By Kurt R. Karst –      

For years we’ve heard rumors of a relatively current list, compiled by FDA, of proceedings pending under the Drug Efficacy Study Implementation (“DESI”) program.  At one time, in the early 1980s, the list was included as an addendum to the Orange Book, but was eventually removed from the publication.  Since then, like the lost Ark of the Covenant, it has fallen into myth.  But like the unwavering Indiana Jones, we initiated our own, FDA-type, archeological hunt, and were able to obtain a copy of FDA’s List of Pending DESI Proceedings.  Fortunately, we didn’t have to deal with a large rolling boulder, dodge poison arrows, and wade through a sea of deadly asps, or battle with a guy named René Emile Belloq to get our prize.  We just had to deal with the FOIA bureaucracy. 

So what is the List of Pending DESI Proceedings and why is it of interest to some folks? 

The DESI program, initiated in the wake of the 1962 Drug Efficacy Amendments, which amended the FDC Act to require that a new drug be proven effective, as well as safe, to obtain FDA approval, required FDA to conduct a retrospective evaluation of the effectiveness of the drug products the Agency had approved as safe between 1938 and 1962.  That retrospective evaluation covered over 3,400 products that were approved only for safety between 1938 and 1962, as well as thousands more so-called “IRS” (identical, related, or similar, see 21 C.F.R. § 310.6(b)(1)) products that entered the market without FDA approval, for a total of 581 DESI reviews covering about 18,400 drugs. 

Although FDA has completed most of the DESI proceedings initiated, a small number have remained unresolved for decades.   These are the DESI proceedings termed “pending” and that are included in the list.  The version of the list we obtained is as of August 2006 and lists seventeen items.  Some of the DESI proceeding in the list have since been closed or are moving forward, such as various DESI cough/cold proceedings (see here) and the proceeding for Trimethobenzamide HCl Suppositories (see here).

Over the years, some companies have used the pending status of a DESI proceeding as a basis to market a particular drug product without obtaining approval of a marketing application from FDA.  Indeed, although FDA states in the Agency’s most recent, September 19, 2011, iteration of its “Compliance Policy Guide: Sec. 440.100 Marketed New Drugs Without Approved NDAs or ANDAs,”  (“Unapproved Drugs CPG”) that “any product that is being marketed illegally is subject to FDA enforcement action at any time,” the Agency also says that there is a general exception to this policy for marketed unapproved drugs subject to an ongoing DESI proceeding.  FDA explains this exception in the Unapproved Drugs CPG as follows:

Some unapproved marketed products are undergoing DESI reviews in which a final determination regarding efficacy has not yet been made.  In addition to the products specifically reviewed by the NAS/NRC (i.e., those products approved for safety only between 1938 and 1962), this group includes unapproved products [IRS] to those products specifically reviewed (see 21 CFR 310.6).  In virtually all these proceedings, FDA has made an initial determination that the products lack substantial evidence of effectiveness, and the manufacturers have requested a hearing on that finding.  It is the Agency’s longstanding policy that products subject to an ongoing DESI proceeding may remain on the market during the pendency of the proceeding.  [Unapproved Drugs CPG at 10 (emphasis added).]

FDA also notes, however, that the pending DESI proceeding exception (like the so-called “grandfather” drug exceptions) is narrowly construed by the Agency:

Products first marketed after a hearing notice is issued with a different formulation than those covered by the notice are not considered subject to the DESI proceeding.  Rather, they need approval prior to marketing.  Under longstanding Agency policies, a firm holding an NDA on a product for which a DESI hearing is pending must submit a supplement prior to reformulating that product.  The changed formulation may not be marketed as a related product under the pending DESI proceeding; it is a new drug, and it must be approved for safety and efficacy before it can be legally marketed. . . .  Similarly, firms without NDAs cannot market new formulations of a drug without first getting approval of an NDA.  [Unapproved Drugs CPG at 10, Footnote 15 (emphasis added).]

So, the List of Pending DESI Proceedings must be used with caution – caveat venditor!  And keep in mind what happened at the opening of the Ark of the Covenant.  

By Riëtte van Laack –

On December 5, 2011, the Food Safety Inspection Service (“FSIS”) of the USDA proposed to amend its regulations concerning label approval of meat and poultry products.  The proposed rule would further expand the types of labels that do not require pre-market approval, and would streamline the labeling regulations by placing all the label approval regulations for meat and poultry products in one Part of the CFR.

Traditionally, the FSIS has interpreted the Federal Meat Inspection Act (“FMIA”) and Poultry Products Inspection Act (“PPIA”) to require that labels for federally inspected meat and poultry products be approved before the meat and poultry products are marketed.  Generally, except when the label is generically approved, establishments must submit for approval sketches of their labels showing all required label features and any special claims that the establishments intend to make, e.g., quality claims, natural claims, and nutrient content claims.  Generic label approval refers to the prior approval of labels or modification to labels by FSIS without sketches being submitted for approval by FSIS.  Generic label approval requires that all the mandatory label features conform to the applicable FSIS regulations.  Although such labels are not submitted to FSIS for approval, they are deemed to be approved and therefore may be used. 

