On March 12, 2014, FDA issues a revised version of the Guidance Document “Administrative Procedures for CLIA Categorization” (the “2014 Guidance”). FDA, Guidance for Industry and FDA Staff, Administrative Procedures for CLIA Categorization (March 2014). The 2014 Guidance replaces the final guidance with the same name originally issued on May 7, 2008. 73 Fed. Reg. 25752 (May 7, 2008). The 2014 Guidance has been revised to include information regarding FDA’s current administrative processes, including CDRH’s eCopy and the 510(k) Refuse to Accept policies. 2014 Guidance at 5. In addition, the 2014 Guidance breaks down the procedures for determination of CLIA Categorization by in vitro diagnostic (IVD) devices under premarket review and other legally marketed IVD devices (e.g., tests exempt from premarket notification). Id. at 5-6. Perhaps most importantly, the 2014 Guidance provides timelines for FDA. In the past, CLIA categorization tended to languish.
For IVD devices undergoing premarket review (e.g., 510(k) or PMA), FDA will automatically create a CLIA tracking number (a CLIA Record “CR” number), which is separate from the premarket application number (e.g., 510(k) “K” or PMA “P” number). Id. at 5. FDA will notify the sponsor of both the CLIA Record number and the premarket submission number. The process by which FDA will determine test complexity will not change. FDA aims to notify applicants of the CLIA categorization of the IVD device within two weeks following a positive marketing application decision (e.g., a substantial equivalence letter for a 510(k) or a PMA approval decision). Id. at 5-6.
For IVD devices that do not undergo premarket review, applicants should submit a request for CLIA categorization to the CDRH Document Control Center. Id. at 6. Although not required, FDA strongly encourages that applicants provide an eCopy of such CLIA categorization requests to expedite the review. FDA will assign CLIA categorization requests a CLIA record number for tracking purposes. FDA will attempt to notify sponsors of the CLIA categorization within thirty (30) days of the request. Id.
FDA maintains a searchable database of CLIA categorizations. If an applicant changes the name of its tests or if the manufacturer or distributor changes, FDA recommends that a new request for CLIA categorization be submitted with the revised labeling to ensure that the record of the test in the public database is accurate. Id. Companies should be aware that this seemingly innocuous step could prompt a more substantive review.
If an applicant is submitting an application for a CLIA Waiver for a moderate complexity test, FDA strongly encourages providing an eCopy of such CLIA Waiver application to expedite the review. CLIA Waiver applications are not accepted for devices that are under premarket review at the time of the submission, unless the application references a Pre-Submission during which agreement was reached for a Dual 510(k) and CLIA Waiver application strategy. Such Dual submission should contain the full 510(k) and CLIA Waiver application in a single submission. The Dual submissions will be subject to the 510(k) Refuse to Accept Policy. The 2014 Guidance also sets forth current performance goals for CLIA Waiver applications:
1 This performance goal applies to both the CLIA Waiver application and the 510(k).
Per the 2014 Guidance, a Substantive Interaction may include “a request for Additional Information (via letter or email), a notification that review will Proceed Interactively (via email), or notification of Waiver Granted (via formal letter).” A MDUFA Decision may include “a notification of Waiver Granted (via formal letter), notification of Waiver Denial (via formal letter), or withdrawal by the sponsor.” Id. at 7-8.
Lastly, for additional information regarding CLIA Waiver applications, the 2014 Guidance suggests referring to the Guidance Document “Recommendations for Clinical Laboratory Improvement Amendments of 1998 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices.” Further, applicants can seek feedback from FDA prior to submitting a CLIA Waiver application or conducting studies in support of such an application through the Pre-Submission program (see our earlier post on the Pre-Submission program). Overall, we think this updated guidance document will be a useful reference for understanding the administrative process for seeking CLIA Categorization or Waiver, and understanding the new, more predictable timeframes.
It was just a little more than three months ago that we blogged on the topic of “premature notice” in the context of a Complaint filed by Otsuka Pharmaceutical Co., Ltd. (“Otsuka”) against Par Pharmaceutical, Inc. (“Par”) concerning Par’s notice of a Paragraph IV certification contained in an ANDA Par submitted to FDA for a generic version of SAMSCA (tolvaptan) Tablets. Since then, we’ve noticed an uptick in the number of premature notices being sent out by ANDA applicants. (We neither take any credit, nor any blame for any increase in premature notices.) Different notice recipients – i.e., NDA holders and patent owners – have chosen different ways to deal with those premature notices . . . unless, of course, the recipient is not even aware that it has received premature notice.
By way of background, an ANDA applicant (or 505(b)(2) applicant) that certifies Paragraph IV to a patent listed in the Orange Book for the listed drug relied on, or RLD, must provide notice of that certification to the NDA sponsor and patent owner. FDC Act § 505(j)(2)(B)(ii) governs the timing of sending that notice. It states:
(ii) TIMING OF NOTICE.—An applicant that makes a [Paragraph IV] certification . . . shall give notice as required under this subparagraph—
(I) if the certification is in the application, not later than 20 days after the date of the postmark on the notice with which the Secretary informs the applicant that the application has been filed; or
(II) if the certification is in an amendment or supplement to the application, at the time at which the applicant submits the amendment or supplement, regardless of whether the applicant has already given notice with respect to another such certification contained in the application or in an amendment or supplement to the application.
Notice sent prior to FDA’s acceptance of an original ANDA is considered premature and ineffective. Some NDA holders/patent owners have decided not to act on premature notice, as seems to be the case with VASCEPA (icosapent ethyl) Capsules, as recently reported by Amarin here on page 31 (and here as well). Others, however, have sued for infringement after receiving premature notice, perhaps out of an abundence of caution. Such an action, although without any regulatory significance insofar as FDA is concerned, could result in ANDA approval earlier than if notice was timely sent. As the court in SB Pharmco Puerto Rico, Inc. v. Mutual Pharm. Co, Inc., 552 F. Supp. 2d 500 (E.D. Pa. 2008), pointed out: premature certification could lead to manipulation of the Hatch-Waxman scheme by “accelerat[ing] the timing provisions and litigation process well beyond the framework that Congress intended.”
Of course, if patent infringement litigation initiated as a result of premature notice is nipped in the bud – i.e., if a case is dismissed before litigation arising from later and valid notice is initiated and made a part of the first case – then it all may be water under the bridge. That seems to be the case with SAMSCA. After Otsuka filed a Motion for Judgment on the Pleadings and the motion was briefed (see here and here), the district court issued an Order granting Otsuka’s request that Par’s notice be considered improper, null, void, and without legal effect, among other things. In the meantime, FDA’s Paragraph IV Certifications List still does not indicate that the Agency has received (i.e., filed) and ANDA with a Paragraph IV certification for a generic version of SAMSCA.
A similar fact pattern is playing out in the U.S. District Court for the Eastern District of Texas, where Allergan, Inc. (“Allergan”) recently filed a Complaint against Watson Laboratories and Actavis Pharma alleging premature notice concerning generic RESTASIS (cyclosporine ophthalmic emulsion) 0.05%. Allergan is seeking, among other things, a “Declaratory Judgment of False Paragraph IV Notification.” Allergan filed suit notwithstanding receiving confirmation from FDA in a letter that Watson’s ANDA was not yet received.
