The American Conference Institute will be holding its FDA Boot Camp conference in New York City from Tuesday, March 20 to Wednesday, March 21, 2012.  A copy of the conference program can be obtained here.  Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will be presenting at the conference in a session on the Hatch-Waxman Amendments and the Biologics Price Competition and Innovation Act of 2009.

The conference will include presentations from a virtual “who’s who list” of FDA regulatory experts on myriad topics, including the approval process, pre-approval concerns, product labeling, clinical trials, adverse events reporting, and patent and non-patent marketing exclusivity issues. 

FDA Law Blog is a conference media partner.  As such, we can offer FDA Law Blog readers a special $200 discount off the current price tier.  The discount code is: FDA 200.  We look forward to seeing you at the conference.

By Kurt R. Karst –      

Last week, FDA Commissioner Margaret A. Hamburg, M.D. announced that the Agency sent to Congress packages for three user fee programs, including proposed statutory language for the fifth iteration of the Prescription Drug User Fee Act (“PDUFA V”), and two new user fee statutes – the Generic Drug User Fee Amendments of 2012 (“GDUFA”) and the Biosimilars User Fee Act of 2012 (“BSUFA”).  FDA previously announced the proposed performance goals and procedures (Fiscal Years 2013 through 2017) for PDUFA V, GDUFA, and BSUFA (here, here, and here), which we reported on here, here, and here.  Noticeably absent from FDA’s submission is proposed statutory language and performance goals and procedures for the next iteration of the Medical Device User Fee and Modernization Act (“MDUFMA”). According to press reports (see here), FDA and industry are still haggling over some issues.  The House Energy and Commerce Committee has scheduled three hearings for February 2012 to consider each of the four user fee programs (see here, here, and here).

Of the various “UFAs” (User Fee Acts) up for consideration by Congress, GDUFA will likely have the most wide-ranging and immediate effects (both on industry and on FDA and the Office of Generic Drugs).  (Biosimilar are still in their infancy.  Earlier this week it was reported that the highly-anticipated and seemingly always “shortly forthcoming” draft guidance from FDA on the Biologics Price Competition and Innovation Act may be further delayed.)  We thought we would take a few minutes to point out a couple of the interesting and unique provisions in the proposed statutory language (as compared to other UFAs), which we alluded to in a previous post after GDUFA negotiations were completed.

User Fee Types and Amounts.  People have already been asking: “What will the GDUFA user fees rates be set at?”  The fact is that nobody (not even FDA) really knows yet exactly what all of the user fee rates will be set at for Fiscal Year (“FY”) 2013 or thereafter, because some of the rates depend on information that still needs to be collected.  That being said, the user fee rates for FYs 2014-2017 will likely be higher than what will be set for FY 2013 given that in FY 2013, $50 million of the total user fee revenue amount of $299 million (adjusted each FY) will come from a one-time ANDA backlog fee.

There are proposed to be four types of fees in two categories – application fees and facility fees.  Application fees, which account for 30% of total fee revenue each FY, include an original ANDA fee and Prior Approval Supplement (“PAS”) fee (one half of the ANDA fee) (both accounting for 24% of the total revenue amount), and a Type II Drug Master File (“DMF”) “first reference fee” (6% of total revenue amount).  There is also a one-time (FY 2013) ANDA backlog fee for ANDAs pending on October 1, 2012.  That fee will be calculated by dividing $50 million by the number of ANDAs in the backlog, which as of January 1, 2012, was at 2,696 ANDAs.  (There was a record 210 original ANDA submissions to FDA in December alone, historically the highest volume month of submission.  A total of 946 original ANDAs were submitted to FDA in 2011.)  The number of ANDAs in the backlog on October 1, 2012 may increase or decrease from the current backlog number as companies decide whether or not to withdraw applications (or perhaps play a game of chicken with other ANDA sponsors). 

A facility fee, which accounts for 70% of total fee revenue each FY, must be paid by both Finished Dosage Form (“FDF”) and Active Pharmaceutical Ingredient (“API”) manufacturers.  FDF facility fees account for 80% of facility fee revenue (56% of the total revenue amount), and API facilities account for 20% of facility fee revenue (14% of the total revenue amount).  There is “a modest fee differential” of not less than $15,000 and not more than $30,000 for foreign FDF and API facilities “reflecting the added costs of overseas inspection.”

For FY 2013, FDA is supposed to set the application fees and ANDA backlog fee by October 31, 2012.  The FY 2013 facility fee rates must be set “within 45 days after the date to comply with the requirement for identification of facilities in [proposed FDC Act § 744G(f)(1)].”  Proposed FDC Act § 744G(f)(1) states in relevant part that “[b]y October 1, 2012, the Secretary shall cause to be published in the Federal Register a notice requiring each person that owns a facility as identified in [proposed FDC Act § 744G(a)(4)(A)] or a site identified in [proposed FDC Act § 744G(f)(3)] to identify each such facility or site.  Each such person shall comply with that requirement within 60 calendar days of the publication of such notice.”

Failure to Pay User Fees.  The penalties for failing to pay GDUFA fees are particularly harsh under the proposed statutory language. 

Failure to pay the ANDA backlog fee will result in placing the ANDA sponsor on an arrears list, “such that no new ANDAs or supplement submitted on or after October 1, 2012 from that person, or any affiliate of that person, will be received within the meaning of [FDC Act § 505(j)(5)(A)] as implemented in [FDA] regulations, until such outstanding fee is paid.”  Proposed FDC Act § 744G(g)(1) (emphasis added). 

Failure to pay the required application fee within 20 calendar days of the due date will result in the application not being received (FDC Act § 505(j)(5)(A)) until the fee is paid.  ANDA receipt date is, of course, particularly important when 180-day exclusivity is at stake.  And the proposed statute recognizes this at § 744G(o), which states:

An [ANDA] that is not considered to be received within the meaning of [FDC Act § 505(j)(5)(A)] because of failure to pay an applicable fee under this provision within the time period specified in [FDC Act § 744G(g)] shall be deemed not to have been “substantially complete” on the date of its submission within the meaning of section 505(j)(5)(B)(iv)(II)(cc).  An [ANDA] that is not substantially complete on the date of its submission solely because of failure to pay an applicable fee under the preceding sentence shall be deemed substantially complete and received within the meaning of section 505(j)(5)(A) as of the date such applicable fee is received.

