC’s position, concluding that the FTC did not establish that any significant change in facts or law had occurred that warranted revision of the Consent Decree.  A difference in opinion between experts was not sufficient reason to modify the Consent Decree.  Moreover, there was no evidence to support the FTC’s contention that the original objective of the 2006 order had not been met.  The Court stressed that a Consent Decree is a negotiated document between parties in which each party gives up its right to prove its position.  Except under special circumstances, a Consent Decree must be enforced as written.  In 2006, FTC and GOL agreed to use the more vague definition of “competent and reliable scientific evidence” and the Court found that the FTC could have anticipated that experts might disagree.  The Court ruled that the FTC cannot now 5 years later, merely because it is no longer satisfied with the negotiated definition, have the Court modify this definition to suit the FTC’s purpose.

By Kurt R. Karst –      

In a move that brings to mind Scene 2 of Monty Python and the Holy Grail, in which a mortician roams the streets ringing a bell and calling out “Bring out your dead!” (a close second being the Monty Python “Dead Parrot” sketch), FDA is announcing, in a notice to be published in the Federal Register on June 14th, that 364 inactive ANDAs will be deemed voluntarily withdrawn unless the Agency is informed otherwise.  The announcement likely kicks off a broader FDA initiative to get a handle on pending ANDAs as the Agency prepares for implementation of the Generic Drug User Fee Amendments of 2012 (“GDUFA”) (here and here).  GDUFA is pending in Congress as part of broader FDA legislation.

Under GDUFA, there is, among other fees, a one-time (Fiscal Year 2013) ANDA backlog user fee that will be calculated by dividing $50 million by the number of ANDAs in the backlog as of October 1, 2012.  Under the proposed GDUFA text, “[e]ach person that owns an [ANDA] that is pending on October 1, 2012, and that has not received a tentative approval prior to that date, shall be subject to a fee for each such application.”  Provided GDUFA becomes law this year, FDA must publish a notice in the Federal Register by October 31, 2012 announcing the amount of the ANDA backlog fee.  That fee must be paid no later than 30 calendar days from FDA’s publication of the Federal Register notice.

As a result of how a backlog ANDA is defined in GDUFA, the true ANDA backlog consists of more than just those applications pending in the Office of Generic Drugs (“OGD”) on October 1, 2012 that have not been acted on (i.e., awaiting an approval, tentative approval, or not approvable/complete response action).  (Today, that number stands at almost 2,900 applications – see the table below).  Instead, the true ANDA backlog consists of all ANDAs not yet acted on, as well as all ANDAs submitted to OGD over the past few decades that are the subject of a not approvable or complete response letter and that have not been withdrawn. 

FDA’s June 14th notice addresses a portion of those ANDAs that will be part of the backlog for GDUFA user fee purposes.  Specifically, the notice addresses so-called “Inactive ANDAs,” which are applications “that have been determined to be incomplete and as to which the ANDA applicant has not communicated with FDA since July 8, 1991.”  Why July 8, 1991?  We understand that the 364 ANDAs listed by FDA are identified in DARRTS (FDA’s Document Archiving, Reporting, and Regulatory Tracking System) as “incomplete” and that the last date on which FDA received correspondence on any of those 364 ANDAs was July 8, 1991.  The date also seems to correspond to a timeframe in which FDA issued a couple of industry letters – in June 1990 and November 1991 – concerning the completeness of applications. 

The Inactive ANDAs predate and are, therefore, not subject to FDA’s regulation at 21 C.F.R. § 314.110(c).  That regulation, which became effective on June 29, 1992, was last amended in July 2008 (73 Fed. Reg. 39,588), and states:

(c) Failure to take action. (1) An applicant agrees to extend the review period under section 505(c)(1) or (j)(5)(A) of the act until it takes any of the actions listed in paragraph (b) of this section [(i.e., resubmission, withdrawal, or request opportunity for hearing)].   For an application or abbreviated application, FDA may consider an applicant’s failure to take any of such actions within 1 year after issuance of a complete response letter to be a request by the applicant to withdraw the application, unless the applicant has requested an extension of time in which to resubmit the application.  FDA will grant any reasonable request for such an extension.  FDA may consider an applicant’s failure to resubmit the application within the extended time period or to request an additional extension to be a request by the applicant to withdraw the application.