Another interesting case is generic EFFIENT (prasugrel HCL) Tablets, 5 mg and 10 mg. In that case, Par sent notice to Eli Lilly and Company (“Lilly”) in December 2013 “stating that Par had included within its ANDA” a Paragraph IV certification to certain patents listed in the Orange Book for EFFIENT. At that time, FDA’s Paragraph IV Certifications List did not identify that FDA had received a Paragraph IV ANDA for generic EFFIENT. Indeed, the list was not updated with such information until February 4, 2012, despited having been updated on January 6 and January 23, 2014 with information on other drugs. Lilly filed a Complaint on January 23, 2014 alleging infringement; however, Lilly’s Complaint is silent with respect to premature notice. Apparently Lilly was unaware that Par’s notice was prematurely sent.
That apparent oversight seems to have been subsequently realized when Lilly filed a Complaint against Par and several other ANDA applicants on March 12, 2014. According to the Complaint:
377. On or about December 9, 2013, Par sent Lilly, Daiichi Sankyo, and Ube a letter, dated December 9, 2013, and an attached memorandum (collectively, the “December Par Notification”) stating that Par had included within its ANDA a certification pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV) that the ’703 and ’325 patents are invalid, unenforceable, and/or will not be infringed by the manufacture, use, importation, sale or offer for sale of the Par Products in the United States (“Paragraph IV Certification”).
378. Plaintiffs filed suit against Par Pharmaceutical in this judicial district on January 23, 2014, 1:14-cv-00109-SEB-TAB, and Par Pharmaceutical filed its Answer on February 28, 2014.
379. On or about January 31, 2014, Par sent Lilly, Daiichi Sankyo, and Ube a second letter, dated January 31, 2014, and an attached memorandum (collectively, the “January Par Notification”) repeating that Par had included a Paragraph IV Certification within the Par ANDA.
380. Unlike the December Par Notification, the January Par Notification represented that the FDA received the Par ANDA for substantive review.
381. Plaintiffs are therefore filing the instant Complaint against Par Pharmaceutical to preserve its right for a 30-month stay under 21 U.S.C. 355(j)(5)(B)(iii) and 21 U.S.C. 355(c)(3)(E)(ii) in response to the January Par Notification.
So what is FDA doing to halt the practice of a company sending out premature notice? We’re not exactly sure yet . . . . but we think that some action is afoot.
The 57th session of the Commission on Narcotic Drugs (“CND”) recently convened in Vienna, Austria. A prominent issue on the first day of the general session included concern over the increased use of cannabis, especially for recreational purposes. The International Narcotics Control Board (“INCB”), which serves as the secretariat for the CND, has expressed a “long-standing concern” about the Netherlands’ policy that authorizes the use and abuse of cannabis in “coffee shops.” In its latest annual report and at the meeting, the INCB identified a new target for this issue: the United States. INCB, Report of the International Narcotics Control Board for 2013 (Mar. 4, 2014). In the report, the INCB provides a detailed summary of the marijuana initiatives in the 21 states and the District of Columbia, while acknowledging that cannabis is still illegal under the Federal Controlled Substances Act. Id. ¶ 374-375, at 49. The INCB also noted the guidance issued by the Attorney General in addressing how the Drug Enforcement Administration (“DEA”) and other federal agencies should react to these state laws. Id. ¶ 370, at 48. It is clear that the INCB is not satisfied with either the state initiatives or the current federal response, concluding that the “use of cannabis in some states of the [U.S.] has not yet been adequately addressed by the federal Government in a manner consistent with the provisions of the drug control Conventions.” Id. at 37. Thus, as far as the INCB is concerned, the federal government should do more to ensure compliance with the international treaties.
It is worth noting that the Single Convention on Narcotic Drugs of 1961 recognizes the use of cannabis for medical and scientific purposes. However, as noted by the INCB, the international treaty sets out specific requirements for establishment, administration, and monitoring of medical marijuana programs as stated in articles 23, 28 and 30. Id. ¶ 169, at 23-24. The INCB does not believe that many existing programs in the U.S. and in other countries comply with these restrictions. Id. ¶ 374, at 49. Moreover, use of cannabis for recreational use, such as is authorized in the Netherlands and some U.S. state initiatives, e.g., Colorado, would never be sanctioned under the international treaties.
In summarizing the INCB report at todays’ plenary session, INCB President Raymond Yans reiterated his concern about cannabis use in some countries, including the United States. For its part, the U.S. delegation responded to Mr. Yans’ statements asserting that: the U.S. remains committed to upholding the international treaties, the U.S. federal government will monitor the cannabis initiatives in Colorado and Washington and make sure they do not lead to new threats, and is committed to maintaining communication with INCB and reduce misunderstandings.
The U.S. continues to be an ardent supporter of the international drug control treaties and an aggressive and vocal voice against drug abuse. However, the state marijuana initiatives, especially those authorizing recreational use, may affect the U.S.’ traditional “high road” approach at least in regard to marijuana use – pun intended.
On March 13, 2014, U.S. Senator Jack Reed (D-RI) and U.S. Representative Ed Whitfield (R-KY) introduced the “Sunscreen Innovation Act” (S. 2141 and H.R. 4250, respectively). The proposed legislation would amend the FDC Act to include a process for the review of potential sunscreen active ingredients. The Act formalizes FDA’s time and extent program for sunscreen active ingredients but imposes time limits on FDA’s review.
In 2002, FDA published final regulations permitting companies to submit a time and extent application (“TEA”) to begin the process to amend an over-the-counter (“OTC”) monograph to add a new active ingredient that has been marketed for a material time and a material extent in the United States or elsewhere. See 67 Fed. Reg. 3060 (Jan. 23, 2002); 21 C.F.R. § 330.14. Under this program, FDA will consider accepting a TEA for inclusion in the OTC drug monograph system of OTC drugs initially marketed in the United States after May 1972. For OTC drugs with marketing experience outside the United States, FDA requires proof that the product: (1) was marketed outside the United States as an OTC drug for purchase by consumers; and (2) was “marketed OTC for a minimum of 5 continuous years in the same country and in sufficient quantity” (although more than a single country may be appropriate depending on the extent of marketing). 21 C.F.R. § 330.14(b). If, after reviewing a TEA, FDA determines that an active ingredient is eligible for OTC monograph inclusion, FDA publishes an eligibility notice in the Federal Register requesting the submission of data demonstrating that the drug is generally recognized as safe and effective (“GRAS/E”) for its intended use. After reviewing the data, FDA may publish a proposed rule, and then a final rule incorporating the new active ingredient into an OTC monograph. In order to market the product, the active ingredient also must be recognized in the United States Pharmacopeia-National Formulary. See21 C.F.R. § 330.14(i).