Failure to pay the DMF fee within 20 calendar days of the due date “will result in the Type II [API DMF] not being deemed available for reference.”  An affected ANDA “shall not be received within the meaning of [FDC Act § 505(j)(5)(A)]” unless the fee “has been paid within 20 calendar days of the Secretary providing the notification to the sponsor of the [ANDA] or supplement of the failure of the owner of the Type II [API DMF] to pay the [DMF] fee . . . .”  Proposed FDC act § 744G(g)(2).

Failure to pay a facility fee within 20 calendar days of the due date will result in several penalties, included what might be the harshest penalty of all – misbranding.  Specifically, proposed FDC Act § 744G(g)(4) (emphasis added below) states that failure to pay a fee will result in:

(A) identification of the facility on a publicly available arrears list, such that no new [ANDAs] or supplement submitted on or after October 1, 2012 from that person, or any affiliate of that person, will be received within the meaning of [FDC Act § 505(j)(5)(A)] as implemented in [FDA] regulations;

(B) any new generic drug submission submitted on or after October 1, 2012 that references such a facility shall not be received, within the meaning of FDC Act § 505(j)(5)(A)] as implemented in [FDA] regulations if the outstanding facility fee is not paid within 20 calendar days of the Secretary providing the notification to the sponsor of the failure of the owner of the facility to pay the facility fee as specified in [proposed FDC Act § 744G(a)(4)(C)]; and

(C) all drugs or [APIs] manufactured in such a facility or containing an ingredient manufactured in such a facility being deemed misbranded under [proposed FDC Act § 502(aa)].

The penalties in [proposed FDC Act § 744G(g)(4)] shall apply until the [facility] fee . . .  is paid or the facility is removed from all generic drug submissions that refer to the facility. 

Proposed FDC Act § 502(aa) (Section 106 of GDUFA) would amend the statute to state that a drug shall be deemed to be misbranded:

If it is a drug, or an [API], and it was manufactured, prepared, propagated, compounded, or processed in a facility for which fees have not been paid as required by [proposed FDC Act § 744G(a)(4)] or for which identifying information required by [proposed FDC Act § 744G(f)] has not been submitted, or it contains an [API] that was manufactured,  prepared, propagated, compounded, or processed in such a facility.

The misbranding provision, which was a point of controversy during GDUFA negotiations, appears to be intended to add some teeth to the proposed user fee statute.

User Fee Refunds.  Although other UFAs, like PDUFA and BSUFA, include user fee waiver/refund provisions (e.g., small business waiver), as well as strict waiver/refund request timelines (i.e., requests must be submitted within 180 days after a fee is due), the proposed GDUFA statute does not.  There is a 75% refund of the application (original ANDA and PAS) fee if an application is not received, see Proposed FDC Act § 744G(a)(3)(D); however, such an application will be subject to a new fee upon resubmission.  See id.  § 744G(a)(3)(E).  It is unclear whether an ANDA sponsor must specifically request in writing a 75% refund of the application fee, or whether such refund is automatic.  Proposed FDC Act § 744G(n) (emphasis added), titled “Disputes concerning fees,” states that “[t]o qualify for the return of a fee claimed to have been paid in error under this section, a person shall submit to the Secretary a written request justifying such return within 180 calendar days after such fee was paid.”  Is a fee subject to the 75% refund provision a fee that can be claimed to have been paid in error, thereby requiring a written refund request?

By JP Ellison –

An important issue relating to when an action by an administrative agency can be challenged in court was argued before the Supreme Court last week.  The case involved administrative enforcement activities of the U.S. Environmental Protection Agency (“EPA”). The case, Sackett v. EPA (Docket No. 10-1062), involved a dispute between EPA and an Idaho couple and has recently received widespread press for the Justice’s sharp questioning of the government (see more here).  Buried within the intricacies of the Clean Water Act and this land use battle was the issue that may be of interest to our readers.

As we have explained in previous posts (here and here), the Administrative Procedure Act (“APA”) is the commonly used vehicle for challenging federal government action.  The APA requires final agency action for a lawsuit to be filed, and it is not uncommon for a case to be dismissed on the grounds that whatever else it represented, what the agency did was not final agency action. 

In the Sackett case, the government argued that EPA compliance orders were not final agency action, and therefore not subject to court review.  “‘The compliance order is not ‘final agency action.’  See 5 U.S.C. 704. A[n] . . . order marks only a step in EPA’s decision-making process, not its consummation.”  At oral argument, the Justices seemed unconvinced.   Justice Scalia asked “when you have something as formal as this which shows that the agency does intend to prosecute, why wouldn't you be able to bring a declaratory judgment action,”? and Justice Breyer observed, “of course a warning isn't reviewable. But this seems to meet the test where that [argument] fails.”

The government acknowledged during the argument that the issue before the Court had potentially wide-reaching ramifications, noting, that “it would cause a huge upheaval in the practices of many agencies to say that declaratory relief is typically available when the agency issued an informal warning.”

A prediction on when and how the Court will address this issue is beyond the scope of this post, but we will be watching for the decision later this year to see whether it sets forth a standard for judicial review of agency enforcement activities that upsets traditional notions of the types of agency action subject to challenge.

By Riëtte van Laack –

USDA’s National Organic Program ("NOP") published a proposed rule that would amend the listing of vitamins and minerals in the National List of Allowed and Prohibited Substances (National List).  The National List identifies non-agricultural synthetic ingredients that may be used in or on “organic” and “made with organic” food.  See 7 C.F.R. § 205.605(b).  Since 2000, the National List has included “Nutrient vitamins and minerals, in accordance with 21 C.F.R. § 101.20, Nutritional Qualify Guidelines for Foods.”  The annotation referring to FDA’s fortification policy at § 101.20 has created confusion and controversy about which nutrients are permitted.  Specifically, it led to questions about whether “accessory nutrients” are permitted (NOP defines “accessory nutrients” as nutrients not specifically classified as a vitamin or mineral but found to promote health, such as DHA, ARA, lutein ester, and taurine).  It also led to questions about whether certain nutrients are permitted for use in or on organic infant formula.  Based on communications with FDA, the NOP learned that FDA’s fortification policy does not apply to infant formula.  Moreover, FDA clarified that so-called “accessory nutrients” are not within the scope of FDA’s fortification policy.   