(2) If FDA considers an applicant’s failure to take action in accordance with paragraph (c)(1) of this section to be a request to withdraw the application, the agency will notify the applicant in writing.  The applicant will have 30 days from the date of the notification to explain why the application should not be withdrawn and to request an extension of time in which to resubmit the application.  FDA will grant any reasonable request for an extension.  If the applicant does not respond to the notification within 30 days, the application will be deemed to be withdrawn.

For the 364 Inactive ANDAs identified by FDA in the June 2012 notice, the Agency will deem them to have been voluntarily withdrawn unless the the sponsor (which includes any successor in interest, because many of the companies identified no longer exist) timely notifies FDA in writing of its intent to actively pursue approval.  To protect confidentiality, FDA delinks the sponsor names and ANDA information.

FDA’s notice on Inactive ANDAs appears to be Phase 1 in the Agency’s efforts to do some house cleaning in anticipation of the enactment and implementation of GDUFA and to develop a master list of backlog ANDAs.  We suspect that Phase 2 will concern pending ANDAs that are the subject of a not approvable/complete response action and that have not been withdrawn.  That cohort of ANDAs is likely to be much larger larger than the 364 Inactive ANDAs.  Phase 3 will likely concern what is typically considered the ANDA backlog (i.e., those ANDAs pending and not yet acted on by FDA) and may not be implemented until GDUFA is enacted. 

By Jeffrey K. Shapiro –

A provision in the House FDA Reform Act of 2012 (H.R. 5651) would require FDA to “regularly publish detailed decision summaries for each clearance of a device requiring clinical data” (Section 704).  The requirement would be applied only on a going forward basis to new clearances.  This provision is not in the companion Senate Food and Drug Administration Safety and Innovation Act (S. 3187).  An earlier Senate proposal (S. 2292) did have this provision, and would have applied it to all clearances, not just those requiring clinical data.  That bill, however, did not move forward to Senate passage.

The House Report for H.R. 5651 says that Section 704 “would add predictability, consistency, and transparency to the medical device premarket review process.”  House Report 112-495 at 26.  Specifically, the Report states:  “Only by creating transparency in decision making can we ensure the review process functions as intended.”  Id. at 27.  The House Report does not elaborate on why this reform would improve the 510(k) system, but it is worth considering this point in more detail.

In each 510(k) review, FDA compares a proposed device to an accepted baseline, which is a “predicate” device generally already cleared to market via a previous 510(k) decision.  The proposed device and the predicate must have the same intended use, but they need not have the same technological characteristics.  The technological differences can be bridged if FDA finds that, based upon the data and information presented, the proposed device implicates the same type of safety and effectiveness questions as the predicate device, and is at least as safe and effective.  This finding is known as “substantial equivalence.”

The 510(k) system, then, consists of a series of case by case adjudications of individual device safety and effectiveness, each one based upon the substantial equivalence comparison just described.  Once a new technology (or technological feature) has received clearance, it then becomes a platform for further incremental improvements.  The system has proven to be adaptable to an almost infinite variety of device technologies, allowing FDA to conduct a meaningful premarket review of safety and effectiveness while still allowing continuous technological innovation.

A persistent criticism of FDA’s implementation of the 510(k) system, however, is a lack of predictability, particularly as to the data that will be required to bridge the gap between proposed and predicate devices.  The lack of predictability leads to delays and friction in the review process. 

A possible root cause of this problem actually may be a lack of transparency.  Specifically, in order for the 510(k) system to operate predictably, the public must have access to the essential information in prior 510(k) decisions, such as the intended use and technological characteristics of the proposed and predicate devices, and the data required to show substantial equivalence.  This information is necessary to allow a sponsor seeking clearance of a proposed device to hunt for predicate devices, learn FDA’s existing data requirements, and/or extrapolate likely additional data requirements that might apply. 

Unfortunately, the essential information is not easily available.  The database of 510(k) summaries is the primary searchable database, and these summaries are wholly inadequate.  They are prepared by the submitter, not FDA, and they are (i) not standardized very well and (ii) tend to be vague and lacking in detail (sometimes intentionally so, to avoid providing potential competitors with useful information about how to achieve clearance).  FDA has forced improvements in the quality of the 510(k) summaries in the past couple of years, but not enough has been done.  It is also impractical for the public to obtain a complete 510(k) file; a Freedom of Information Act request is required and the fulfillment time is typically a year or more.  (An article describing the various techniques for trying to gather this information can be found here.)