In 1983, FSIS issued its first regulations providing for generic label approval for some types of labels.  In 1995, FSIS significantly expanded the types of labels eligible for generic label approval to include labels for products with a standard of identity, single ingredient products that do not bear a voluntary statement, labels for meat and poultry products not intended for human food, etc.  Although this expansion resulted in a significant reduction of the number of labels subject to prior approval, the regulations remained restrictive regarding the types of labels subject to generic approval.  For example, a change in the order of predominance of ingredients of a non-standardized product such as meat pizza still required sketch approval by FSIS.  Consequently, a large number of sketches continued to be submitted, burdening the industry and FSIS.  Therefore, 16 years after the first expansion of generic label approval, the Agency proposes to further expand the types of labels that can be generically approved.  The Agency estimates that the proposed amendments will reduce the number of labels requiring approval in the first year by approximately 70%.  The reduced burden on FSIS will allow the Agency to better focus on, and direct its resources to, other consumer protection and food safety activities.

Under the proposed rule, establishments will have the responsibility to ensure that all the basic requirements (i.e., product name, safe handling statement, ingredient listing, address line, net weight, legend, safe handling instructions, nutrition labeling for multi-ingredient products, and the country of origin and mark of inspection of the foreign system for imported meat and poultry products) are met.  Only certain types of labels bearing statements and claims that are likely to present policy issues and have health or economic significance will remain subject to premarket approval (e.g., labels for temporary approval, labels for products produced under religious exemption, labels for export with labeling deviations, and label claims and special statements, including “natural” and “organic” statements).  However, when a product label contains a special statement or claim, FSIS will only evaluate that special statement or claim, not the mandatory statements.  Special statements will not include allergen statements, sell by dates (and other calendar date statements), “fresh” statements on poultry, statements concerning the USDA approved quality control system logo, and statements required on irradiated products; FSIS believes industry has sufficient experience with these special statements, and that the regulations (and guidances) for these special statements clearly prescribe the applicable requirements, such that no review by FSIS is required.  

Comments may be submitted through February 3, 2012.

On December 2, 2011, Hyman, Phelps, & McNamara filed comments (here and here) to the controversial draft guidance on New Dietary Ingredient (“NDI”) notifications that FDA issued in July 2011.  We have a keen interest in the draft guidance and have previously posted on it here, here, here, and here. 

The current draft guidance ignores the balance struck by the Dietary Supplement Health and Education Act of 1994 (“DSHEA”) between ensuring safety and minimizing unnecessary and unreasonable regulatory requirements for dietary ingredients and supplements.  Implementation of this draft guidance would severely disrupt the market for dietary supplements and impose extraordinary burdens on industry and FDA.  Therefore, the comments request that FDA withdraw the draft NDI guidance and reissue a guidance that reflects the intent behind DSHEA and that can be implemented in a practicable manner within FDA’s limited resources.  In addition, they encourage FDA to articulate its rationale for its interpretation of the various NDI provisions in the law.

Although differing from some trade association comments in significant ways, HP&M’s comments request that the draft NDI guidance be withdrawn, consistent with the comments of the Alliance for Natural Health, the American Herbal Products Association, the Consumer Healthcare Products Association, the Council for Responsible Nutrition, the Natural Products Association, and the United Natural Products Alliance – see here and here. 

By Kurt R. Karst –      

Just one day after FDA announced a December 16th public meeting and comment period to discuss the Agency’s proposed recommendations for a user fee program for biosimilar biological products for Fiscal Years (“FYs”) 2013 through 2017 (see our post here), the Agency will announce in a December 8, 2011 Federal Register notice – a prepublication version of which is available here – a December 19th public meeting and comment period (Docket No. FDA-2010-N-0381) to discuss the Agency’s proposed recommendations for enactment of a Generic Drug User Fee Act (“GDUFA”) to collect fees and use them for the review of ANDAs and associated Type II Active Pharmaceutical Ingredient Drug Master Files (“DMFs”), and for conducting associated inspections for Fiscal Years (“FYs”) 2013 through 2017.  FDA also released a draft version of the “Generic Drug User Fee Act Program Performance Goals and Procedures” negotiated with the generic drug industry over many months earlier this year and that would accompany any GDUFA legislation enacted next year.

As we previously reported upon the completion of GDUFA negotiations back in September, the aims of a generic drug user fee program are three-fold:

(1) Safety – “To ensure that industry participants, foreign or domestic, who participate in the U.S. generic drug system are held to consistent high quality standards and are inspected biennially, using a risk-based approach, with foreign and domestic parity.”

(2) Access – “To expedite the availability of low-cost, high-quality generic drugs by bringing greater predictability to the review times for abbreviated new drug applications, amendments and supplements, increasing predictability, and timeliness in the review process.”

(3) Transparency – “To enhance FDA’s ability to protect Americans in the complex global supply environment by requiring the identification of facilities involved in the manufacture of generic drugs and associated active pharmaceutical ingredients and improving FDA’s communications and feedback with industry in order to expedite product access.” 

The agreement reached between FDA and the generic drug industry is complex (to say the least) and will make significant changes to the ANDA review process that FDA says will put “FDA’s generic drugs program on a firm financial footing and [provide] additive resources necessary to assure timely access to safe, high-quality, affordable generic drugs.” 