Although FDA indicated it would “strive to complete TEA evaluations in 90-180 days,” FDA has not approved the TEA for a single sunscreen active ingredient (or any other ingredient) since the regulation was adopted in 2002. Only recently did FDA issue its first determinations that data were insufficient to establish GRAS/E status for the sunscreen ingredients amiloxate and diethylhexyl butamido triazone (here and here). FDA had determined amiloxate and diethylhexyl butamido triazone eligible for the TEA program in 2003 and 2006, respectively.
The proposed Act keeps the TEA program largely intact but sets a specific time frame for FDA’s review and specifies a role for the agency’s Nonprescription Drugs Advisory Committee (“NDAC”). Existing FDA eligibility requirements will be maintained. Eligibility determinations will be made by FDA Division of Nonprescription Regulation Development. Currently pending ingredient submissions that FDA already has determined to be eligible for the TEA program, will be considered eligible for the new review and approval process (i.e., they need not be re-reviewed for eligibility).
Under the proposed Act, once FDA has determined that the ingredient is eligible, it must submit the ingredient application to NDAC for a safety and effectiveness recommendation. During the review process, NDAC would receive data from the public and communicate with the application’s sponsor to seek clarifying or additional information. FDA must accept or reject the Committee's recommendation.
The Act requires that the new submissions be reviewed within 11 months and that the current backlog (six TEAs for sunscreen active ingredients are pending) must be reviewed within 8 months. Moreover, as proposed, FDA would be required to submit reports to Congress regarding its progress.
Unrelated to the TEA program, the proposed Act also requires that FDA issue determinations regarding testing and labeling of sunscreen sprays and labeling of sunscreen drug products with SPF above 50.
Does meeting the FTC legal standard for claim substantiation protect claims from action by the National Advertising Division (“NAD”)? If you think the answer should be “yes,” read on.
FTC consent decrees often leave open the possibility that unsubstantiated claims may be resumed based on new data. NAD takes a different position on the resumption of discontinued claims, as is made clear in a recent press release concerning the product Procera.
As a matter of general NAD policy, if the advertiser in an NAD case has agreed to discontinue a particular type of claim, it may not, absent “extraordinary circumstances,” introduce new data to support the same or materially similar claims to those previously reviewed and rejected in an NAD compliance review. Under NAD procedures, such cases ordinarily are automatically referred to the FTC for review. Whether new studies that meet the legal test for substantiation have been conducted is irrelevant to the NAD.
In the case of Procera, NAD had issued a decision in 2009 recommending that the advertiser discontinue certain claims. When NAD recently found that the advertiser was again making similar claims, NAD contacted the advertiser, which agreed to discontinue all but one of the similar claims. According to the advertiser, the claim at issue was substantiated by data from a study that was completed after NAD’s 2009 review.
As NAD makes clear at the end of the press release, “an advertiser in an NAD proceeding may not, absent extraordinary circumstances, submit new evidence after the fact as support for claims that were the subject of an earlier proceeding.”
In a conversation with Lee Peeler, President and CEO of the Advertising Self-Regulatory Council (ASRC) and Executive Vice President of the Council of Better Business Bureaus, we received ASRC’s explanation for the difference between NAD’s policy and the FTC’s approach. According to Mr. Peeler, both the NAD and FTC begin from a common starting point: the legal requirement that all objective claims in advertising be substantiated BEFORE they are made. Failure to have preexisting substantiation violates the FTC Act and self- regulatory standards. Once a violation of either the FTC Act or self-regulatory standards has been determined the processes and the consequences sometimes diverge.
Under most but not all FTC orders you are permitted to resurrect claims for which the FTC has found a lack of substantiation provided the claims are substantiated based on newly acquired evidence. Of course, given the consent decree, if the advertiser is wrong the consequences can be severe, ranging from fines for every ad found to be in violation to civil or even criminal contempt. We say “most” here because some FTC orders do contain outright prohibitions of certain types of claims and in those instances no subsequently acquired evidence is considered.
According to Mr. Peeler, effective self-regulation is necessarily different from effective government regulation. The NAD process is a voluntary system that advertisers participate in. Once an advertiser makes a commitment to discontinue certain claims, it is critical to the success of the system that the advertiser honor those commitments. The system operates on the good faith of the participants: there are no fines, penalties or sanctions other than referral.
Mr. Peeler views the NAD Procedures position on after acquired evidence as critical to the self-regulatory system. “Otherwise”, Mr. Peeler said, “the self-regulatory system would become an ‘endless loop’ with no finality and no consequences for continuing to make the same claim over and over again as long as some new evidence was introduced in each proceeding. The speed and finality that have made the system so successful would be undermined. ” Therefore, to discourage recidivism and conserve resources, NAD has adopted a policy of automatically referring to FTC any claims that NAD has already reviewed and that have been discontinued, even if the advertiser argues that new studies l support the claims.
This policy is set forth in NAD’s published procedures, although the implications of the policy may not be clear to advertisers. The NAD procedure at issue is ASRC Policies and Procedures § 3.8, “Closing a Case”:
When a case has been concluded with the publication of a NAD/CARU decision or, when a panel has turned over a decision to the Chair, and when the Chair has executed the procedures in Section 3.6 of these “Procedures,” the case will be closed and, absent extraordinary circumstances, no further materially similar complaints on the claim(s) in question shall be accepted by NAD/CARU, except as provided for in Section 4.1.
As stated more clearly in the Procera press release, the phrase “no further materially similar complaints on the claim(s) in question shall be accepted by NAD/CARU” in these written procedures means that NAD will refer such claims to the FTC.
Of course, advertisers are free to conduct new studies to support claims that NAD has rejected, and absent an FTC order or FDA rule prohibiting them, advertisers may legally make claims that are substantiated, even if NAD has found that, prior to the new studies, the same claim was not substantiated. However, advertisers need to be aware that the repetition of NAD-rejected claims is likely to result in a referral to the FTC as a result of NAD’s policy for handling such claims.
The best approach is always to make sure you have substantiation for your claims BEFORE you make them. If you are already subject to an FTC order or an NAD decision, it is best to consult with counsel and independent experts in the relevant scientific field before making covered claims. For more on the FTC’s approach to claim substantiation go here.
We have long been waiting for a company to sue FDA for failing to issue an export certificate. Unfortunately, we may need to wait a bit longer for a case that will resolve the standards for when FDA must issue an export certificate. Today, one can argue that FDA is “allowing” companies to sell products in the U.S. when FDA is unreasonably prohibiting the same products from being shipped outside the U.S.
As background, export certificates, while not mandated by the Federal Food, Drug, and Cosmetic Act (“FDC Act”), have become a practical requirement for many companies seeking to market their U.S.-manufactured products globally. Foreign customers and importing countries generally require that these FDA-issued certificates accompany the import of a regulated product, and some countries rely on certain types of export certificates before issuing their own product approvals/registrations. Under the FDC Act Section 801(e)(4), exporters may request, and if criteria are met FDA is required, to issue an export certificate within 20 days of a request.