To provide clarity as to which nutrients may be added to organic food and organic infant formula, NOP now proposes to amend the National List to state:  “Vitamins and minerals.  For food – vitamins and minerals identified as essential in 21 C.F.R. § 101.9.  For infant formula – vitamins and minerals as required by 21 C.F.R. § 107.100 or § 107.10.”  Thus, the proposed rule would permit use in organic food and infant formula of the essential vitamins A, C, K, D, E, thiamin, riboflavin, niacin, B6, B12, biotin, folic acid, and pantothenic acid, and the essential minerals calcium, iron, phosphorus, magnesium, zinc, iodine, copper, potassium, selenium, manganese, and chloride.  In addition, the essential minerals chromium and molybdenum would be permitted in organic food but not in organic infant formula, and the essential nutrients choline, inositol, and sodium would be permitted in organic infant formula but not in organic food.  Nutrients that do not fall within the identified categories of vitamins and minerals, e.g., EPA and DHA, would no longer be permitted in organic food and infant formula, unless these nutrients are specifically included in the National List.  To allow industry time to submit petitions for inclusion of these nutrients in the National List, NOP proposes a compliance date of two years after the rule is finalized.

The NOP is specifically seeking comments regarding the delayed compliance date and on the actual economic impacts of the proposed action on industry, including small entities.  Comments may be submitted until March 12, 2012. 

By Kurt R. Karst –      

FDA recently denied a 2008 citizen petition (Docket No. FDA-2008-P-0291) requesting that the Agency amend its drug label regulations to require that product labels include the Orange Book-listed NDA number under which the product is approved.  According to the petition, “[i]ncreasingly, it has become more difficult for pharmacists to determine the status of the prescription drug products on his or her shelf.  Due, in part, to the accelerated pace of corporate mergers and acquisitions, the labels on many drug products no longer contain the information necessary for identification of that product in the Orange Book.”  Two examples used in the petition are authorized generics (defined at FDC Act § 505(t)(3)) and distributirs that relabel or repackage drug products.  In both cases, such products are not specifically identified in the Orange Book, but can be traced back to an approved drug product.  According to the petitioner, PRN Publishing, requiring the application number on drug product labels would allow pharmacists “to quickly and easily determine the equivalence status of any drug product by simply comparing the [application] number on the bottle to the [application] numbers listed in the Orange Book under the heading of the particular drug in question.”

FDA, in its petition denial, says that the Agency does not agree that a requirement to add the application number to product labels (both products approved under NDAs and ANDAs) would address the issues identified by PRN Publishing.  Tackling each of the petitioner’s examples, FDA says with respect to authorized generics that:

because an authorized generic drug shares the same NDA number as the branded innovator product, the authorized generic would not be identified separately from the branded drug in the Orange Book.  Pharmacists could be confused when they look up an NDA number in the Orange Book and find only a listing for the innovator product (which would not match in certain respects the label of the authorized generic drug in hand). 

And with respect to distributors, FDA comments that:

because distributors that relabel or repackage drug products do not separately identify their products for listing in the Orange Book, such marketed drugs would not be traceable by searching the Orange Book.  Pharmacists could be confused when they look up the application number in the Orange Book and find only a listing for the approved application holder (which would not match the label of the product in hand).

Finally, FDA notes that there are also several factors that need be taken into account when considering whether or not to amend the Agency’s drug label requirements, including “the Agency’s statutory mandate, space limitations, alternatives, potential for confusion, and potential safety risk.”  “Weighing these and other considerations in deciding how to use agency resources to efficiently and effectively promote and protect the public health,” FDA concluded that it is not necessary at this time to amend its drug label regulations to require companies to identify the application number under which the product is approved and marketed.

Curiously, neither the citizen petition nor FDA’s response discusses now-repealed FDC Act § 301(l).  Prior to the enactment of the 1997 FDA Modernization Act (“FDAMA”), FDC Act § 301(l) prohibited the use in labeling of any representation or suggestion that “approval of an application with respect to such drug . . . is in effect under section 505 . . . .”  FDAMA § 421 removed this vestigial remnant of the 1938 FDC Act.  Although the legislative history surrounding the repeal of FDC Act § 301(l) is a bit sketchy, it appears to be related to legislation introduced as far back as 1985 by Representative Henry Waxman (D-CA) – H.R. 2244, The FDA Approval Labeling Act – that proposed to amend the FDC Act to permit use of the statement “FDA Approved” in drug product labeling and advertising.  Subsequent to the repeal of FDC Act § 301(l), FDA has stated, in the context of the promotion and advertising of a drug, that companies can use the statement “FDA Approved” in labeling pieces and advertisements for prescription drugs, provided the company has approval for the drug product with respect to which the statement is made. 

We also note that in December 1998, FDA stated in a draft guidance document, titled “Placing the Therapeutic Equivalence Code on Prescription Drug Labels and Labeling” (FDA Docket No. 1998D-1266), that the Agency “believes it is legally permissible to allow the therapeutic equivalence code [identified in the Orange Book] linked to the proprietary name of the reference listed drug product to be placed on container labels and/or drug product labeling,” and that with the repeal of FDA Act § 301(l), “any legal arguments that therapeutic equivalence ratings should not be used in the labeling are moot.”  FDA never finalized the draft guidance, and, in fact, removed the draft guidance from its website after receiving adverse comments.  We understand that FDA currently has no public position on the issue of including in generic drug labeling a therapeutic equivalence code or similar information. 

While we’re on the topic of application numbers, we thought it would be helpful to provide folks with a Rosetta Stone of sorts with respect to FDA’s application numbering system, which changed not too long ago with FDA’s implementation of the Document Archiving, Reporting and Regulatory Tracking System (“DARRTS”).

• Application Nos. 00001 to 13000 (approximately): Pre-1962 NDA approvals (evaluated under DESI)
• Application Nos. 13000 (approximately) through 20,000 series applications: Post-1962 NDA approvals
• 40,000 Series Applications: ANDAs for generic versions of pre-1962 NDA approvals (A continuation of the 80,000 series applications.)
• 50,000 Series Applications: Old antibiotic NDAs approved under now-repealed FDC Act § 507
• 60,000 Series Applications: Old antibiotic ANDAs approved under now-repealed FDC Act § 507 (Some of the early 60,000 numbers could be considered innovator products.  For example, early in this numbering system when the NDA sponsor wanted a new manufacturing site, we understand that FDA assigned a 60,000 series application number. So the early 60,000's were probably NDAs in disguise. The 50,000 and 60,000 series numbers were the identification system used because of Form 5's and Form 6's.)
• 70,000 Series Applications: Contemporary, post-Hatch-Waxman ANDAs (The pre-/post-MMA ANDA No. cutoff – December 8, 2003 - is approximately ANDA No. 076925.)
• 80,000 Series Applications: ANDAs for generic versions of pre-1962 NDA approvals
• 90,000 Series Applications: Contemporary, post-Hatch-Waxman ANDAs (A continuation of the 70,000 series applications.  Beginning around October 2007, it is believed that the 90,000 series combined all ANDAs, such that the 40,000, 60,000, and 80,000 series numbers were no longer used.)
• 200,000 Series Applications: Post-DARRTS applications; numbers are assigned sequentially to NDAs and ANDAs