In our previous post, we discussed some of the financial and metrics aspects of the proposed program, and also noted that the program is structured based on five cohorts of submission dates for original ANDAs corresponding to the five fiscal years under GDUFA.  To recap, the total amount of annual funding from GDUFA user fees is supposed to be set at $299 million in FY 2013 (and at $299 million plus an annual adjustment in FYs 2014-2017), and would come from application fees and facility fees.  FDA states in the draft goals letter that:

legislative language will require that approximately 70% of GDUFA fees shall be derived from facility fees (for facilities producing or pending review to produce active pharmaceutical ingredients or finished dosage forms for a generic drug application), approximately 30% of GDUFA fees shall be derived from application fees (DMF Fees and ANDA and PAS (Prior Approval Supplement) Fees).  As discussed and agreed by the various industry business segments, overall fees will be divided 80 percent to 20 percent between the finished dosage form (FDF) and API and manufacturers, respectively in industry.   In the first year of the program, $50 million of the total GDUFA user fee funding shall be generated by a one time backlog fee for ANDAs pending (except for ANDAs that are pending but have received tentative approval) on October 1, 2012.

As part of a GDUFA program, FDA would agree to make several “enhancements,” including ANDA review efficiency enhancements, DMF review efficiency enhancements, inspection efficiency enhancements, and other efficiency enhancements.   For example:

• FDA will develop enhanced refusal to receive standards for ANDAs and other related submissions by the end of year 1 of the program and will publish such standards in advance of implementation.
• For ANDAs in the year 1 and 2 cohorts, FDA will expedite review of Paragraph IV applications that are submitted on the first day that any valid Paragraph IV application for the drug in question is submitted. Expedited review will be implemented consistent with existing procedure for expediting applications as set forth in CDER’s MAPP 5240.3, and will also include those applications that become eligible for approval during the review period as a result of no blocking exclusivities, patent(s) and/or applicable stays based on appropriate documentation submitted. 
• FDA will employ a risk-adjusted biennial CGMP surveillance inspection model for inspection of generic API and FDF manufacturers, with the goal of achieving parity of inspection frequency between foreign and domestic establishments in FY 2017 and will prioritize inspections of establishments associated with ANDAs that are otherwise approvable or eligible for tentative approval except for an outstanding inspection, as well as establishments that have not been inspected previously.
• During the five years of the program, FDA will undertake a study of foreign government regulator inspections (CGMP and bioequivalence), report findings publicly, and develop a program to utilize foreign inspection classifications when and where appropriate.

The draft goals letter also states that “FDA will strive to review and act on all ANDAs that are submitted on the first day that any valid Paragraph IV application for the drug in question is submitted within 30 months of submission to avoid causing first applicants to inadvertently forfeit 180-day exclusivity eligibility under 21 U.S.C. § 355(j)(5)(D)(i)(IV).”  With median ANDA approval times hovering around 33 months these days, forfeiture of 180-day exclusivity eligibility under the failure to obtain timely tentative approval statutory provision has been a significant industry concern.  The enactment of a human generic drug user fee program to speed up ANDA review will (hopefully) make forfeiture less likely.

With the user fee funding “FDA will hire and train at least 25 percent of incremental staff in FY 2013, 50 percent in FY 2014 and will strive to complete GDUFA-funded human resources hiring goals in FY 2015 as necessary to achieve the program’s performance metrics and goals,” according to the goals letter.  It is unclear how many of the new hires will be direct hires to the Office of generic Drugs. 

With respect to FDA’s goals for acting on submissions, the draft goals letter tackles original applications, amendments, PASs, Type II DMFs, controlled correspondence, CGMP inspections, and the ANDA backlog.  For original ANDAs:

• FDA will review and act on 60 percent of original ANDA submissions within 15 months from the date of submission for the year 3 cohort.
• FDA will review and act on 75 percent of original ANDA submissions within 15 months from the date of submission for the year 4 cohort.
• FDA will review and act on 90 percent of original ANDA submissions within 10 months from the date of submission for the year 5 cohort.
• For ANDAs in the year 1 and 2 cohorts, FDA will expedite review of Paragraph IV applications that are submitted on the first day that any valid Paragraph IV application for the drug in question is submitted.

ANDA amendment review would be governed by a complex system in which they are categorized as Tier 1, Tier 2 or Tier 3.  (With the exception that “unsolicited amendments that are submitted to a pending ANDA that are neither Tier 1, Tier 2 or Tier 3 amendments, but rather are routine or administrative in nature and do not require scientific review . . . will not lengthen or impact the original review goal date.”)  Tier 1 and Tier 2 amendments would be subject to detailed metrics, whereas there would not be metrics for Tier 3 amendments.  Each of the amendment types is defined in the draft goals letter. 

For PAS review, the draft goals letter provides the following:

• FDA will review and act on 60 percent of PASs not requiring inspection within 6 months from the date of submission for receipts in FY 2015; FDA will review and act on 60 percent of PASs requiring inspection within 10 months from the date of submission for receipts in FY 2015.
• FDA will review and act on 75 percent of PASs not requiring inspection within 6 months from the date of submission for receipts in FY 2016; FDA will review and act on 75 percent of PASs requiring inspection within 10 months from the date of submission for receipts in FY 2016.
• FDA will review and act on 90 percent of PASs not requiring inspection within 6 months from the date of submission for receipts in FY 2017; FDA will review and act on 90 percent of PASs requiring inspection within 10 months from the date of submission for receipts in FY 2017.

With respect to the ANDA backlog, the draft goals letter states that “FDA will review and act on 90 percent of all ANDAs, ANDA amendments, and ANDA prior approval supplements regardless of current review status (whether electronic, paper, or hybrid) pending on October 1, 2012 by the end of FY 2017.”   The original ANDA backlog stood at about 2,500 ANDAs a month ago.  That number may decrease as sponsors decide whether or not they want to pay the backlog fee. 