There are several types of export certificates (see here and here) that exporters may request – those that certify a product may be legally marketed in the U.S. as well as those that simply certify a product may be legally exported from the U.S. A typical reason FDA may refuse to issue the first type of export certificate for a drug or device is FDA’s concern over whether the company is manufacturing the product in conformance with current good manufacturing practices (“cGMPs”) or FDA’s quality system regulations (“QSRs”). In fact, FDA often refuses to issue these certificates if the company has received a Warning Letter relating to those regulations. We are aware that in such circumstances, FDA has refused to issue an export certificate until the Warning Letter “close-out” process has been completed. As we have previously blogged, this close-out process can take many months and it is unclear whether the delay is due to industry failure to correct serious regulatory problems or whether FDA is unwilling to conduct prompt follow-up to confirm corrections. FDA’s failure to timely issue a Warning Letter “close-out” in many instances may lead to its failure to issue an export certificate – even where the company may already be in substantial compliance. When FDA fails to issue an export certificate, it can effectively destroy a company’s ability to market its U.S. manufactured product outside the U.S. although there may be no impact on the company’s sales in the U.S. market, because FDA has not taken enforcement action to block the domestic sales of relevant product.
We were eager to read Pharmaceutical Innovations, Inc. (“PI”)’s complaint seeking declaratory judgment and injunctive relief to compel the FDA to issue a Certificate to Foreign Government (“CFG”), a type of export certificate that certifies a product may be legally marketed in the U.S. PI manufactures and markets ultrasound gel, which is regulated by FDA as a medical device. As we read the complaint, and reviewed FDA’s website, we were curious as to PI’s assertion that FDA has not taken any action to restrain PI from distributing its devices in interstate commerce. FDA’s website shows that, in addition to a Warning Letter relating to QSR violations, certain lots of PI’s products are the subject of an open Class I recall, and that Deputy U.S. Marshals, at FDA’s request, had seized certain lots of PI’s product in April 2012. This action was undertaken less than one month before FDA’s denial of PI’s request for a CFG in May 2012. In addition, the July 2011 Warning Letter to PI advises, “Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.” According to FDA’s website, the PI Warning Letter has not, to date, been subject to “close-out.”
PI maintains that it is currently manufacturing and distributing its products in the U.S. with no action from FDA to restrain the manufacture or distribution of these products. PI also maintains that it has “responded fully and completely to the warning letter as well as to subsequent FDA inspectional observations and has repeatedly expressed its desire to meet with FDA officials to address the issues raised therein.” PI further alleges that FDA has not responded to numerous written communications and verbal requests to FDA representatives for a meeting. It is unclear whether FDA still has concerns about the quality of PI’s product, or whether FDA resources are hampering its ability to issue a Warning Letter “close out.” If the issue is the latter, FDA’s inability to timely issue a Warning Letter “close out” is unreasonably (and unfairly) harming the company’s ability to obtain a CFG. If the former, one could argue that FDA’s failure to take further action against products in domestic commerce could be viewed as FDA “allowing” the company to distribute products that FDA would otherwise view as adulterated or misbranded.
We are anxious to see whether PI will be successful in its suit. If not, we will wait to see whether, if the facts were different, a lawsuit filed by another company without a Warning Letter “close-out” could be successful in requiring FDA to issue an export certificate.
Defendants Wellness Support Network, and co-owners Robert and Robyn Held, marketed two diabetes products – Diabetic Pack and Insulin Resistance – as medical foods. In 2005 and 2006, FDA issued two Warning letters to them (here and here), claiming the products were marketed as unapproved drugs. In 2007, the FTC sent them a Civil Investigative Demand. This culminated in a lawsuit filed by the FTC against them in 2010.
The FTC alleged that the Defendants’ promotion of “medical food” products intended to treat diabetes was deceptive and unsubstantiated. According to the FTC, the Defendants marketed their products as clinically proven natural solutions for blood glucose control and diabetes. Allegedly, the Defendants’ website posted “dramatic claims” of effectiveness, including “new diabetes break-through,” reduces the effect of diabetes, “money back guarantee,” a clinically proven solution with a 90% success rate and “no side effects guaranteed,” and various testimonials.
On February 20, 2014, the U.S. District Court for the Northern District of California granted the FTC’s motion for summary judgment on liability, redress, and injunctive relief, and denied the defendants’ cross-motions.
The Court had previously rejected the Defendants’ argument that the products as medical foods were not subject to the FTC requirements. The Court held that FDA regulations concerning medical foods were irrelevant to the FTC’s determination as to the validity of the advertising claims. Medical foods are subject to the same standard as other products, i.e., whether the advertising claims are truthful and not misleading.
The Court’s recent decision also rejected Defendants’ First Amendment claims, ruling that the right of free speech does not extend to false, deceptive, or misleading commercial advertising. The Court held that Defendants’ claims were false because the Defendants did not perform clinical studies and did not test the actual product; instead the Court ruled that the Defendants based their claims on information about certain of the products’ ingredients collected on the internet.
The Court found that the Company and the individual defendants were jointly liable, because both individuals were at least recklessly indifferent to the falsity of the material representations. Robert Held founded and co-ran the Company and formulated the products based on his research on the internet. Although there was no evidence that Robyn Held had been involved in the formulation of the products, or was involved in determining the accuracy of the claims, the Court deemed her liable based on the evidence that she played a significant role in running the Company of which she was a co-owner, was extensively involved in the development of advertising claims, knew that Robert had no relevant formal scientific or medical training, and knew that the products have never been clinically tested.
The Court ordered restitution of almost 2.2 million dollars based on the Defendants’ net revenue minus refunds. It also imposed a broad injunction against the Defendants for a twenty-year period. The Defendants are barred from making certain claims related to diabetes, metabolic syndrome, blood glucose levels, and insulin unless the claims are supported by at least two randomized, double-blind, placebo controlled clinical studies, conducted by different researchers, independently of each other, and results, considered in light of the entire body of relevant and reliable scientific evidence, are sufficient to substantiate that the representations are true. Other claims are barred unless they are supported by “competent and reliable evidence.”
It is unknown whether the Defendants will appeal the decision.
Sabra Dipping Co., LLC ("Sabra") submitted a citizen petition (Dokcket No. FDA-2014-P-0259) asking FDA to establish a standard of identity ("SOI") for hummus. The proposed SOI would define hummus as “the semisolid food prepared from mixing cooked, dehydrated, or dried chickpeas and tahini” with one or more of several designated optional ingredients. Chickpeas would have to be “the predominant ingredient by weight, except water,” and the finished product would have to contain at least 5% by weight tahini.
As noted in the petition, FDA tentatively identified general principles for food standards in a notice of proposed rulemaking issued in 2005, and the petition frames it statement of grounds in accord with those principles. The petitioner argues that the proposed SOI is needed to promote honesty and fair dealing in light of the growing popularity of hummus in the U.S., and “the introduction of dips and spreads that are not based on the traditional ingredients of chickpeas and tahini but nevertheless are labeled as ‘hummus.’” The petition includes exhibits listing examples of such products. The petitioner maintains that the SOI would eliminate “the potential for economic fraud and deception through the substitution or addition of ingredients that destroy the basic nature and essential characteristics of hummus.” In support of the proposition that chickpeas and tahini are the essential characteristics of hummus, the petition points to recipes dating back to the 13th century, and to the fact that “hummus” is the Arabic word for “chickpea,” among other factors. Although not noted in the petition, common dictionary definitions of “hummus” include references to chickpeas and sesame seeds (see, e.g., here).