The bottom line is that the public is operating from a different and degraded database as compared to FDA reviewers, who have access to complete 510(k) files and also have institutional knowledge of their prior decisions.  The current lack of access to important decision data creates a cloudy picture that leads to unpleasant surprises when FDA reviewers impose data requirements that were not discernible from the public 510(k) summaries.

Section 704 would provide at least a partial remedy to this problem.  As the House and Senate conferees reconcile their companion bills, they should certainly include section 704 of the House bill.  However, section 704 is really too timid.  It should be extended to require decision summaries for all new 510(k) clearances, as was proposed in S. 2292, not just the approximately 10%requiring clinical data.  Indeed, the use of decision summaries is not new.  It was implemented almost ten years ago by the Office of In Vitro Diagnostics (“OIVD”).  As stated in OIVD’s FY 2005 Annual Report (P. 28):

In an effort to provide stakeholders with the scientific / regulatory basis for FDA’s decisions . . . OIVD . . . implemented the use of a standardized Premarket Decision Summary Template across all the OIVD divisions. 

The Premarket Decision Summary Template summarizes the basis on which an in vitro diagnostic device was cleared under a 510(k) submission. OIVD implemented the use of this standardized premarket Decision Summary Template in August 1, 2003. The decision summaries have been continuously posted on the OIVD webpage and the public has full access to them through the 510(k) database.

OIVD has continued posting decision summaries to this day.  Congress should simply require FDA to extend this useful practice to the Office of Device Evaluation (“ODE”).  If ODE lacks sufficient resources, then Congress should provide the necessary funding.  However, it is not obvious that such funding is needed.  The ODE reviewers undoubtedly document their review decisions now.  It should not require significant additional resources to create a standard template, complete it for each 510(k) review, and post it to the 510(k) database.  The experience of OIVD should be a guide as to what level of resources will be required.

REMINDER:  HP&M is hosting a webinar, Garbage Runs, Fake Identities, and Surprise Home Visits; Strategies to Deal With FDA's Nontraditional Investigative Tools, on Wednesday, June 20, 2012 from 12:30 – 2:00 p.m. ET.  Click here to register.

By Jennifer D. Newberger –

On June 5, 2012, the Department of Health and Human Services Office of Inspector General (“OIG”) released a report titled “Scientific Disagreements Regarding Medical Device Regulatory Decisions.”  A number of scientific disputes at the Center for Devices and Radiological Health (“CDRH”) received media attention between 2008-2010.  Perhaps in an effort to address the management of scientific disputes, in October 2009, CDRH issued new policies and procedures addressing their resolution.  The OIG report was intended to:  1) describe the types of disputes that arose between 2008-2010; 2) determine whether CDRH followed the requisite procedures and regulations when addressing such disputes; 3) assess the implementation of the new policies and procedures; and 4) identify challenges in addressing scientific disputes.

The October 2009 guidance formalized the process to resolve internal scientific disagreements.  The first step in the process is an informal discussion between the reviewer and the manager.  If that discussion is unsuccessful, the manager may submit an “initiation memorandum” to the Ombudsman, who reviews the memorandum to determine “whether it is complete and eligible for the new process.”  To be eligible, “the disagreement must be scientific and related to a regulatory decision.”  The Ombudsman then assigns a manager not involved in the initial disagreement to review the memorandum, discuss the disagreement with involved parties, and attempt to resolve the issue.  If resolved, the reviewer and manager submit a “joint memorandum” to the administrative file documenting the resolution and its basis.

If the dispute is not resolved, the manager “must make a decision on each disputed issue on the basis of a review of evidence in the administrative file and any other relevant resources” and must document that decision in a decision memorandum that will be included in the administrative file.  The manager must then send the memorandum to the Ombudsman and all involved parties.  If any party is not satisfied, he or she may appeal for review by a higher supervisory level, up to and including the Center Director, after which the appeal may be taken to the FDA Commissioner. 