The draft goals letter also includes a Regulatory Science Plan with several items of interest.  In FY 2013, FDA would address bioequivalence of local acting orally inhaled drug products, local acting topical dermatological drug products and local acting gastro-intestinal drug products, product- and patient-related factors affecting switchability of drug-device combination products, and physicochemical characterization of complex drug substances.  In FY 2014, topics would include a recommendation for a draft guidance “to clarify FDA recommendations with regard to complex product development” and guidance to help limit ANDA deficiencies.

Draft legislation to implement GDUFA has not yet been publicly released, but you can be assured that it is chock-full of interesting provisions.  Presumably the draft legislation will see the light of day early next year when a formal bill is introduced in Congress.

Additional Reading:

• GPhA Statement

Hyman, Phelps & McNamara, P.C., the nation’s largest boutique food and drug regulatory law firm, seeks a mid-level to senior associate or counsel with substantial experience in medical device law and regulation to assist with a growing practice.  Strong writing skills are required.  Compensation is competitive and commensurate with experience.  HP&M is an equal opportunity employer.

Please send your curriculum vitae, transcript, and a writing sample to Jeffrey N. Wasserstein (jnw@hpm.com).

By Jennifer D. Newberger –

On December 5, 2011, Senator Scott Brown (R-MA) introduced S. 1943, the “Novel Device Regulatory Relief Act of 2011.”  The bill is intended to amend section 513 of the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to expedite the process for requesting de novo classification of a device.  The de novo review process is a compromise between the 510(k) clearance process and the more rigorous premarket application (“PMA”) approval process, generally reserved for higher risk devices.  It was added to the FDC Act to address novel devices that lack a predicate device but pose only a low to moderate risk, making them ill-suited to the PMA process.

Senator Brown’s bill builds on and clarifies language proposed by Rep. Brian Bilbray in October to modify the de novo process, discussed in our previous blog post.  Both bills include language allowing a sponsor to submit a de novo classification request without awaiting a written determination from FDA that the device is not substantially equivalent (“NSE”) and therefore classified into class III, even if the manufacturer knows there is no appropriate predicate.  That is the only change proposed in Rep. Bilbray’s bill, and therefore left open the question of whether the sponsor would nevertheless be required to submit the 510(k), or if the sponsor need not submit the 510(k) and could instead submit the de novo petition first.  As discussed in our previous blog post, we interpreted the language in Rep. Bilbray’s bill to allow the sponsor to submit a de novo petition without submitting a 510(k) notification.

The language proposed by Senator Brown appears to clarify this ambiguity.  He adopts the same language proposed by Rep. Bilbray, permitting a sponsor to submit a de novo petition without awaiting a written notification of a class III determination.  He also proposes language stating that “[a]ny person that is required to submit” a 510(k) notification, and determines that there is no applicable predicate device, “may submit a request for initial classification of the device” and may recommend a specific classification to FDA.  The bill states that FDA may decline the petition if it believes an appropriate predicate device exists.

The addition of this language clarifies that adoption of this bill would provide two distinct alternatives for 510(k) submitters who believe no appropriate predicate device exists for their low- to moderate-risk device:  (1) submit a 510(k) knowing that no predicate exists, and then submit a de novo petition before receiving an NSE determination, or (2) submit a de novo petition without submitting a 510(k) notification.  While both options improve upon the current requirement to submit a 510(k) notification and await a written determination, it seems that most applicants would elect the second option—submit the de novo petition without submitting a 510(k) notification.  As discussed in our previous blog post, the sponsor should probably seek input from FDA prior to submitting an initial classification request, to determine whether FDA agrees that the de novo approach is appropriate.  Given the current inefficiencies associated with the de novo process, this seems like something both parties should be willing to do.

By Kurt R. Karst –      

On December 7, 2011, FDA will publish a Federal Register notice – a prepublication version of which is available here – announcing a December 16th public meeting and comment period (Docket No. FDA-2011-N-0326) to discuss the Agency’s proposed recommendations for a user fee program for biosimilar biological products for Fiscal Years (“FYs”) 2013 through 2017.  The meeting and comment period is required by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), which was enacted on March 23, 2010 as part of the Affordable Care Act, and which created, under new section 351(k) of the Public Health Service Act (“PHS Act”), a route to obtain approval of biosimilar and interchangeable versions of a reference product licensed under PHS Act § 351(a).  The December announcement follows a May 2011 notice (see our previous post here) FDA held with public and industry stakeholders regarding the development of a § 351(k) application user fee program for FYs 2013-2017. 

FDA’s notice includes both a discussion of the proposed user fees, and the Agency’s proposed performance goals and procedures for the next five FYs.  Each topic is discussed below.

Proposed User Fees.  FDA proposes the establishment of four types of biosimilars user fees.  Three of the fees – the one-time application fee, and the annual product and establishment fees – are well known to industry and would be set equal to the rates established under the Prescription Drug User Fee Act (“PDUFA”) for a particular FY.  For FY 2012, the PDUFA fees are $1,841,500 (application), $520,100 (establishment), and $98,970 (product) – see our previous post here.  