The petitioner also maintains that the proposed standard would improve the nutritional quality of the food supply because the combination of chickpeas and tahini results in a product with improved protein quality. The petitioner also notes that the proposed SOI would be consistent with food standards established in certain Middle Eastern countries, the EU, and by Codex.
In a recent post we described the Generic Pharmaceutical Association’s amicus brief in the POM case, which urged the Supreme Court to “be cognizant of the differences” among FDA regulated products. In particular, GPhA urged that ‘[e]ven if petitioner is allowed to proceed with certain aspects of its claim, the Court should make clear that such a decision does not license second-guessing explicit FDA approvals, and in particular, FDA approvals under the agency’s authority to review and approve the licensing, labeling, and marketing of pharmaceuticals.” That admonition from GPhA was brought to mind by a recent district court ruling regarding Lanham Act claims against a manufacturer of generic buproprion hydrochloride, in a case brought by the brand manufacturer.
The regulatory history of buproprion is described here in detail, but suffice it to say, FDA determined generics to be bioequivalent, and then reversed course a number of years later.
In the Lanham Act case, in an unusually long footnote, the district court ruled that “Plaintiff has alleged numerous instances in which Defendant made literally false statements as to the bioequivalence of [the generic].”
The generic defendant moved to dismiss. The court characterized the defendant’s argument as follows:
Defendant, in its motion to dismiss, claims that the Food Drug and Cosmetics Act (the “FD&C”) delegates decisions of bioequivalence to the FDA. Defendant argues that Plaintiff is attempting to relitigate the decision of the FDA and/or privately enforce the FD&C, both of which are prohibited. Furthermore, Defendant claims that as the FDA originally designated Budeprion XL as bioequivalent to Wellbutrin XL, the statement cannot be false or misleading as a matter of law and private litigation over that fact is precluded.
After a review of the Lanham Act legal landscape regarding FDA regulated products, the district court sets forth the following analysis:
In the matter sub judice, the Court notes that initially the FDA approved of the ANDA for Budeprion XL and, in doing so, approved of it as bioequivalent to Wellbutrin XL. Compl. ¶¶ 27, 36-39. If Budeprion XL retained that FDA approval then Plaintiff’s claim under the Lanham Act, as it relates to statements alleging bioequivalence, may very well have been preempted under the Lanham Act. See Sandoz, 902 F.2d at 231. The FDA, however, subsequently determined that Budeprion XL was not bioequivalent to Budeprion. Defendant argues that the FDA’s previous decision “does not change history” and that the 2012 decision is “a new decision based on new information.” Def.’s Mem. 22, ECF No. 14, Apr. 3, 2013. Defendant claims that this later decision did “nothing to change the fact that Budeprion was, until that change of position, rated AB and found bioequivalent,” and that the “FDA’s change of position cannot be the basis for retroactive liability”. Def’s Mem 23.
Defendant’s argument misstates Lanham Act liability, Plaintiff’s theory of the case, and the preclusive effect of an FDA decision upon a private Lanham Act action. Lanham Act liability is triggered by literally false statements and does not require intent, knowledge, recklessness, or negligence on the part of the Defendant, thus good faith reliance on the FDA’s previous decision is not dispositive. See, e.g., Novartis Consumer Health, Inc., 290 F.3d at 586; U.S. Healthcare, Inc., 898 F.2d at 922-923. FDA findings have a preclusive effect on Lanham act liability not because “mere compliance with the FDCA or with FDA regulations will always (or will even generally) insulate a defendant from Lanham Act liability,” Pom Wonderful LLC v. Coca-Cola Co., 679 F.3d at 1178, but rather because courts should not second guess the scientific determinations of the FDA as the FDA is better suited and statutorily enabled to make such decisions, Sandoz, 902 F.2d at 231. As the FDA has allegedly found that the two drugs are not bioequivalent, the FDAs scientific findings would not preclude the Court from eventually making a determination that Wellbutrin XL and Budeprion XL were not bioequivalent.
The court goes on to note other bases upon which it concluded that the complaint states a claim, but as to the above, the upshot of the court’s analysis is that even though FDA initially determined that the product was bioequivalent, it reversed course, and therefore, a Lanham Act claim was not barred. Although the court suggests that this does not constitute second-guessing FDA, it is hard to see how FDA’s decision is not second-guessed if Lanham Act liability can attach during a time when FDA’s bioequivalence decision was in effect. More generally, the court’s reasoning seems to raise the prospect that a company could be subject to Lanham Act liability for something that the FDA had specifically authorized if the agency later changed its mind.
A denial of a motion to dismiss is not appealable, so this case will likely play out in the district court for the immediate future. If nothing else, this case reinforces our view that the steady stream of Lanham Act cases involving FDA regulated products will continue.
We previously posted (here and here) about the Supreme Court case that will be argued next month in which the parties are debating the proper interplay between the Federal Food, Drug, and Cosmetic Act (“FDC Act”) and the Lanham Act. Briefly, the issue in the case is whether POM’s Lanham Act false and misleading advertising claims against Coke’s Minute Maid product are barred because those claims are based on the labeling of a product regulated by the U.S. Food and Drug Administration (“FDA”) under the FDC Act.
Although filed in support of neither party, the SG’s brief was supportive of POM in that it reiterated the view expressed in the brief the SG filed when the Court was deciding whether to take the case that the Lanham Act claim should have been allowed “insofar as it concerns features of the juice’s label that are not specifically addressed by the FDCA or FDA’s regulations.” In the merit brief, the SG argued that the “Lanham Act claim is barred only to the extent the FDCA or FDA regulations specifically require or authorize the challenged aspects of the . . . label.” in further explaining the government’s position, and rejecting the argument that something akin to conflict preemption was required, the SG argued that “impossibility is not the proper standard for finding preclusion here.” Rather, according to the SG, a Lanham Act claim should be barred when “it would directly contravene FDA’s judgment by declaring misleading what the expert agency expressly found nonmisleading.” At the same time, the SG reiterated its view that the 9th Circuit, which had decided the POM case, employed “faulty reasoning” in concluding something akin to “‘so-called field preemption’ cases.” The SG argued that “Congress did not intend the FDCA or its implementing regulations to occupy the field of juice labeling to the exclusion of other federal laws.”
The GPhA amicus brief, although also filed in support of neither party, read as though more aligned with Coca-Cola/Minute Maid’s position. Perhaps more importantly to its members, the GPhA brief stressed that regardless of what the Supreme Court decided with respect to food products, pharmaceuticals and other products such as devices, were regulated and approved differently than foods. Accordingly, GPhA urged the Court, in announcing any rule, to “be cognizant of the differences” among FDA regulated products. The state attorneys general and ITA briefs argued for a more expansive interpretation of the permissible scope of the Lanham Act than either the SG or GPhA.
