The U.S. Court of Appeals for the Eighth Circuit recently issued an opinion in the case of Lytle v. U.S. Department of Health and Human Services, Nos. 14-3715, 15-1214 (8th Cir. Aug. 21, 2015), affirming that private membership associations (“PMAs”) cannot thwart FDA’s regulatory authority over the marketing of medical devices through distribution of devices only to PMA members. The decision, arising from two related cases from the United States District Court for the District of South Dakota and a long regulatory history, affirmed the district court’s dismissal of pro se appellant Dr. Larry Lytle’s action for declaratory judgment challenging FDA’s authority to execute administrative warrants to inspect his laser-device businesses.
Specifically, Dr. Lytle argued that, because his companies’ laser devices were only distributed to members of his PMAs, FDA had no authority to regulate those devices. Not surprisingly, FDA disagreed that membership in a private club excluded its jurisdiction, and the Eighth Circuit agreed with the government’s position. Citing section 201(e) of the Federal Food, Drug, and Cosmetic Act, (defining persons subject to the Act to include associations) and another recent case finding that a cow-sharing PMA that gave raw milk to members was not immune from regulation by FDA, the court held that the activities of Dr. Lytle and his companies fell under FDA’s regulatory authority.
In addition to affirming the dismissal of the declaratory judgment in the first case, however, the court remanded the second case, in which the district court entered a preliminary injunction against Dr. Lytle to prevent him from manufacturing, processing, holding, or distributing laser devices for medical uses not approved by FDA, for further consideration of whether the injunction could have been more narrowly tailored.
Dr. Lytle, a dentist whose license was permanently revoked by South Dakota in 1998, has been marketing his lasers since 1997 and sparring with FDA over them since 2002. Given this history and this decision inviting more inspections and a narrower injunction, this story is likely to have further chapters. But it is not likely that other efforts to avoid FDA jurisdiction by forming PMAs will find success in the courts.
FDA issued a warning letter to Hampton Creek alleging that its Just Mayo products are misbranded, in part because they purport to be a food governed by a standard of identity – namely, mayonnaise – that the products fail to meet. This alleged violation was at the heart of a lawsuit filed against Hampton Creek last year by Unilever, which Unilever subsequently dropped so that Hampton Creek could “address its label directly with industry groups and appropriate regulatory authorities” (see Unilever’s press release here). To the extent any such efforts were undertaken by Hampton Creek, they appear to have been unsuccessful in warding off FDA’s warning letter. The focus now shifts to whether the company can devise a way to resolve FDA’s concerns without having to make changes so extensive as to adversely affect the brand’s early success.
In addition to expressing concerns with the product names and logo, FDA found that the labels include unauthorized use of nutrient content and health claims. These alleged violations, coupled with the alleged violation of the standard of identity, can be expected to serve as grist for the plaintiffs’ bar. The take-away for start-ups is fairly straightforward: in a highly regulated sector such as food, success will quickly draw attention to regulatory non-compliance, and good intentions can’t be counted on to keep the hounds at bay.
An August 28, 2015 letter to Judge Paul Engelmayer, U.S. District Court for the Southern District of New York, from the attorneys representing Amarin, Inc. (“Amarin”) indicated that the parties on both sides of Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. filed May 7, 2015), may be engaged in settlement discussions. See Joint Letter, Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. Aug. 28, 2015), ECF No. 75 (“Joint Letter”). We previously discussed the court’s decision granting Amarin’s Motion for Preliminary Injunction (“PI Motion”) against FDA prosecution for Amarin’s off-label promotion of Vascepa here. In an Order issued three days after the court’s decision, Judge Engelmayer directed the parties to confer no later than August 24 and submit a joint letter no later than August 28 regarding “the future course of and next steps in the case.” Order, Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. Aug. 10, 2015).
The Joint Letter stated that “[t]he parties have agreed to explore the possibility of settlement” in the case and requested that further proceedings be stayed until October 30, 2015. At that time, the parties would file another joint letter to the court, providing notice regarding the next steps they plan to take.
Certainly FDA, on the heels of losing the PI Motion, may believe it is likely to lose the case on the merits if the case proceeds to final judgment. Settlement may allow FDA to cut its losses at this point and regroup on its strategy concerning the regulation of off-label promotion.