By Riëtte van Laack –

The Animal Medicinal Drug Use Clarification Act of 1994 (“AMDUCA”) amended the FDC Act § 512(a) allowing veterinarians to prescribe extralabel use of certain approved animal and human drugs for animals.  (Extralabel use includes use in species not listed in the labeling, use for other indications than listed in the labeling, use of drugs approved for humans in animals, and deviation from the labeled withdrawal time).  Such extralabel use is permitted provided the use is prescribed by a veterinarian, the drug has been approved by FDA, a veterinarian-client relationship exists, the extralabel use is for therapeutic use (i.e., not for production use), and the use does not result in a violative food residue.  Special rules apply for drugs administered in water and extralabel use in feed is not permitted.  If, however, FDA determines that the extralabel use of an approved drug “presents a risk to the public health [the Agency] may, by order, prohibit [the extralabel] use.”  FDC Act § 512(a)(4)(D).

On January 6, 2012, FDA issued an order prohibiting the extralabel use of certain Cephalosporins in food-producing major species.  As explained in the order, FDA believes that the specified extralabel uses present a risk to public health because these uses in animals have not been evaluated for safety to animals and humans.  Specifically, FDA is concerned about the possible effect of certain extralabel uses in animals on antimicrobial resistance of microorganisms that have been associated with diseases in humans, including pneumonia, skin and tissue infections, pelvic inflammatory disease, and serious gastrointestinal infections in children.  As a result, treatment of these infections in humans with human cephalosporin drugs may be ineffective or require drugs with more serious side effects.

More than three years ago, FDA issued a similar order prohibiting the extralabel use of cephalosporin antimicrobial drugs in animals.  See 73 Fed. Reg. 38110 (July 3, 2008).  However, after extending the comment period, and receiving numerous substantive comments, only few of which supported the order, FDA decided to revoke the 2008 order.  See 73 Fed. Reg. 71923 (Nov. 26, 2008).   The majority of the comments felt that the 2008 order was too broad in scope, would have negative consequences for animal health, and was not based on sound scientific evidence.  In response, the current order is more narrowly tailored to prohibit only certain extralabel uses of certain cephalosporins.

FDA’s current order prohibits the extralabel use of cephalosporin antimicrobial drugs (except cephapirin) in the food-producing major animals, i.e., cattle, swine, chicken, and turkeys, 1) for disease prevention purposes, 2) at unapproved doses, frequencies, durations, or routes of administration, and 3) for use in a species and production class for which the drug has not been approved.  Extralabel use of cephalosporins in food-producing minor species, such as rabbits, is not affected by the order.

The order has been applauded by various advocates for control of antimicrobial drugs in food-producing animals – see here, here, and here. 

Unless revoked or modified by FDA, the order becomes effective April 5, 2012.  Comments may be submitted until March 6, 2012.

By Riëtte van Laack –

In a strongly worded letter to FDA Commissioner Hamburg dated December 22, 2011, the principal authors of the Dietary Supplement Health and Education Act of 1994 (“DSHEA”), Senators Orrin Hatch (R-UT) and Tom Harkin (D-IA), requested that FDA immediately withdraw the Draft New Dietary Ingredient Guidance ("Draft NDI Guidance") because it undermines DSHEA in unacceptable ways.

The Senators’ letter is consistent with industry’s concerns over the Draft NDI Guidance.  As examples of FDA’s misinterpretation the Senators included FDA’s view that a manufacturer must submit an NDI notification for every dietary supplement containing an NDI, FDA’s assertion that synthetic copies of botanical ingredients can never be a dietary ingredient, FDA’s unduly broad interpretation of what constitutes chemical alteration, and the Agency’s narrow definition of “old dietary ingredient.” 

The Senators request that, as part of the process of withdrawing and rewriting the guidance, Commissioner Hamburg direct her staff to meet with the Senators’ staff to further discuss concerns with the guidance in more detail.

On December 2, 2011, Hyman, Phelps, & McNamara filed comments to the controversial Draft NDI Guidance requesting that it 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 our previous post here. 

By Kurt R. Karst –      

In what appears to be the first federal court decision on the so-called Reference Listed Drug (“RLD”) theory of liability, Judge Marvin H. Shoob of the U.S. District Court for the Northern District of Georgia (Atlanta Division) recently ruled in Moore v. Mylan, Inc., No. 11:1-cv-03037-MHS (N.D. Ga. Jan. 5, 2012), that a failure-to-warn claim against a generic drug manufacturer whose drug product has been designated by FDA as the RLD is preempted under the U.S. Supreme Court’s June 23, 2011, 5-4 landmark decision in PLIVA Inc. v. Mensing, 131 S. Ct. 2567 (2011).  In Mensing, the Supreme Court ruled that generic drug manufacturers are not permitted to change their labeling except to mirror the label of the brand, RLD manufacturer whose drug product is approved under an NDA.

As we previously reported in what has been referred to by some FDA Law Blog readers as the “Betelgeuse Post,” the RLD theory posits that FDA’s regulations impose new or additional responsibilities on an ANDA sponsor whose drug product is unilaterally designated by FDA as an RLD, and that the Court’s Mensing decision is inapplicable under such circumstances.  Often, FDA designates an ANDA-approved drug product as an RLD once the brand-name RLD drug product (usually approved under an NDA) is discontinued and withdrawn from the market; however, the Moore decision shows us that the RLD theory of liability can arise in other circumstances.

DILANTIN KAPSEALS (extended phenytoin sodium) Capsules, 100 mg, is a brand-name anti-epileptic drug product marketed by Pfizer’s Parke-Davis unit that FDA approved on August 27, 1976 under ANDA No. 084349 (presumably as a generic version of a pre-1962 drug under the pre-Hatch-Waxman ANDA approval procedures, based on the 80,000 series application number).  On December 28, 1998, FDA approved Mylan’s ANDA No. 040298 for a generic version of DILANTIN KAPSEALS Capsules, 100 mg, pursuant to FDC Act § 505(j), which was added by the 1984 Hatch-Waxman Amendments.  After approving a suitability petition (Docket No. 2000P-1462), FDA approved, on December 6, 2001, two additional strengths under ANDA No. 040298 – 200 mg and 300 mg – stating that “[t]he new strengths of Extended Phenytoin Sodium Capsules USP, 200 mg and 300 mg, can be expected to have the same therapeutic effect as that of the listed drug product upon which the Agency relied as the basis of safety and effectiveness” – i.e., DILANTIN KAPSEALS Capsules, 100 mg.   The 200 mg and 300 mg drug products are listed in the Orange Book with the brand name PHENYTEK, and the 300 mg strength is designated as an RLD. 