Typically, other than the SG’s office, amici do not request and are not given oral argument time before the Court, so this is likely the last word for most of those submitting amicus briefs. To date there is no indication whether the SG’s office will participate in the oral argument. If the SG’s office does participate, I’m hoping that one of the Justices asks how the position put forward by the SG would operate in an instance in which the FDA had “specifically authorized” conduct via a guidance document, enforcement discretion, Orange Book listing, or some other action, but not in regulations.
Regardless of the Court’s decision later this year, Lanham Act litigation involving FDA regulated products is unlikely to subside. We’ll be monitoring the oral argument and decision in this case and other Lanham Act cases of interest.
It was only about a year ago when the topic du jour was generic drug labeling and whether federal law – the FDC Act and FDA’s implementing regulations – preempts state-law product liability claims (failure-to-warn, design defect, failure-to-conform/update, etc.) against generic drug manufacturers. In fact, we were so inundated with generic drug labeling preemption issues at the time that we titled a March 13, 2013 post “Preemption, Preemption, and More Preemption.”
Well, it’s happened again. It seems that hardly a day goes by now without something new happening in the generic drug labeling preemption arena. Of course, back in 2013, the hubbub was all about the U.S. Supreme Court’s consideration of Mutual Pharm. Co., Inc. v. Bartlett, 133 S. Ct. 2466 (2013) (subsequently decided) and the Court’s previous decisions in PLIVA Inc. v. Mensing, 131 S.Ct. 2567 (2011) (holding that FDA’s regulations preventing generic drug manufacturers from changing their labeling except to mirror the label of the brand-name manufacturer preempt state-law failure-to-warn claims against generic drug manufacturers, because it is impossible for generic drug manufacturers to comply with both federal and state duties to warn) and Wyeth v. Levine, 555 U.S. 555 (2009) (holding that a state-law tort action against a brand-name drug manufacturer for failure-to-warn is not preempted). In Bartlett, the Court held that state-law design-defect claims that turn on the adequacy of a drug’s warnings are preempted by the FDC Act and under the Court’s decision in Mensing. The fallout of those decisions (in addition to a multitude of court decisions all over the map, such as in Pennsylvania – see our previous post here – and a recent decision out of Illinois in Dolin v. Smithkline Beecham Corp. concerning brand-name manufacturer liability for a generic version of its drug product) was FDA’s November 13, 2013 proposal (see our previous post here) to allow generic drug manufacturers to independently update product labeling (with respect to product safety) through the Changes Being Effected (“CBE-0”) supplement process that is currently only available to brand-name drug manufacturers whose products are approved under an NDA.
FDA’s ANDA CBE-0 proposal has resulted in the bivouacking of various parties in anticipation of what could be many skirmishes and a protracted battle over the future of the generic drug industry.
Not long after FDA published its proposal, several Republican members of Congress expressed “grave concerns” about the proposed rule in a letter to FDA Commissioner Margaret Hamburg, M.D. As we previously reported, the lawmakers express the belief that FDA’s proposal “would conflict directly with the statute, thwart the law’s purposes and objectives, and impose significant costs on the drug industry and healthcare consumers,” and requested that the Agency “explain and reconsider this departure from decades of settled practice.” FDA lodged its response in a a February 26, 2014 letter to the lawmakers. In that response, FDA cites to the Agency’s Preliminary Regulatory Impact Analysis concerning some of the cost issues raised by the lawmakers, and also clarifies the proposal. For example, FDA comments that “[d]uring its review of a generic drug manufacturer’s [CBE-0] supplement, FDA would consider submissions by the brand drug manufacturer and other generic drug manufacturers related to the safety issue and determine whether the labeling update is justified and whether modifications are needed.” In that case, “FDA would make an approval decision on proposed labeling changes for the generic drug and the corresponding brand drug at the same time, so that brand and generic drug products have the same FDA-approved labeling.”
The Generic Pharmaceutical Association (“GPhA”) has also expressed its own concerns about FDA’s proposal. In February, GPhA put out an Overview and Assessment of FDA’s proposal saying that it is unjustified and unwarranted (see our previous post here). A follow-up economic assessment concludes that FDA’s proposal, if implemented, would result in an estimated $4 billion in additional U.S. health care costs annually. More recently, GPhA hosted a briefing on Capitol Hill highlighting its concerns about the proposal, and showcased a March 6, 2014 letter sent to FDA by myriad healthcare organizations saying that “FDA and others need to fully explore the potential unintended consequences that the Rule may have on patient access and national health care costs,” and that “[p]ermitting labeling changes for generic drugs without FDA approval counters 30 years of law requiring generic and brand medicines to have the same labels.”
Those forces in favor of FDA’s November 2013 proposed rule are also gathering. Last week, just three days after a hearing on FDA’s proposal before the House Committee on Energy and Commerce Subcommittee on Health was postponed, a group of Democrat lawmakers announced that they had sent a letter to FDA supporting the proposal.
According to the bicameral group of lawmakers, who urge FDA to prioritize the release of a final rule, the Agency’s proposal “is critically important to ensure that the public is informed as soon as possible when new safety information becomes available, and to ensure that labeling for a prescription drug remains up-to-date even when the branded drug is no longer being marketed or has not undergone a labeling update to reflect newly discovered risks.” And not only does “[e]mpowering a drug manufacturer to update certain safety information while FDA reviews the change, instead of requiring prior FDA approval” (emphasis in original) make good sense they say, because it “will allow generic drug manufacturers to communicate safety information in a timely way,” but it helps incentivize generic drug manufacturers given concers about tort liability:
The Proposed Rule achieves an important public safety goal by restoring these incentives for generic manufacturers to warn consumers of safety risks. Especially in light of resource constraints facing FDA, the potential for tort liability provides an important tool in incentivizing compliance with existing reporting obligations, to the benefit of American consumers.
This is certainly not the last word we’ll hear about FDA’s proposal. As noted above, we’re just in the set-up stage to the battle.
A bill introduced in the Maryland House of Delegates, HB 0596, would require wholesale distributors to notify their pharmacy customers at least thirty days prior to “imposing a limit on the quantity” of prescription drugs or devices distributed to the pharmacy. The bill would further require wholesale distributors to provide updates, at least weekly, on the quantity of the drug or device available to the pharmacy while a limitation is in effect.
The bill is likely intended to assist pharmacies in managing inventories and avoid potential shortages for their patients, however, it would create significant hardships for distributors to anticipate shortages related to manufacturer availability. For example, a wholesale distributor may not know a month out that it may not have adequate drug or device inventory for sale to pharmacy customers. In addition, the bill, if enacted, would create potential conflicts with Drug Enforcement Administration (“DEA”) regulations that require distributors, manufacturers and other registrants to design and operate a system to disclose suspicious controlled substance orders and to report such orders to the local DEA office. 21 C.F.R. § 1301.74(b). Suspicious orders include orders of unusual size, orders that deviate substantially from a normal pattern and orders of unusual frequency. Id.