The big difference for biosimilars is the proposed fourth fee type – the Biosimilar Product Development (“BPD”) fee for products in development.  It is a fee that would initially be due either upon the date of submission of an Investigational New Drug Application (“IND”) pursuant to FDC Act § 505(i) “describing an investigation that FDA determines is intended to support a biosimilar biological application for a product,” or within five days after FDA grants a request for a so-called “BPD Meeting” (discussed below) for a product.  According to the proposal, the initial BDP fee would be equal to 10% of the PDUFA application fee established for a particular FY.  After paying the initial BDP fee, sponsors would pay an annual BPD fee (due on or before October 1st each year) until the sponsor submits a § 351(k) application that is accepted for filing, or until the sponsor discontinues participation in the BPD program for the product.  The cumulative BPD fees paid by a sponsor for a product would be subtracted from the application fee.  Front-loading the fees in this manner, says FDA, will allow the Agency “to generate fee revenue in the near-term and to enable sponsors to have meetings with FDA early in the development of biosimilar biological product candidates.”      

Some other highlights concerning the proposed BPD fees include:

• Only one BPD fee per product will be assessed regardless of the number of proposed indications for the biosimilar product;
• Each person that has submitted an IND before the date of enactment of legislation authorizing the biosimilars user fee program, and that FDA determines is intended to support a § 351(k) application for a product, will be subject to the initial BPD fee;
• An IND sponsor may discontinue participation in the BDP program only after withdrawing the affected IND, and must do so by August 1 of the year of discontinuation to avoid incurring a fee for the next FY;
• A sponsor that has discontinued participation in the BPD program for a product must pay  a reactivation fee equal to twice the initial BPD fee for that fiscal year in order to resume participation in the BPD program for that product;
• Failure to pay the any of the BPD fees (i.e., initial, annual, or reactivation) would result in FDA refusing to grant a BPD Meeting relating to the biosimilar biological product for which the fees are owed.  In addition, “if a sponsor that owes BPD fees submits an IND that FDA determines is intended to support a biosimilar biological product application, FDA would not consider the sponsor’s IND to have been received under [FDC Act § 505(i)(2)].”  For a sponsor with an existing IND, FDA would impose a “financial hold” prohibiting the sponsor from continuing the investigation.  Finally, if a sponsor has failed to pay required BPD fees, then any § 351(k) or supplement submitted by that sponsor “would be considered incomplete and would not be accepted for filing until all fees owed by the sponsor have been paid.”

Proposed Performance Goals and Procedures.  FDA’s notice includes a summary of the proposed performance goals for a number of items, including proprietary name review, major dispute resolution, clinical holds, special protocol assessments, first cycle performance goals, and, as discussed below, review performance goals and meeting management goals.  The full description of FDA’s proposed performance goals and procedures for the biosimilars user fee program are in the draft biosimilars user fee commitment letter that is hot off the presses.

FDA’s proposed review performance goals include goals for biosimilar biological product application submissions and resubmissions, supplements with clinical data, and original manufacturing supplements.  As with the initial iteration of PDUFA, FDA takes a step-wise approach over the first few FYs to reach a goal of 90% for original and resubmitted § 351(k) applications.  This is depicted in the tables below.

Performance Goals for Original and Resubmitted Applications and Supplements

Performance Goals for Original and Resubmitted Supplements

Proposed additions to FDA’s meeting lexicon are five types of meetings related to a sponsor’s biosimilar biological product development program:

• Biosimilar Initial Advisory Meeting – This is an initial assessment meeting limited to a general discussion regarding the feasibility of licensure under PHS Act § 351(k), and general advice on the expected content of the development program if the § 351(k) route is feasible. 
• BPD Type 1 Meeting – Similar to a Type A meeting under PDUFA, this is “a meeting which is necessary for an otherwise stalled drug development program to proceed (e.g. meeting to discuss clinical holds, dispute resolution meeting), a special protocol assessment meeting, or a meeting to address an important safety issue.”
• BPD Type 2 Meeting – This is a meeting for the sponsor and FDA to discuss a specific issue, such as a proposed study design or endpoints, or to discuss questions seeking targeted advice from FDA regarding an ongoing development program.
• BPD Type 3 Meeting – This is an in-depth data review and advice meeting that may include “substantive review of full study reports, FDA advice regarding the similarity between the proposed biosimilar biological product and the reference product, and FDA advice regarding additional studies, including design and analysis.”
• BPD Type 4 Meeting – This is a meeting to discuss the format and content of a § 351(k) application or supplement. 

FDA’s target timeframes for the various meeting types are shown below.  FDA’s performance goals for the meetings begin with 70% in FY2013 and progress to 90% by FY2017.

After the December 16th public meeting, will finalize its user fee and performance goal proposals, revising them as necessary in response to comments or concerns raised at the public meeting and in docket comments.  Under § 7001(f)(1) of the Affordable Care Act, FDA must transmit its recommendations to Congress by January 15, 2012.

Additional Reading:

• PhRMA Statement on Biosimilar User Fees

By Ricardo Carvajal - 

Recent FDA actions suggest that dietary supplement firms who fail to correct deficiencies in their GMP’s do so at their peril.  For example, FDA recently filed a complaint for permanent injunction against ATF Fitness Products, Inc. et al. ("ATF"), a manufacturer and distributor of dietary supplements.  The complaint alleges that a recent inspection found numerous deviations from the GMP requirements at 21 C.F.R. Part 111.  The complaint further alleges that ATF engaged in substitution of dietary ingredients and dietary supplements so as to render misbranded certain of its products, and that ATF failed to reports serious adverse events.  The complaint contends that ATF “did not respond to the Form FDA-483 or promise to correct all of the deficiencies,” and that a prior audit by a consultant had identified numerous significant GMP deviations that were the same as those identified by FDA.