In Moore, which was initially filed in the State Court of Fulton County and was removed to the U.S. District Court for the Northern District of Georgia (Atlanta Division) based on federal diversity jurisdiction, the Plaintiffs alleged, among other things, that the decedent, George L. Frazier, ingested Mylan’s 100 mg phenytoin drug product and that he suffered certain adverse reactions that were caused by the drug product.  According to the Plaintiffs, both Pfizer and Mylan had a duty to warn the decedent, his physician, and the public of the health risks associated with their drug products, among myriad other claims in the Complaint. 

Of particular interest to us is Plaintiffs’ assertion that “FDA’s designation of Mylan’s 300-mg phenytoin as an RLD gave Mylan the authority to use the [Changes Being Effected (‘CBE’)] process to change its 300-mg phenytoin label,” and that as such, the court should employ the impossibility preemption analysis utilized in the U.S. Supreme Court’s March 2009 decision in Wyeth v. Levine, 555 U.S. 555 (2009).  Under Plaintiffs’ theory, wrote Judge Shoob:

Mylan would have had two avenues for changing the label on the generic 100-mg phenytoin: (1) after Mylan changed the 300-mg label, Mylan would have been required to change the generic 100-mg phenytoin label to match the label of the 300mg label because the generic l00-mg must match the RLD; or (2) because Mylan was an RLD holder of 300-mg phenytoin, Mylan had the same rights as a brand name drug manufacturer, and therefore, could have used the CBE process to change the 100-mg phenytoin label.

Mylan, in its Motion to Dismiss – response and reply briefs available here and here – argued that Plaintiff’s case against Mylan is preempted by Mensing, regardless of product-liability claim.

Judge Shoob found several problems with Plaintiffs’ arguments, including that:

[P]laintiff assumes without authority that because Mylan’s 300-mg phenytoin was designated as the RLD, Mylan is “considered as having the same rights and obligations as a ‘brand-name’ manufacturer of phenytoin,” including the right to use the CBE process to change labels.  However, plaintiff has not shown how Mylan acquired all of the same rights as a brand name drug manufacturer simply by manufacturing one drug that was an RLD.  Plaintiff has not shown that Mylan’s manufacture of one RLD converted Mylan into brand name drug manufacturer with the right to use the CBE process to change the label of any of its drugs or how listing 300-mg as an RLD converted the generic 300-mg phenytoin into a brand name drug. [(Internal citations omitted)]

Accordingly, Judge Shoob found that: (1) “FDA’s designation of Mylan’s 300-mg phenytoin as an RLD would not have permitted Mylan to use the CBE process to change the label of 100-mg phenytoin to conform to state law;” (2) “Plaintiff has not shown any other federal statute or regulation that would have allowed Mylan to change the 100-mg phenytoin label;” and (3) “Mylan, as the generic drug manufacturer of 100-mg phenytoin, was prevented from independently changing the 100-mg label to conform with state law.”  As such, any failure-to-warn claim is preempted by Mensing, wrote the court in dismissing Plaintiffs’ claim against Mylan and granting Mylan’s Motion to Dismiss. 

The Moore decision is the first federal court decision we are aware of in which a court has ruled on ANDA RLD theories of liability.  In November 2011, Judge Douglas H. Hurd of the Superior Court of New Jersey recognized in an Oral Ruling in Sincoskie v. West-Ward Pharms., No. MER-L-2643-10 (N.J. Super. Ct. Law Div. Nov. 4, 2011), that regardless of whether FDA unilaterally has designated a manufacturer’s ANDA drug product as the RLD, “[t]he bottom line is that they are an ANDA manufacturer and that’s the whole distinction here.” 

Thanks to Matt Wendler of Pietragallo Gordon Alfano Bosick & Raspanti, LLP for alerting us to the Moore decision.

By Riëtte van Laack –

On January 3, 2012, the U.S. Pharmacopeial Convention (“USP”), a scientific organization that publishes the Food Chemical Codex (“FCC”), an international compendium of quality specifications for food ingredients, announced proposed standards for probiotic food ingredients. The proposed standards will be included as new Appendix XV. 

The latest FCC Forum, the free-access on-line publication of proposed FCC standards, proposes standards to be included as new FCC Appendix XV, titled “Microbial Food Cultures Including Probiotics.”  The proposed standards provide a broad description of microbial food cultures (“MFCs”).  Taxonomically and functionally diverse, MFCs include species of a broad range of bacteria, yeasts and fungi.  The proposed FCC standards divide MFCs into two categories: MFCs with a technological role, e.g., starter cultures, and MFCs with a functional role, i.e., those that impart a health benefit.  The proposed FCC standards employ the FAO/WHO definition of probiotics, i.e., “live microorganisms, which when administered in adequate amounts confer a health benefit on the host.”

The proposed quality specifications include identification and enumeration, intended use in food, safety, regulatory status, and purity.  Under the proposed standards probiotics must be identified at the strain level (in contrast starter cultures may be identified at the genus or species level, depending on the requirements of their use).  USP asserts that this level of specification is important for safety (e.g., presence of transferable antibiotic resistance traits) and in supporting health claims. 

Although enumeration of probiotics cannot be generalized, probiotic activity typically relies on the number of live microorganisms and viability is essential at the time of consumption.  Thus, viability through the end of the shelf life in the food matrix is an important characteristic.

The proposed standards are general and applicable to all probiotics.  Future standards development work by USP may include individual standards for specific probiotic strains.

By Jeffrey K. Shapiro, Jeffrey N. Gibbs & Jennifer D. Newberger –

It is essential to FDA’s proper functioning that stakeholders have a viable appeals process.  This means a process that is timely, transparent, and fair.  A viable appeals process is an essential “check and balance” to limit arbitrary and capricious decision making, to correct erroneous decisions, and to maintain consistency in decisions.

As discussed in a prior blog post, in the medical device arena, the appeals process is not functioning well, and is in urgent need of reform.   Over the years, the statute and regulations have become encrusted with a multitude of overlapping procedures that are so expensive and time consuming, that they are practically useless.  At the same time, the most viable procedure, a request for supervisory review under 21 C.F.R. § 10.75, has not functioned well, at least in recent years.