In reviewing use of the scientific resolution procedures and applicable regulations, OIG used the following sources:  “CDRH administrative files; an online survey of CDRH reviewers and managers; interviews with CDRH officials and other stakeholders; and CDRH's current and former policies, procedures, and guidance documents.”  OIG ultimately identified 36 administrative files to review, 33 of which used the pre-October 2009 procedures, and three of which used the new, more formal procedures.  OIG acknowledges that the actual numbers of agreements could have been much higher, since CDRH did not begin tracking scientific agreements until 2010. 

The scientific disagreements reviewed by OIG involved a variety of issues, and were not often directly related to clearance or approval of a medical device.  Rather, only 1/3 of the resolutions led to the clearance or approval of a device.  The other 2/3 dealt with processes prior to clearance or approval.  This may serve as some comfort to individuals who believed, based on publicly available information, that many of the disagreements between reviewers and managers led to managers making decisions to clear or approve devices when the reviewers expressed concern about the safety or effectiveness of the device.  The OIG report indicates that many of the issues for 510(k) devices were related to whether a device was eligible for review through the 510(k) process, appropriate device labeling, and identification of an appropriate predicate device.  For PMAs, disagreements related to clinical trial design, the need for additional data, and appropriateness of labeling.

OIG also looked at the type of documentation included in the administrative files, and found that five of the 36 lacked any documentation related to the disagreement, and 22 contained formal memoranda.  Nine files contained emails or other documentation referencing the scientific disagreements, rather than formal memoranda.  OIG found that CDRH has not specified who is responsible for upkeep of the administrative file and documenting decisions related to the disagreement.  Additionally, OIG found that not all CDRH managers and reviewers were trained on the new scientific disagreement procedures released in October 2009, and CDRH did not track who received the training.  Many reviewers stated that they do not even know how to initiate the new procedures.

Perhaps one of the most interesting findings is that approximately 20% of survey respondents indicated they were concerned that expressing a scientific disagreement to management could adversely affect their careers.  OIG also found a small numbers of reviewers who “reported incidents in which they felt some pressure to change elements of their written reviews or to not document a scientific disagreement.”  The majority of respondents, however, indicated they felt comfortable discussing scientific disagreements with their peers and managers.

Based on its findings, OIG recommended FDA do the following:  1) define more clearly its requirements for documenting and resolving scientific disagreements; 2)  train all reviewers and managers on the new policies and procedures for resolving scientific disagreements; and 3) more clearly assign accountability for the contents of the administrative files of all submissions.  The OIG report states that FDA concurs with the recommendations and has outlined plans to implement them.  Hopefully, reviewers will feel comfortable taking advantage of the procedures available to them to express disagreements without fearing an adverse impact on their careers.  Because this report included a review of only three disagreements undertaken in accordance with the new procedures, it will be interesting to see, in a few years, what impact the new procedures have on the resolution of scientific disagreements.

By Diane B. McColl - 

The days of having to deal with those pesky adhesive labels on citrus fruit may be over.  FDA has announced a final rule approving the use of a carbon dioxide laser for etching information, such as product code, on the surface of citrus fruit.  The surface etching is intended to replace the adhesive label.

More than five years ago, Durand-Wayland, Inc. (later joined by Sunkist Growers Inc.), represented by Hyman, Phelps & McNamara, P.C., filed a food additive petition (Docket No. FDA-2007-F-0390) for the use of a carbon dioxide laser for etching information on the surface of certain foods.  The Petition was subsequently amended to focus on the etching of citrus fruit. 

FDA evaluated both the potential chemical effects and the potential microbiological risk from etching the surface of citrus fruit.  The Agency concluded that use of the carbon dioxide laser to etch information on foods does not generate any new chemical substances that are not also typically generated by conventional cooking.  The agency evaluated a study conducted by the University of Florida Citrus Research and Education Center and concluded that “Salmonella bacteria present on orange surfaces prior to etching by the carbon dioxide laser, and that contaminate orange surfaces after laser etching, do not infiltrate, survive, or grow during subsequent storage to a level that presents a potential public health hazard significantly greater than the survival or growth of Salmonella bacteria on oranges that are not etched by the carbon dioxide laser.”  No Salmonella was found in the juice portion of any sound, decay-free etched oranges.   In other words, there is no material difference between etched and unetched citrus fruit.  FDA concluded that the laser etching of citrus fruit is safe and the food additive regulations are amended accordingly.  Public comments may be submitted within 30 days of publication of the final rule.

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