In order to comply with DEA’s current interpretation and enforcement of this regulation, most distributors have designed systems to include “thresholds” or limits as part of a program to identify, review, evaluate and report suspicious orders. Moreover, once a distributor has identified a suspicious order, they are obligated to report this order to DEA and, logically, should not fill this order (or future orders for controlled substances) until these issues are resolved. Distributors also may not want to disclose the thresholds or specific components of their compliance systems to customers to avoid customers attempting to circumvent the limits. Therefore, decisions by distributors to report and not fill orders as required by DEA regulations could violate the proposed Maryland bill’s thirty day notification requirement.
The proposed legislation warrants monitoring and will need to be amended to resolve conflicts with federal law. As of January 2014, there were 978 wholesale distributors licensed by Maryland.
Yes, this post relates to yet another off-label settlement between a pharmaceutical company and the federal government. But some aspects of this recent settlement, coupled with other recent cases, might indicate noteworthy trends in how these cases are being resolved. The defendants are Endo Health Solutions, and its subsidiary, Endo Pharmaceuticals Inc., based in Malvern, Pennsylvania. The drug is Lidoderm, a prescription drug patch that FDA approved to treat pain associated with post-herpetic neuralgia, or PHN. The government alleged (here and here) that Endo marketed Lidoderm for general, non-PHN related pain indications, including lower back pain, diabetic neuropathy, and carpal tunnel syndrome. The company’s global settlement included a civil payment of $171.9 million, a criminal fine of $20.8 million, and a Corporate Integrity Agreement governing the company’s ongoing practices.
Two U.S. Attorney’s Offices bifurcated the matter, with the civil investigation managed by the U.S. Attorney’s Office in Philadelphia, and the criminal investigation handled by the Northern District of New York. Dealing with multiple U.S. Attorney’s Offices can be complicated, but we have seen improved cooperation between multiple offices in recent cases.
Endo managed to escape a corporate criminal charge by entering into a deferred prosecution agreement (“DPA”) with the government. In the DPA, the company admitted to certain criminal conduct, and agreed to pay a criminal fine and to impose enhanced compliance measures (many of the compliance provisions appear to overlap with the requirements of the Corporate Integrity Agreement). The DPA will not be final until it is accepted by the court.
The government used asset forfeiture techniques to buttress the criminal penalty. As part of the resolution, the parties agreed to settle an in rem action the government had brought against a $10 million wire transfer intended for Endo Pharmaceuticals. It is unclear from the publicly available pleadings how the government traced the wire transfer, but suffice it to say that money transfers of this magnitude do not go unnoticed when a company is in the crosshairs of a criminal investigation. The government argued that the money constituted proceeds from a violation of the FDC Act, and therefore was subject to asset forfeiture under 18 U.S.C. § 981(a)(1)(C). As part of the criminal plea, the parties agreed to forfeit the $10 million wire transfer, plus pay an additional $10 million monetary fine. Asset forfeiture is a powerful tool for the government, and one law enforcement agencies particularly prefer because the money is earmarked to further fund their investigative efforts.
Every breath you take Every move you make Every bond you break Every step you take I'll be watching you
Every single day Every word you say Every game you play Every night you stay I'll be watching you
Our apologies to Sting and The Police, but we were reminded of the lyrics from “Every Breath You Take” the other day when we learned about the “Automated Litigation Tracking System” being run by the Office of General Counsel of the Department of Health and Human Services, the parent agency of FDA. As a law firm that is involved in litigation with FDA on a fairly regular basis, we are certainly not surprised that HHS and FDA would want to know relevant information about companies or individuals who are suing the government or who are defendants in cases brought by the government. We were, however, surprised to learn about the Automated Litigation Tracking System that is located at the old Parklawn Building in Rockville, Maryland where many of us FDA alumni used to work. With recent disclosures about National Security Agency surveillance and the report last week [http://oversight.house.gov/wp-content/uploads/2014/02/FDA-Staff-Report-final.pdf] from Senator Charles Grassley (R-IA) and Congressman Darrell Issa (R-CA) about FDA monitoring of employee emails we thought this might be a timely topic.
According to the government’s description of the litigation tracking system, records are maintained on individuals “who are involved in litigation with the Department [of HHS] or the United States (regarding matters within the jurisdiction of the Department) either as plaintiffs or defendants in both civil and criminal matters.” Also included are individuals who “either file administrative complaints[s] with the Department or are the subject of administrative complaints initiated by the Department …” and individuals “who are named parties in cases in which the Department believes it will or may become involved ….” What is not clear is the type or extent of records that are automatically tracked. We hope that only publicly available information is tracked and maintained but does that include for example court records from divorce proceedings or child custody cases? What about financial contributions to political candidates? The government’s description says only that the records contain information to identify “the people involved in each case.” We are aware, for example, that FDA is tracking company websites using this system. What else is FDA tracking?
Among the “routine uses” of this information are communications “with, among others, Federal, State, and local law enforcement agencies, private individuals, public and private hospitals, allegedly negligent parties, private attorneys, insurance companies, the United States Attorney and other Federal officials and agencies, individual law enforcement officers and tribal officials. These communications are all for the purpose of investigating, settling, or denying claims and subsequent litigation action.”
Although we don’t pretend to know the extent to which FDA is tracking companies it regulates, it is prudent to assume that if your company is (or may be) in litigation with FDA – or is potentially subject to enforcement action – FDA is watching every move you make, every step you take.
On February 18, 2014, the FDA issued the Final Guidance “Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff” (the “Pre-Sub Guidance”). FDA, Guidance for Industry and FDA Staff, Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff (February 2014). Subsequently, on February 26, 2014, FDA held a webinar regarding the Pre-Sub Guidance (the “Webinar”). During the Webinar, FDA explained the key provisions of the Pre-Sub Guidance, and discussed various types of requests for feedback that are covered by the guidance. FDA will be posting a transcript, audio recording and slides will be available here.
As you may remember from our earlier post, a draft of the Pre-Sub Guidance was issued in July 13, 2012. The draft guidance was issued to document the expansion of the pre-Investigational Device Exemption ("IDE") program to include requests for feedback on other device pre-market submission types such as premarket approval ("PMA") applications, humanitarian device exemption ("HDE") applications, and premarket notification (510(k)) submissions. The draft guidance also broadened the program to include devices regulated by the Center for Biologics Evaluation and Research ("CBER").
Since the issuance of the draft guidance, the Pre-Sub program has been a useful mechanism for applicants and study sponsors to obtain feedback from FDA. Similarly to the draft guidance, the Pre-Sub Guidance provides direction as to when a Pre-Sub is particularly useful. For example, a Pre-Sub is recommended (i) before conducting a long-term or material investigation of a new device, particularly, if the device involves novel technology, a “first of a kind” indication for use, or does not have a clear regulatory pathway, and (ii) before conducting a clinical study without an IDE, including clinical studies outside the US, non-significant risk clinical studies and IDE exempt studies. Pre-Sub Guidance at 9-10. Although the Pre-Sub process can be useful in many situations, it is not for everything, including general information requests or questions regarding FDA policy or procedures, and requests for clarification regarding technical guidance documents. Id. at 12.