Late last month, the Center for Devices and Radiological Health ("CDRH") issued a draft guidance document on “CDRH Appeals Processes.”  The guidance provides general information about the various appeals processes available to individuals “who disagree with a decision or action taken by CDRH and wish to have it reviewed or reconsidered.”  This guidance, if finalized, would replace a 1998 guidance document about medical device appeals and the 2001 guidance describing the Dispute Resolution Panel. 

The new draft guidance does a good job of explaining all of the various complicated appeals processes that are available.  The 1998 guidance presented the types of decisions that might be appealed and provided guidance on the various processes available for each type of decision.  The new guidance focuses instead on explaining the appeal procedures, i.e., request for supervisory review, Medical Devices Dispute Resolution Panel ("MDDRP"), the various types of petitions, the various types of hearings, and judicial review.  This approach seems to make the material more understandable.

The 1998 appeals guidance did have a useful set of tables with the essentials of each procedure and the “pros” and “cons” of each.  These are unfortunately omitted from the new draft guidance.  It would be helpful to retain them, perhaps in an appendix.

Perhaps the most welcome aspect of the new draft guidance is the detailed description of the supervisory review process.  In most cases, this type of appeal is the only one that is practical.  Until now, however, there has been very little written by FDA about how it works, other than the bare bones of the regulation itself (i.e., 21 C.F.R. §  10.75) and a fairly cursory description in the 1998 appeals guidance.  The new draft guidance removes some of the mystery about the workings of this procedure.

The draft guidance appears intended to be descriptive of the existing procedures and not to introduce reforms.   At the same time, there do seem to be some new wrinkles, although they are not labeled as such.

First, the draft guidance does set out written time frames for review that, if followed, could significantly reduce industry frustration with the process.  For instance, the draft guidance states that a review meeting or teleconference will be scheduled within four to six weeks of receipt a request for such review, and a decision on the appeal will be communicated within six weeks of submission of the written appeal or appeal meeting.  These time frames are consistent with oral targets that CDRH officials have conveyed over the years, but they generally have not been followed.  It is unclear if putting these time frames in writing will lead CDRH to adhere to them more consistently.  If not, it would be more useful to sponsors for CDRH to provide actual timeframes, rather than aspirational timeframes to which CDRH will not be able to adhere.

Second, the new draft guidance specifically states that sponsors may appeal decisions that are not final.  Though the 1998 guidance stated that a 10.75 appeal may be appropriate for appealing requests for additional information, the new draft guidance states that 10.75 review may be available for disputes involving a pre-IDE submission, Warning Letter, and request for additional information associated with an adverse event report.  The draft guidance notes that most of these appeals for “intermediate” decisions would be “paper appeals,” meaning that, barring exceptional circumstances, there would be no teleconference or in-person meeting.  The draft guidance states that this paper appeal process for intermediate decisions will help “streamline” the process for these reviews.  What the new draft guidance does not address, however, is how these types of “intermediate” decisions (of which there may be many) can be reviewed in a manner that will not significantly affect the timeframe for review of “final” decisions, e.g., an NSE or PMA denial.

Third, the draft guidance introduces the concept of “telescoping” the review process, meaning that, in “certain unusual circumstances,” a supervisor may discuss the issues on appeal “with individuals at a higher organizational level.”  Circumstances for which this may be appropriate include matters pertaining to regulatory issues, new policy questions, or highly complex scientific questions.  In some cases, these circumstances “may also warrant referral of the review directly to the next-level supervisor, up to and including the Center Director,” in which case the review “will be considered to have been undertaken by the next-level supervisor.”  The decision to telescope a review may be undertaken solely by CDRH, and CDRH will document the rationale for such a decision in the appeal decision letter.

Fourth, the draft guidance states that in “matters that are particularly complex or novel, the submitter may request that the review authority refer the dispute to an Advisory Panel to make a recommendation to the review authority” or may “request that the review authority consider referring the matter to one or more external Subject Matter Experts.”  To our knowledge, such use of external expertise has not previously been available under section 10.75.  While the submitter may request use of external expertise, CDRH drafts the document to be provided to the external expert “that states the issue(s) in dispute and includes relevant documents for review.”  In order to ensure that the external expert receives a summary reflective of both FDA’s and the submitter’s perspective on the issues, we believe both parties should have the opportunity to provide information to the expert.

Fifth, both the 1998 guidance and the new draft guidance state that the appeal may not include any new information and may be based only on information already contained within the administrative record.  The new draft guidance states that a submitter “can add graphs, simple analyses, or other minor clarifications,” but may not add “additional data that has not been previously reviewed, or substantially different analyses of existing data.”  In certain circumstances, this prohibition against new information may present an issue of fairness.  For instance, a submitter may have data that would respond to an issue raised in an NSE letter, but the submitter may not have previously submitted the data because CDRH had not raised the issue.  The submitter should not be prohibited from presenting that data in an appeal to support its position that the NSE letter was issued in error.

In our view, the draft guidance is helpful.  At the same time, actual reform of the appeal process is badly needed.  As discussed in more detail in a prior blog post, the creation of an Office of Appeals might facilitate fairer, prompter and more consistent handling of appeals.  This could be done through guidance if it is a voluntary alternative to a traditional supervisory review.  If successful, the project could be made mandatory by notice and comment revision of 21 C.F.R. § 10.75. 

Ultimately, a thoroughgoing rationalization and reform is needed of all the relevant statutes and regulations relating to the appeals process.  This overhaul would require congressional action, and is not likely to happen any time soon.  In the meantime, if FDA could adhere strictly to the time frames for supervisory review set forth in the draft guidance, that would be a significant step forward. 

It would also be helpful if FDA could begin to publish annual metrics revealing how they are handling appeals.  For instance, FDA should at least disclose figures on how many appeals are initiated each year, their disposition (i.e., whether the original decision was affirmed, reversed, or modified), and the median time to completion.  This kind of information would help industry better understand the appeals process and also could be used to formulate an intelligent reform agenda.

By Susan J. Matthees –

Earlier this week, the U.S. Court of Appeals for the District of Columbia Circuit affirmed the U.S. District Court for the District of Columbia’s decision granting FDA’s Motion to Dismiss a lawsuit filed in April 2010 by a group of ear candle advocates.  As we previously reported, ear candle advocates filed suit after FDA issued about 15 Warning Letters to companies marketing ear candles, an alternative medicine practice that advocates claim improves general health and well-being.  FDA stated in the Warning Letters that ear candles are unapproved devices, a determination the ear candlers alleged violated their First, Ninth, Tenth, and Fourteenth Amendment Rights.  