Amarin too may have something to gain if it settles. With the leverage of its victory on the PI Motion, Amarin may be able to obtain FDA approval for Amarin to continue to promote the use of Vascepa in patients with persistently high triglycerides, perhaps through at least the reporting of results from the REDUCE-IT trial in approximately 2018. The court, in its decision on the PI motion, was not prepared to extend its injunction for any given period of time, given that the court’s Opinion was based on the “current record,” thus the court recognized that statements Amarin may make today that are fair and balanced “may become incomplete or otherwise misleading in the future as new studies are done and new data is acquired.” Opinion and Order at 66, Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. Aug. 7, 2015).
One important question now is: what happens if Amarin is settled? The most significant effect might be that the parties agree, as a term of settlement, to jointly request that the court vacate its August 7, 2015, Order granting Amarin’s PI Motion. We certainly think vacating the court’s August 7 Order could be a term on the table during settlement negotiations, but it remains to be seen whether Amarin and the other plaintiffs would agree to such a term, if they agree to settle at all.
Even if the August 7 Order is vacated, it may, like other significant rulings, live on. Readers may recall the Washington Legal Foundation (“WLF”) line of cases that challenged FDA’s regulations concerning off-label promotion. In particular, WLF filed a lawsuit claiming that certain FDA Guidance documents violated First Amendment protection of commercial speech. Washington Legal Foundation v. Henney, 202 F.3d 331, 332-334 (D.C. Cir. 2000). In that case, the district court granted WLF’s summary judgment motion, holding that FDA’s applicable Guidances violated the First Amendment, and enjoined FDA from prohibiting manufacturers’ dissemination of “enduring materials” as well as suggesting content to Continuing Medical Education program providers. Id. at 334. On appeal, during oral arguments before the Court of Appeals for the D.C. Circuit, FDA conceded that neither the Federal Food, Drug, and Cosmetic Act (“FDCA”) nor FDA Guidance documents gave FDA authority to restrict manufacturer speech in these areas. Id. at 335. With that admission on the record, there was no longer a “constitutional controversy between the parties that remain[ed] to be resolved,” and the court dismissed FDA’s appeal and vacated the district court’s decisions and injunctions declaring parts of the FDCA and FDA guidance documents unconstitutional. Id. at 335, 336. However, the district court’s reasoning and holding as it applied to FDA regulation of the dissemination of off-label information continued to carry weight and perhaps provided the impetus for later challenges to such regulation.
Ultimately, we cannot Predict whether the Amarin case will be settled or, if so, whether the principles articulated by the court expounding and expanding on United States v. Caronia, 703 F.3d 149 (2d Cir. 2012), will carry future weight. But, we continue to watch the Amarin case and its further developments.
Hardly a week goes by without news of FDA’s priority review voucher (“PRV”) programs. The last several weeks are no exception. In this blog post, we focus on five key updates related to FDA’s tropical disease and rare pediatric disease (“Pediatric”) PRV programs:
United Therapeutics Corporation (“United Therapeutics”) sold its Pediatric PRV for $350 million;
FDA added Chagas disease and neurocysticercosis to its list of eligible tropical diseases;
Sanofi-Adventis (“Sanofi”) successfully redeemed a Pediatric PRV to beat Amgen to market and became the first PCSK9 cholesterol therapy approved in the U.S.;
The Senate released its own version of the Advancing Hope Act; and
Three Duchenne muscular dystrophy sponsors received rare pediatric disease designation.
PRV Prices Continue to Climb
On August 19, United Therapeutics announced the sale of its rare Pediatric PRV for an incredible $350 million to AbbVie Inc. We discussed FDA’s issuance of this Pediatric Voucher to United Therapeutics for Unituxin here. As the graph below shows, the value of PRVs continues to climb dramatically.
FDA Adds Chagas Diseases and Neurocysticercosis to the List of Qualifying Tropical Diseases
On August 20, 2015, FDA published a final order to add two new diseases, Chagas disease and neurocysticercosis, to the list of qualifying tropical diseases. Recall that, in order for a drug product to be eligible for a PRV, four requirements must be met:
The application must be for a listed tropical disease;
The application must be submitted either as a 505(b)(1) NDA or a 505(b)(2) application;
The drug that is the subject of the application must not contain a previously-approved active moiety; and
The application must qualify for a 6-month priority review under FDA’s policies.