As another example, FDA filed a seizure complaint against dietary supplements manufactured and distributed by Syntec Nutraceuticals that are alleged to have been prepared, packed or held under conditions that do not meet GMP requirements.  According to the complaint, FDA’s most recent inspection identified a number of significant violations that were similar to those identified in two previous inspections.  Some of the supplements are also alleged to have been marketed as unapproved new drugs.

When coupled to DOJ’s announcement of prison terms in another case arising in part from GMP violations (see our prior blog posting here), the ATF and Syntec cases suggest that significant and continuing alleged GMP violations can be expected to weigh heavily into FDA’s decision to pursue court action.

By Riëtte van Laack –

Representative Louise Slaughter (D-NY) recently sent a 4-page letter to FDA expressing her discontent with the Agency’s action (or lack thereof) related to antibiotic use in animal agriculture.  Specifically, Rep. Slaughter criticizes:

1. FDA’s delay in finalizing the industry guidance #209, titled the Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals;

2. The lack of transparency in the annual report regarding antibiotic use in animals required by the Animal Drug User Fee Amendments (“ADUFA”); and

3. FDA’s rejection of two citizen petitions – see here – requesting that FDA withdraw approvals for the nontherapeutic use of certain antimicrobials in food producing animals.  (As we previously reported, both petitions are the subject of an ongoing lawsuit.) 

Rep. Slaughter urges FDA to follow the proactive precautionary principle allegedly used in European and Asian countries.  

Citing a recent report by Tufts University School of Medicine concerning the correlation between antibiotic use in food animals and antibiotic ineffectiveness in humans and the recent outbreak related to antibiotic-resistant Salmonella causing 136 people to be infected Slaughter urges FDA to take action.  She requests that FDA provides additional details concerning the use of certain antibiotics above and beyond what ADUFA requires, and provide additional details concerning the use of antibiotics in food producing animals and the type and amount of antibiotics used in human medicine.  Rep. Slaughter also questions FDA’s explanation for the publication of a revised report on the 2010 ADUFA sales data. 

Reminding FDA of its public mandate to protect pubic health rather than protect agriculture industry, Rep. Slaughter requests the Agency take action.

Rep. Slaughter has a long history of interest in antibiotic use in food producing animals.  She is the sponsor of the Preservation of Antibiotics for Medical Treatment Act, which would, among other things, phase out the non-therapeutic use in livestock of medically important antibiotics. 

By Ricardo Carvajal –

FDA issued a warning letter to a food manufacturer for labeling as “all natural” a product that contains disodium dihydrogen pyrophosphate, purportedly a synthetic chemical preservative.  The letter cites an alleged violation of FDC Act § 403(a)(1), under which a food is deemed misbranded if its labeling is false or misleading in any particular.  As noted in the letter, “FDA considers use of the term ‘natural’ on a food label to be truthful and non-misleading when ‘nothing artificial or synthetic…has been included in, or has been added to, a food that would not normally be expected to be in the food.’”

The letter is notable for the fact that the “all natural” claim is the only violation cited.  Evidently, FDA considers the misuse of a “natural” claim significant enough to warrant the issuance of a warning letter, even in the absence of other violations.  The letter closes with good generic advice: “We recommend that you review all of your product labels to be consistent with our policy to avoid additional misbranding of your food products.”

FDA Law Blog is pleased to announce that we’ve been selected as one of the LexisNexis Top 25 Torts Law Blogs of 2011!  Here’s what the folks at LexisNexis had to say:

The Top 25 group includes some of the best talent in the blogosphere and creates an invaluable content aggregate for all segments of the Torts Law practice.  Most good blogs provide frequent posts on timely topics, but the authors in this year’s collective take their blogs to a different level by providing insightful commentary that demonstrates how blogs can—and do—impact and influence the world of business and corporate law.

We’re blushing.

Obviously, our focus is on FDA law, not tort law; however, some of the topics we touch on – such as preemption – do bleed over into the tort world.  We’re honored to be among such a stellar group of honorees – you can see the full list here.  

And while we have your attention, we’ll take this opportunity to remind you that you can follow us on Twitter.  We tweet thoughout the day on new FDA decisions, petitions, legislation . . . . the whole gamut. 

By Kurt R. Karst –      

In what appears to be the second guidance of its kind, FDA proposed in a draft bioequivalence guidance document issued earlier this week that companies seeking approval to market generic versions of RITALIN LA (methylphenidate HCl) Extended-Release Capsules must, in addition to demonstrating bioequivalence using the traditional metrics of area under the plasma concentration versus time curve (“AUC”) and maximum (i.e., “peak”) drug concentration (“Cmax”), demonstrate bioequivalence using certain partial AUC (“pAUC”) metrics.  FDA’s proposal follows an April 2010 meeting of FDA’s Pharmaceutical Science and Clinical Pharmacology Advisory Committee at which FDA discussed, among other things, the use of pAUC for the evaluation of ANDAs for products with complex pharmacokinetic profiles. 