The District Court granted FDA’s Motion to Dismiss on the ground, among others, that the Warning Letters were not final agency action subject to judicial review under the Administrative Procedure Act (“APA”).  The Court of Appeals affirmed this decision, explaining that the Warning Letters are not final agency action because “they neither mark the consummation of the agency’s decisionmaking process nor determine the appellants’ legal rights or obligations.”  Citing FDA’s Regulatory Procedures Manual, the Court noted that FDA Warning Letters provide an opportunity for a company to correct their actions before the Agency initiates enforcement actions and are merely “informal and advisory.”  The Court also noted that FDA does not commit to taking action in a Warning Letter and that FDA acknowledges that it can only ban a device through a formal process that was not taken in this case.  Because there was no final agency action, the ear candlers’ claims could not hold a candle to the requirements of the APA.   

The D.C. Circuit’s decision is consistent with previous judicial rulings.  Indeed, it appears that almost every court to consider the question has held that an FDA Warning Letter does not constitute “final agency action.”  See, e.g., Biotics Research Corp. v. Heckler, 710 F.2d 1375 (9th Cir. 1983); Clinical Reference Lab., Inc. v. Sullivan, 791 F. Supp. 1499 (D. Kan. 1992), rev’d sub nom. on other grounds, United States v. Undetermined No. of Unlabeled Cases, 21 F.3d 1026 (10th Cir. 1994); Estee Lauder, Inc. v. FDA, 727 F. Supp. 1 (D.D.C. 1989); IMS Ltd. v. Califano, 453 F. Supp. 157 (C.D. Cal. 1977).  More recently, the U.S. District Court for the District of Wyoming considered the issue in Cody Laboratories, Inc. v. Sebelius in the context of a Warning Letter for a marketed unapproved drug and found there was not final agency action.  On appeal, the U.S. Court of Appeals for the Tenth Circuit did not grapple with the issue.  However, in 1992, Den-Mat Corporation sued FDA for sending a Warning Letter that concluded that its product was a drug, not a cosmetic.  The Warning Letter stated that FDA would recommend that actions be taken against the products, and Den-Mat reported that its business was suffering as a result of the letter and would continue to suffer until there was a determination whether FDA was correct in its position.  FDA sought to have the case dismissed, but the U.S. District Court of the District of Maryland permitted a company to continue a case against FDA because FDA’s warning letter stated an “unqualified intent” to take affirmative action against the company.  Den-Mat Corporation v. United State of America, No. MJG-92-44, 1992 U.S. Dist. LEXIS 12233 (D. Md. Aug 17, 1992). The court stated that FDA may have “gone beyond a statement of its position and taken an affirmative action to enforce its decision.”  There was no similar affirmative action by FDA in the case against the ear candlers.

By Kurt R. Karst –

In what appears to be a further sign of FDA’s efforts to clamp down on differences between brand-name Reference Listed Drugs (“RLDs”) and their proposed generic counterparts, FDA’s Office of Generic Drugs (“OGD”) is now looking more closely at tablet size differences.  The increased scrutiny may be intended to address, at least in part, criticism about some generic drugs not acting the same as their brand-name counterparts (see our previous post here). 

OGD recently issued letters to companies with pending ANDAs for one product, stating that the applications are not approvable because of tablet size differences when compared to the corresponding strengths of the RLD.  According to the letters:

The larger tablet size poses greater potential safety issues such as choking, tablet arrest, and prolonged transit time, which could result in esophageal injury and/or pain.  The larger tablet size also raises product efficacy concerns due to patients’ inability or unwillingness to swallow the larger tablets. . . .  Therefore, from a clinical standpoint, this product is unacceptable for approval as a generic and we recommend that you redesign your product to be closer in size to the relevant strengths of the RLD.

The legal basis for FDA’s decision is not stated in the letters, but may be based on FDC Act § 505(j)(4)(H), which states that FDA shall approve an ANDA unless the Agency finds that:

information submitted in the application or any other information available to the Secretary shows that (i) the inactive ingredients of the drug are unsafe for use under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug, or (ii) the composition of the drug is unsafe under such conditions because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included.

Unfortunately, the letters do not provide any guidance on what is an acceptable size difference between a proposed generic and its corresponding RLD, leaving ANDA sponsors with several questions, including whether OGD is taking a one-size-fits-all approach (i.e., a set, permissible size difference applicable to all generics) or a case-by-case approach.  Absent guidance on an acceptable size difference, ANDA sponsors will be stumbling around in a dark room, unable to make informed decisions on how to redesign their products.  Such concerns are heightened when there is a patent on the RLD that covers size (or shape).  And what about drug products already on the market?

OGD gave a heads-up that the Office would be looking more closely at tablet size (as well as shape and color) during a presentation at the October 2011 GPhA/FDA Fall Technical Conference.  According to Dr. Vilayat Sayeed, Director, Division of Chemistry III., OGD, draft guidance is in the works and will published to address concerns about generic tablet size, shape, and color compared to the RLD.  Clearly, FDA has decided to move forward with its policies before issuing guidance. 

Once published, FDA’s guidance on tablet size, shape, and color will join a host of other recent guidances that address generic drug sameness issues.  In January 2011, FDA issued draft guidance titled “Size of Beads in Drug Products Labeled for Sprinkle” after OGD issued several refuse-to-receive letters to generic drug applicants who had proposed products with fewer beads (e.g., mini-tablets) than in the RLD product, making sprinkling the product on food an impossibility, according to FDA.  In the guidance, FDA suggests a maximum bead size of 2.0 mm for drug products labeled for sprinkle based on information demonstrating that food is chewed to approximately 2 mm in median particle size before swallowing.  More recently, in August 2011, FDA issued draft guidance, titled “Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation,” in which the Agency discusses the need for consistent scoring between a generic product and its RLD.

Ratcheting up ANDA standards may be one way for OGD to gain better control of the ANDA review queue, particularly with the likely enactment of the Generic Drug User Fee Act (“GDUFA”) in 2012 (see our previous posts here and here).  Among other things under GDUFA, FDA will agree to certain staged performance goals and will commit to substantially reducing the ANDA backlog.  In addition, the draft version of the “Generic Drug User Fee Act Program Performance Goals and Procedures” states that by the end of year 1 of the program “FDA will develop enhanced refusal to receive standards for ANDAs and other related submissions.”  FDA is supposed to, under the agreement with the generic drug industry, publish those standards in advance of implementation.  The enhanced standards, which we understand are intended to provide more clarity as a whole for less experienced filers and to improve agency efficiency, are not related to topics such as tablet size.