Thus, a sponsor for a drug that treats Chagas disease or neurocysticercosis that meets the requirements above would be eligible for a tropical disease PRV.
Section 524(a)(3)(R) of FD&C Act permits FDA to include “[a]ny other infectious disease for which there is no significant market in developed nations and that disproportionately affects poor and marginalized populations.” (Emphasis added.) In its final order, the Agency also affirmed its commitment to using “a flexible approach” to tropical disease designations based on “scientifically informed, qualitative assessment of disease candidates.” FDA also announced the establishment of a public docket that will remain open to receive future suggestions for tropical disease designations. That docket is here.
The final order explains FDA’s interpretation of the key elements of section 524(a)(3)(R) of FD&C Act:
“Developed nations” - According to the order, “FDA will use a country’s presence on the World Bank’s list of ‘low income economies’ . . . as evidence that the country should not be considered a ‘developed nation’ for purposes of ‘tropical disease’ determination.”
“No significant market” - FDA notes the difficulty in providing a rigid definition of “no significant market” and instead proposes the following factors be considered in determining whether a “significant market” exists in developed countries: (1) occurrence of the disease in developed nations; and (2) the existence of a sizeable indirect market for the tropical disease drug (e.g., government, including the military) that would constitute a financial incentive for drug development.
Disproportionately affects poor and marginalized populations - As with the term “no significant market,” FDA rejected a single definition in favor of four factors that must be weighed. These factors are: (1) the proportion of global disability-adjusted life years for the disease that is attributable to developing countries; (2) the relative burden of the disease in the most impoverished populations within the countries in which it is found; (3) the relative burden of the disease in infants, children, and other marginalized segments of the population; and (4) whether WHO has designated it as a neglected tropical disease.
Applying these standards, FDA exercised the authority granted to it by the Adding Ebola to the FDA Priority Review Voucher Program Act in December 2014 and added Chagas disease and neurocysticercosis to its list of diseases that qualify for the tropical disease voucher program.
Bonus: On August 24, 2015, Mid-Atlantic BioTherapeutics, Inc. submitted a citizen petition requesting that FDA add the rabies virus to the list of qualifying tropical diseases. Notably, rabies is on WHO’s list of neglected tropical diseases, as is cysticercosis/taeniasis.
Sanofi Successfully Uses its PRV
On August 19, 2015, FDA announced that Sanofi-Adventis had redeemed a Pediatric PRV for its Praluent (alirocumab) NDA. With its approval on July 24, 2015, Praluent became the first approved PCSK9 cholesterol therapy in the United States. The PCSK9 therapeutic class is expected to a blockbuster, with sales projected to be in the billions of dollars per year.
The interesting part of this story is that Amgen’s Repatha beat Sanofi’s Praluent to market in Europe; but, ostensibly, through its redemption of a rare pediatric disease priority review voucher, Sanofi was able to reach the U.S. market before Amgen. The Praluent approval came a month ahead of Repatha’s August 27, 2015 PDUFA date and approval.
Drugs that are first-to-market often enjoy considerable benefits over second-comers. U.S. payers, for example, are quick to cover new drugs, and products that are first-to-market often have significant marketing advantages and sales momentum. Sanofi’s $67.5 million move to accelerate its entry into the U.S. market for its PCSK9 therapy will be closely watched. After all, it will be a bellwether of whether industry can justify the high prices paid for priority review vouchers. If things go well for Sanofi, the demand for and price of subsequent PRVs should be high.
An Update to the Advancing Hope Act
In March 2014, Representative G.K. Butterfield (D-NC) introduced the Advancing Hope Act (H.R. 1537) in the House of Representatives. In our post on the bill, we noted the effort to make the Pediatric Voucher program permanent. We also noted the bill’s proposal to change the tropical disease voucher program. At the time, we noted that such changes not only seemed out of place, but they could be counterproductive.
On July 28, 2015, the Advancing Hope Act (S. 1878) was introduced in the Senate. The Senate version of the bill scrapped the amendments to the tropical disease priority review voucher program. Instead, the Senate version proposes to make the Pediatric Voucher program permanent and to designate pediatric cancers and sickle cell anemia as rare pediatric diseases.