The Pre-Sub Guidance has been expanded from its draft form (obvious from its length alone, growing from 35 pages to 53 pages). The Pre-Sub Guidance encompasses Pre-Subs and also various meetings with FDA, including:
Formal early collaboration meetings to provide direction regarding development and testing of devices that require a clinical study(ies) to support their pre-market applications (“Determination Meetings” pursuant to Section 513(a)(3)(D) of the Federal Food, Drug, and Cosmetic Act (the “Act”) and “Agreement Meetings” pursuant to Section 520(g)(7) of the Act);
Meetings required no later than 100 days after receipt of a PMA application (“Day-100 Meetings” pursuant to Section 515(d)(3) of the Act);
Informal meetings to discuss additional information requests on pending pre-market submissions (“Submission Issue Meetings”);
Requests for determination regarding whether a proposed clinical study is exempt from or subject to the IDE regulations, and if a study is subject to the IDE regulations, whether a study is significant risk or non-significant risk (“Study Risk Determinations”); and
Meetings to inform or educate FDA about devices in development and/or planned submissions without requesting feedback (“Informational Meetings).
79 Fed. Reg. 9226, 9227 (Feb. 18, 2014). All Pre-Subs and meeting requests will be referred to by FDA as “Q-Subs” and will be assigned a Q number (Q followed by two digits for the year and four digits representing the order in which it was received). Pre-Sub Guidance at 5. Appendix 1 of the Pre-Sub Guidance contains recommendations for each type of Q-Sub. Id. at 31.
The major changes in the final Pre-Sub Guidance from the draft guidance include:
Revisions to broaden the overview of possible mechanisms for FDA feedback prior to a planned submission;
Reorganization to include a discussion of the various request types first, followed by a section regarding meeting procedures, which applies to all feedback mechanisms that request a meeting or teleconference;
Revisions to include an acceptance review process, including an acceptance checklist for all Q-Subs; and
Revisions to clarify that if more than one year has passed since the Agency provided feedback on a Q-Sub and the applicant has not submitted an application to the Agency, the applicant can confirm the validity of the prior feedback by calling the lead reviewer or the branch chief.
79 Fed. Reg. at 9928. Regular readers of our Blog will also be happy to hear that the Pre-Sub Guidance states that applicants must submit an eCopy, thereby correcting the inconsistency that existed between the draft guidance and the eCopy Guidance. Pre-Sub Guidance at 6. Applicants should ensure that their Pre-Submissions comply with the requirements of the final guidance document for the eCopy Program for Medical Device Submissions (the “eCopy Guidance,” we previously blogged on the guidance here and here.)
One other administrative change that FDA emphasized during the Webinar was the change to the process for meeting minutes. Following the meeting or teleconference, the applicant should draft meeting minutes and submit the draft (including any slides from the meeting) to the Document Control Center (“DCC”) within 15 calendar days of the teleconference or meeting. In the draft guidance, meeting minutes were submitted to the lead reviewer following the meeting. In the Pre-Sub Guidance, the draft minutes will be logged as a formal amendment to the Q-Submission. The Webinar presenters explained that FDA will review and edit the meeting minutes, if necessary, within 30 days of receipt. FDA’s edited version, if edits were made, will become the final record of the meeting/teleconference 15 calendar days after the applicant receives FDA’s edits, unless the applicant submits a “meeting minutes disagreement” during that timeframe. A “meeting minute disagreement” should be filed by the applicant as an amendment to the Q-Sub through the appropriate Document Control Center. Id. at 29. These procedures underscore how the process has been greatly formalized compared to the Pre-IDE process.
Although FDA received comments regarding the timeframe for providing responses to Pre-Subs (a goal of 75 to 90 days in the draft guidance), this time frame has not changed for Pre-Subs. However, the Pre-Sub Guidance does contain a helpful chart with the feedback timeframes for each type of Q-Sub:
Id. at 5. During the Webinar, FDA explained that the Q-Sub review timeline will not change if the underlying pre-market submission has been granted priority review.
The most interesting of the changes to the Pre-Sub Guidance is certainly the addition of the Q-Sub Acceptance Checklist (Appendix 2), which applies to all Q-Subs except for PMA Day 100 Meeting requests. Id. at 47. FDA intends to perform an “Acceptance Review” within 14 calendar days of receiving a Q-Sub that includes a valid eCopy. Id. at 6. As explained during the Webinar, the Acceptance Review will be performed by the reviewing branch at the Center. The Acceptance Review is intended to “(1) determine if the request meets the definition of the identified Q-Sub type and (2) determine if a qualifying request is administratively complete.” Id. If the submission does not include sufficient information to allow the Agency to make these determinations then the applicant will receive a notice indicating the reasons that the submission was not accepted. During the Webinar, FDA explained that it will begin performing the Acceptance Review in the next few weeks.
In addition, the Webinar presenters stated that the Acceptance Review will be performed in parallel with the timeframes listed in the table, above. For example, if an applicant submits a Submission Issue Meeting request, the first 14 days of the 21 day timeframe for review will be allocated to the Acceptance Review. Thus, the total timeframe for Submission Issue Meeting review will be 21 days, not 35 days (14 days for Acceptance Review + 21 days for substantive review). In fact, FDA noted during the Webinar that it understands the urgency of Submission Issue Meetings, and plans to perform the Acceptance Review for these Q-Subs in less than 14 days, if possible.
The Pre-Sub Guidance attempts to distinguish the Acceptance Review from the 510(k) and PMA Refuse to Accept (RTA) Policies by not including a list of required elements, which need to be in a Q-Sub in order for it to be accepted. In fact, the Pre-Sub Guidance indicates that, if the Q-Sub includes the basic information necessary for FDA to provide the requested feedback and/or identify the appropriate attendees for scheduling of a meeting or teleconference, then “additional clarifying or explanatory information” can be provided after acceptance upon request of the lead reviewer, if needed.
We certainly hope that the Pre-Sub Acceptance Review has better success than the 510(k) RTA process (some of the issues with the 510(k) RTA process are discussed in our recent post here). As of September 2013, approximately 60% of all newly filed 510(k)s were refused under the RTA. CDRH Meeting FDASIA Goals, Confirms Compliance Re-Org, DEVICES & DIAGNOSTICS LETTER (FDA News, Falls Church, V.A.), Sept. 30, 2013, at 1. If 60% of new Pre-Subs are refused under the Pre-Sub Guidance’s Acceptance Review, it would unduly delay requests for feedback that are often times meant to take place early in the development and planning process. Thus, this could cause delays to device approvals/clearances and/or initiation of clinical trials for new devices, which could discourage companies from conducting clinical trials in the United States (note: one of FDA’s strategic priorities for 2014-2015 is to encourage sponsors of clinical trials to conduct those trials in the United States rather than overseas and to do so early in the device development process (see our earlier post here). Even with this added administrative hurdle for applicants to navigate, we expect that the Pre-Sub Program will continue to be a useful process for applicants to receive feedback from FDA prior to or in connection with nearly any type of device pre-market submission and/or clinical study design.
1 This performance goal applies to both the CLIA Waiver application and the 510(k).