Additional Reading:

• New England Journal of Medicine – Why Do the Same Drugs Look Different? Pills, Trade Dress, and Public Health

By James R. Phelps –

Over the New Year's Day weekend, The New York Times reported on the shortage of ADHD drugs, with this quote:  “‘We have reached out to the D.E.A. and told them that there are shortage issues,’ said Valerie Jensen, associate director of the F.D.A.’s drug shortage program. ‘But the quota issues are outside of our area of responsibility.’”  The DEA responded, contending that there is plenty of supply, and the manufacturers are to blame for the shortages, saying, according to the Times: “… any supply disruptions (are attributable) to decisions made by manufacturers.”  Sorting out the “blame” will depend upon understanding the process by which manufacturers are able to work within the quota system.

Production of the supply of Schedule II drugs is controlled by DEA through quotas granted by the agency, on a yearly basis.  Manufacturers must calibrate production based upon DEA’s decision concerning how much they may produce (i.e., within the quota allocations granted by DEA based on the company’s submissions to the agency).  In order for the system to work properly, DEA should process quota requests in a predictable and timely manner.  Further, the agency should articulate clearly the bases upon which it makes quota allocations.   

It would be of interest for the public to be provided the usual timelines for quota requests and DEA responses.  Does DEA routinely grant quota allocations in time for sensible manufacturing decisions?  A public expression of the criteria that DEA uses in setting quotas would also help to clarify the situation.  The manufacturers, dependent upon DEA for quotas, might not be the best source to expose any difficulties that exist, so perhaps congressional oversight is warranted.

The controversy, with its dreadful health implications, brings to light – again – the tension that exists between the medical regulation and the police regulation of those medicines that might be abused.  Most would agree that patient access should be the priority; patients who require these medicines should receive the same respect and attention as any other medical patient.  Certainly the policing of drugs through quotas should be done in an efficient, thoughtful manner.

The Food and Drug Law Institute’s (“FLDI”) annual Food Week Conference is being held in Washington, DC on January 23-26, 2012.  FDLI Food Week features a two-day introduction to food law and regulation, as well as three days of advanced programming on advertising and labeling, food safety, and global issues.  Hyman, Phelps & McNamara, P.C. Director Ricardo Carvajal is presenting at the conference.  As a result, we secured a discount code for our friends and colleagues.  To receive a 15% discount off registration, use the following promotional code: FOODPRTNR.  To register for the event and to view a copy of the conference brochure, see here.

By Kurt R. Karst –      

Representatives Cliff Stearns (R-FL) and Ed Towns (D-NY) recently introduced H.R. 3737, the Unlocking Lifesaving Treatments for Rare-Diseases Act (“ULTRA”).  The bill would amend the FDC Act to “improve access to the existing accelerated approval pathway for patients with life threatening ultra-rare genetic diseases with the added attribute of promoting private investment in new biotechnology companies and job growth in the United States,” according to a statement issued by Rep. Stearns.  More specifically, the bill would amend FDC Act § 506 (titled “Fast Track Products”), added to the statute by the 1997 FDA Modernization Act, to permit FDA to approve an application for a drug designated both as an orphan drug and as a fast track product using a “surrogate endpoint” as defined in proposed FDC Act § 506(e)(2).  In addition, the orphan disease or condition must affect a “small number of patients in the United States,” which is short-hand for an ultra-rare or ultra-orphan disease – a disease or condition with a U.S. prevalence that some have pegged at 6,000 or fewer people (see here).

FDC Act § 506 is generally considered to have codified FDA’s December 1992 accelerated approval regulations, under which the Agency will accelerate the approval of certain new drugs and biologics for serious or life-threatening illnesses, and when such products provide a meaningful therapeutic benefit to patients over existing treatments.  These accelerated approval regulations are located in Subpart H (21 C.F.R. Part 314) of FDA’s drug regulations, and in Subpart E (21 C.F.R. Part 601) of the Agency’s biologics regulations.  If a product meets these criteria, then FDA may grant marketing approval based on a demonstrated effect on a surrogate endpoint reasonably likely to predict clinical benefit and a sponsor’s commitment to complete with due diligence the required postmarketing studies to confirm the product’s clinical benefits.  A surrogate endpoint is an alternative measurement of the symptoms of a disease or condition that is substituted for measurements of observable clinical symptoms.  Surrogate endpoints are expected to predict clinical benefit (or harm, or lack of benefit or harm).

Specifically, under FDA’s accelerated approval regulations at 21 C.F.R. § 314.510, “FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity” (emphasis added).  Similarly, under FDC Act § 506(b), FDA “may approve an application for approval of a fast track product under [FDC Act § 505(c)] or [PHS Act § 351] upon a determination that the product has an effect on a clinical endpoint or on a surrogate endpoint that is reasonably likely to predict clinical benefit” (emphasis added). 

For more prevalent diseases, there may be independent clinical data that make a surrogate endpoint reasonably likely to predict clinical benefit; however, “[m]ost ultra-rare diseases do not have the same pre-existing body of clinical management or historical study data currently required to utilize the [accelerated approval] pathway,” according to a recent article co-authored by Dr. Emil D. Kakkis of the Kakkis EveryLife Foundation For Rare Diseases on the potential effects on investment in the development of treatments for low prevalence rare diseases with  improved access to accelerated approval.  Thus, according to the article, “[w]ith this essential requirement for independent clinical data, the [accelerated approval] pathway is virtually unavailable for novel drugs developed for untreated ultra-rare diseases.”  The Kakkis EveryLife Foundation was a major driving force behind H.R. 3737 – see here and here – and worked with Rep. Stearns to build support for the legislation. 

To address the issue raised by Dr. Kakkis, ULTRA would amend the law to provide that for a product for an ultra-rare disease or condition designated both as an orphan drug and as a fast track product, FDA “may use a surrogate endpoint for the approval of the drug as a fast track product based on the existence of reasonable scientific data that support and qualify the relevance of the surrogate endpoint to the disease state and treatment.”  In addition, the legislation says that FDA “shall not require clinical treatment data or other historical clinical data on the surrogate endpoint as a prerequisite to assessment of the surrogate endpoint under this subsection if such data are not available;” however, FDA “may take into consideration any reliable clinical data that are readily available and published.”  The bill would also require FDA to issue guidance “providing details and options for qualifying surrogate endpoints without clinical data” within one year of the date of enactment of ULTRA.