Rare Pediatric Disease Designations Granted for DMD
On August 19, FDA awarded rare pediatric disease designation to BioMarin’s, Sarepta’s, and Santhera’s investigational products for Duchenne Muscular Dystrophy. With the rare pediatric disease designation, each company will likely be eligible for a Pediatric Voucher upon approval of its drug product.
On August 27, 2015, FDA published its much–anticipated views on the non-proprietary naming of biological products. Set forth in a proposed rule, a draft guidance, and a blog post, FDA proposes that a four letter suffix “devoid of meaning” be part of the name of all biological products, including reference products and biosimilar biologics. The proposal solicits public feedback on whether in the alternative the suffix should not be meaningless but instead be derived from the name of the license holder. The proposal also states that the four letter suffix will be different for each product except perhaps interchangeable products. For interchangeable products, FDA declines to make a naming decision but instead solicits feedback on two alternatives: whether interchangeable products should also have distinct suffixes or share the same one. By largely taking the position advocated by the makers of reference products, the proposal has already elicited negative comments in some quarters.
How a biosimilar should be named has been one of the hottest issues in biosimilars (see our previous posts here, here, here, and here), despite it being an issue upon which the BPCIA is silent. Advocates for unique non-proprietary names insist that they are necessary to ensure safety, accurate adverse event reporting and the preservation of physician and patient choice. On the other hand, advocates for use of the same name argue that the safety and pharmacovigilance concerns are minimal and that different names will be a major barrier to marketplace acceptance of biosimilars. The European Union long ago decided that distinct names were necessary, and the issue has been squarely in front of FDA since the BPCIA’s passage. In addition, FDA has on two occasions approved biologics with unique non-proprietary names: (1) tbo-filgrastim for a Teva product approved before the BPCIA was passed; and (2) filgrastim-sndz, approved in March for Sandoz’s Zarxio but with a specific FDA notation that the non-proprietary name was a placeholder subject to change.
The draft guidance leads off with a simple summary of the Agency’s position: “FDA’s current thinking is that shared nonproprietary names are not appropriate for all biological products. There is a need to clearly identify biological products to improve pharmacovigilance and, for the purposes of safe use, to clearly differentiate among biological products that have not been determined to be interchangeable.” FDA further explains that it hopes to avoid “inadvertent substitution” of products, facilitate pharmacovigilance “when other means to track a specific dispensed product are not readily accessible,” encourage routine use of suffixes in ordering, prescribing, dispensing, and recordkeeping, and “avoid inaccurate perceptions of the safety and effectiveness of biological products based on their licensure pathway.”
Under the new system, FDA’s naming convention for biological products will be to assign a proper name that will include a “core name” and a designated suffix. For originator biological products, FDA will make the core name the name adopted by the USAN Council for the drug substance. For other biological products (e.g., “related,” biosimilar, and interchangeable products), the core name will be the name of the drug substance contained in the relevant previously licensed product.
FDA believes that use of a shared core name will indicate a relationship among products. FDA chose to use a suffix instead of a prefix so that products with the same core name will be grouped together in electronic databases and thereby to help health care providers identify products.
FDA intends to apply this naming convention to both newly licensed and previously licensed biological products.
A few products will be exempt: biological products for which a proper name is provided in the regulations (e.g., 21 C.F.R. part 640), and “certain categories of biological products for which there are well-established, robust identification and tracking systems to ensure safe dispensing practices and optimal pharmacovigilance (ISBT 128 for cord blood products).” For previously licensed products, in most cases FDA will simply attach a hyphen and the four letter suffix to the product’s original proper name, one exception being the tbo-filgrastim product mentioned earlier, which will lose its prefix and gain a suffix.
As for the selection of those suffixes “devoid of meaning,” for new products FDA wants the sponsors of full BLAs to propose a suffix during the IND phase. For existing products, FDA is considering the most effective regulatory approach and intends to provide will provide additional information. In the near term, however, FDA is using the proposed rule to assign distinguishing suffixes to six products, including the Amgen, Teva and Sandoz filgrastims, Neulasta, Epogen, Procrit and Remicade. These products were selected because either they are referenced by approved or publicly announced pending biosimilar applications, or are related products to those reference products. FDA advises applicants for new biosimilar products to also propose a four letter suffix.