RITALIN LA, which is approved under NDA No. 021284, is a multiphasic modified-release formulation designed to release a bolus of methylphenidate followed by slower delivery later in the day.  Other multiphasic methylphenidate drug products include METADATE CD (methylphenidate HCl) Extended-Release Capsules (NDA No. 021259) and CONCERTA (methylphenidate HCl) Extended-Release Tablets (NDA No. 021121).  FDA’s proposal for generic RITALIN LA is to require three studies – one study under fed conditions and two studies under fasting conditions (in one of which the contents of the drug are sprinkled over a spoonful of applesauce).  For the fed study, FDA says that “[t]he partial AUCs, AUC0-4 and AUC4-t, have been determined to be the most appropriate parameters for evaluation of the drug bioavailability responsible for the quick onset and sustained maintenance of the clinical response throughout the 24 hr dosing period,” and, along with other bioequivalence measures, “will ensure that the pharmacokinetic profiles and clinical effects of test and reference products are sufficiently similar.”  With respect to both of the fasting studies, FDA says that the pAUCs of AUC0-3 and AUC3-t are most appropriate, and, along with other bioequivalence measures, “will ensure that the pharmacokinetic profiles and clinical effects of test and reference products are sufficiently similar.”  The proposed 3- and 4-hour pAUCs are consistent with FDA’s proposals at the April 2010 advisory committee meeting.

FDA’s proposal to require pAUC measurements for purposes of approving ANDAs for generic versions of RITALIN LA appears to be the second instance in which FDA has issued drug product-specific bioequivalence guidance seeking such information.  In a guidance finalized in October 2011 for generic versions of AMBIEN CR (zolpidem tartrate) Extended Release Tablets (NDA No. 021774), FDA established the pAUCs of AUC0-1.5, AUC1.5-t in the required fasting study.  The finalization of the zolpidem bioequivalence guidance was preceded by an October 2010 response to a June 2007 citizen petition (Docket No. FDA-2007-P-0182).  In its response, FDA agreed that AUC and Cmax are not adequate to demonstrate bioequivalence and discussed what were at that time the proposed pAUCs for generic AMBIEN CR.

Notably absent from FDA’s announcement earlier this week of the availability of new draft bioequivalence guidances, including RITALIN LA, were draft bioequivalence guidances for generic METADATE CD and CONCERTA.  After all, all three of the multiphasic methylphenidate drug products – RITALIN LA, METADATE CD and CONCERTA – were up for discussion at the April 2010 advisory committee meeting.  Their absence, however, may be explained by the existence of long-pending citizen petitions submitted in March 2004 for CONCERTA (Docket No. FDA-2004-P-0151) and in May 2004 for METADATE CD (Docket No. FDA-2004-P-0290).  Both of the citizen petitions request that FDA require certain pAUC measures in connection with ANDA approvals.  FDA may have delayed issuing product-specific guidances for these two drugs until the Agency has wrapped up responses to the citizen petitions and is poised to make ANDA approval decisions. 

By Jeffrey K. Shapiro –

In our continuing quest to enlighten, we are launching today an occasional series that will examine significant or interesting warning letters involving medical device companies.

As you probably know, FDA issues warning letters to allege violations of the Federal Food, Drug, and Cosmetic Act and/or implementing regulations.  A warning letter is a statement of FDA’s enforcement position and a threat to pursue legal remedies if the target does not comply.  Usually, the alleged violation does not break new ground.  But, on occasion, FDA issues a warning letter that reveals a new or little known enforcement position.  This type of warning letter will be our critical focus.

Case in point:  A recent warning letter issued by the Philadephia District to a ventilator company appears to create a new standard for reporting malfunctions in life sustaining or life supporting devices or implantable devices.

As background, a malfunction complaint is reportable to FDA if a recurrence would be likely to cause or contribute to a death or serious injury.  See 21 C.F.R. § 803.50(a)(2).  In this case, there were complaints of ventilator malfunction that were not reported that FDA apparently believes should have been reported.  This led FDA to issue a Form 483 observation.  The warning letter followed.

The warning letter does not describe the malfunction events at issue.  The story gets interesting, however, when FDA assesses the firm’s response to the Form 483 observation.  Apparently, the firm had revised its reportability criteria to limit reportability to “ventilator failure modes that result in a loss of therapy.”  This limitation seems perfectly reasonable.  If a malfunction is not capable of causing a loss of therapy, almost by definition it is unlikely to cause or contribute to a serious injury or death.  Therefore, such malfunctions do not trigger the regulatory requirement for reportability.

Yet, FDA rejected the proposed limitation.  The agency relies upon the preamble to the medical device adverse event reporting (“MDR”) regulation.  See 60 Fed. Reg. 63,578, 63,585 (Dec. 11, 1995) (comment 12).  This comment expresses FDA’s interpretive view that a malfunction involving a life sustaining or life supporting device is reportable.

This citation is not adequate to support FDA’s position.  In context, the preamble statement seems merely intended to establish an enforcement presumption that loss of therapy in a life sustaining or life supporting device is likely to cause a serious injury or death.  The preamble does not appear to intend that literally every possible malfunction in such a device will be reportable even if the basic regulatory requirements for reportability are absent.  (Even if that were FDA’s intent, the agency legally cannot alter the basic terms of a regulation via a preamble statement.)

For example, if a red light bulb in an “on” switch indicator in a ventilator is off because internal wiring has gone bad, but a white bulb next to it still works and the user can tell that the device is “on,” there would be no interruption in treatment due to this malfunction and no death or serious injury could occur.  Therefore, this malfunction is not reportable under the MDR regulation.  Under the approach taken in FDA’s warning letter, however, it would appear that this malfunction would need to be reported.

FDA’s final statement in the letter (on this topic) states:  “[Y]our firm should submit an MDR for complaints referencing ventilator failures.”  This statement introduces a new ambiguity by using the term “failures” rather than “malfunctions.”  it appears that FDA is using these terms interchangeably, even though they really are not synonymous.  In any event, in light of the warning letter’s earlier rejection of a policy limiting reportability to malfunctions resulting in a loss of therapy, FDA’s position appears to be that all ventilator malfunctions are reportable without further analysis as to whether they meet the reporting criteria in the MDR regulation.  If so, FDA’s position extends well beyond the plain language of the MDR regulation.

It is hard to know whether this warning letter is simply a “one off” or a harbinger.  Under the previous administration, Chief Counsel’s office was required to review the legal sufficiency and consistency with agency policy of all warning letters.  Now that this review is restricted to warning letters that present significant or novel legal issues, it is not clear whether this warning letter received legal review. 

What is clear is that the reasoning of this warning letter is not limited to ventilators.  It would appear to be applicable to any device deemed life sustaining or life supporting, e.g., insulin infusion pumps, dialysis machines, cardio pulmonary bypass pumps, critical care diagnostic monitors, automated external defibrillators, insulin infusion pumps, and the like.  In light of this warning letter, manufacturers of all such devices will need to keep a wary eye on FDA’s enforcement of the MDR regulation. 

The International Conference on Drug Development (“ICD2”), formerly known as the International Industrial Pharmacy Conference, continues its annual tradition of offering an informal forum for the exchange of ideas concerning the drug discovery and development process.  The 2012 conference, which is presented by The University of Texas at Austin College of Pharmacy, is scheduled for February 27-29, 2012 at the Barton Creek Conference Center in Austin, Texas.  The 2012 conference theme is “Fostering Innovation and Translational Research in Support of Public Health and Economic Growth.”  Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will present at the conference during a session titled “Legal Considerations to Establish Biosimilarity and Therapeutic Interchangeability.”

The ICD2 conference is known for bringing together national and international scientists from academia, the pharmaceutical industry, the biotechnology industry, and regulatory agencies for the opportunity to learn about and discuss new initiatives for finding a better way to develop new drugs and improve the quality of existing drug products.   Information about the 2012 conference, including registration information, is available here.  A copy of the conference agenda is available here.

By Kurt R. Karst –      

Last week, the Government Accountability Office (“GAO”) released a report, titled “Food and Drug Administration: Better Coordination Could Enhance Efforts to Address Economic Adulteration and Protect the Public Health,” in which the GAO examines FDA’s approaches to detecting and preventing so-called “economic adulteration” of food and medical products, and the challenges FDA faces in detecting and preventing such adulteration.  The report responds to requests from Representatives Henry Waxman (D-CA), Frank Pallone (D-NJ), and John Dingell (D-MI) that the GAO review how FDA oversees the safety of products to prevent and respond to economic adulteration.  The requests followed two high-profile cases of economic adulteration involving melamine and melamine-related compounds in pet foods and oversulfated chondroitin sulfate in the blood thinner heparin – in both cases, the products were imported from China.

Economic adulteration (also known as “economically motivated adulteration”) is defined in the report to mean “the fraudulent, intentional substitution or addition of a substance in a product for the purpose of increasing the apparent value of the product or reducing the cost of its production, i.e., for economic gain.”  Economic adulteration includes, for example, “dilution of products with increased quantities of an already-present substance (e.g., increasing inactive ingredients of a drug with a resulting reduction in strength of the finished product, or watering down of juice) to the extent that such dilution poses a known or possible health risk to consumers, as well as the addition or substitution of substances in order to mask dilution.”  (The definition of “economic adulteration” used in the GAO report is the same definition FDA proposed in April 2009 as a working definition for “economically motivated adulteration” – see 74 Fed. Reg. 15,498 (Apr. 6, 2009).)  Economic adulteration, a form of “intentional adulteration” whose primary purpose is financial gain, differs from other types of adulteration – both intentional adulteration, whose primary purpose is to cause harm (e.g., bioterrorism or sabotage), and “unintentional adulteration” (e.g., adulteration for failure to follow good manufacturing practices) – says GAO in the report.  The FDC Act does not make a distinction between intentional and unintentional adulteration, but rather prohibits the introduction of adulterated food, drugs, and medical devices into interstate commerce.  Similarly, “FDA primarily approaches economic adulteration as part of its broader efforts to combat adulteration in general, such as efforts to ensure the safety of imported products.”

FDA officials and stakeholders GAO interviewed in preparing the report noted several key challenges to detecting and preventing economic adulteration, including increased globalization, an increase in supply chain complexity, and difficulties with gathering information from industry (due to concerns about sharing proprietary information).  To enhance FDA’s efforts to combat economic adulteration, GAO recommends that Commissioner Hamburg take three actions: (1) officially adopt a working definition of “economic adulteration,” because “[w]ithout such a definition, when FDA detects adulteration, it is more difficult for the agency to make a distinction between economic adulteration and other forms of adulteration to guide the agency’s thinking about how to be more proactive about this issue;” (2) “provide written guidance to agency centers and offices on the means of addressing economic adulteration;” and (3) “enhance communication and coordination of agency efforts on economic adulteration,” because “[w]ithout such communication and coordination, in these times of economic uncertainty, FDA may not be making the best use of its scarce resources.”

FDA notes in the Agency’s response to the GAO report that FDA recently established the Working Group on Economically Motivated Adulteration (“WEMA”), which is comprised of staff from all FDA centers, the Office of Regulatory Affairs, and Office of the Commissioner.  WEMA, which held its first meeting on September 23, 2011, and will use the Agency’s proposed working definition of economically motivated adulteration to identify topics of broad Agency interest, “seeks to encourage information sharing across FDA on issues relevant to economically motivated adulteration.”