FDA mandates that the proposed suffix should be four lowercase letters, be unique and be “devoid of meaning.” The proposed suffix should not be promotional, “such as by making misrepresentations with respect to safety or efficacy,” not include abbreviations commonly used in clinical practice and therefore subject to misinterpretation, not contain or suggest any drug substance name or core name, not look similar to the name of a currently marketed product or to any other product’s suffix. FDA encourages applicants to conduct due diligence on their proposed suffixes.
FDA’s non-decision on interchangeables is set forth very simply:
FDA intends to apply the naming convention described in this guidance to interchangeable products licensed under section 351(k) of the PHS Act in an original application or a supplement and is considering two alternative approaches:
1. Distinct from the reference product: An applicant for a proposed interchangeable product submitted in an original application under section 351(k) of the PHS Act would propose a unique suffix composed of four lowercase letters for use as the distinguishing identifier included in the proper name designated by FDA at the time of licensure (see section V of this guidance). An applicant seeking a determination of interchangeability in a supplement to its 351(k) application would keep the existing suffix.
2. Shared with the reference product: An applicant for a proposed interchangeable product submitted in an original application or a supplement under 351(k) of the PHS Act would be assigned the same proper name and suffix as its reference product.
FDA's proposal elicited at least one immediate negative reaction. In a statement, Dr. Bertrand C. Liang, Chairman of the Biosimilars Council (a division of GPhA), stated: “The FDA’s proposals today on naming conventions for biosimilars warrant serious scrutiny for their potential to erect barriers to patient access to new, more affordable medicines, and jeopardize their safety. Because the Biosimilars Council shares the agency’s deep commitment to patient safety, we believe that biologics and biosimilars should be required to have the same International Nonproprietary Name (INN) with no added 'FDA-designated suffix.'”
The comment period on the draft guidance is open for 60 days, and the comment period on the proposed rule is open for 75 days.
As we reported in a previous post, the House Committee on Energy and Commerce requested that FDA answer a number of questions regarding how FDA Centers issue and publicly disclose Untitled Letters (“ULs”). As readers may recall, the letter to FDA questioned whether FDA’s practices concerning the issuance and disclosure of ULs has been “consistently fair, effective, or efficient” and solicited responses to numerous questions to provide color to the same. In its brief response, FDA reiterated its general policies regarding the issuance and dissemination of ULs, clarified, to some extent, its approach on disclosure, and addressed the Committee’s assertion that FDA had ulterior motive in the timing of public disclosure of certain ULs.
FDA answered the Committee’s questions concerning the issuance of ULs by stating that ULs are means to “communicate and provide formal notice” to companies that FDA has determined a violation of FDA regulations has occurred that does not rise to the threshold of a WL. FDA further stated that ULs provide “the factual basis regarding the violation,” communicate FDA’s concerns, but do not commit FDA to take enforcement action for such violation. In answering these questions, FDA generally related information from its Regulatory Procedures Manual (“RPM”). For example, FDA pointed to the RPM sections that describe certain types of Warning Letters (“WLs”) and ULs reviewed as a matter of course by FDA’s Office of Chief Counsel – additional detail can be found in RPM Exhibit 4-1 (here).
More noteworthy was FDA’s response regarding public disclosure – that is, posting to FDA’s website – of ULs. FDA clarified that Center-specific policies concerning the posting of ULs apply, but only when such policies do not conflict with the Agency’s approach to posting ULs proactively in consideration of its obligations under the Freedom of Information Act (“FOIA”). FDA said that FOIA requires FDA to post “any Agency record subject to the FOIA,” including ULs, if:
FDA has received three or more FOIA requests for a copy of such record; or
The “content relates to a matter of significant public interest” and FDA expects to receive multiple FOIA requests for the record.
In defending its approach, FDA stated: “[t]his approach is consistent with Federal law, Department of Justice Guidelines, President Obama’s January 21, 2009, FOIA Memorandum, and Attorney General Holder’s March 19, 2009, Memorandum.” Further, FDA said that Centers may utilize approaches that “provide a greater measure of transparency” by proactively posting ULs. FDA also said that it has been “encouraged” to go beyond the legal requirements for public disclosure when deemed appropriate by FDA Centers. Finally, FDA noted that its Centers regulate a broad array of products that vary widely in terms of risk as well as the availability of resources, both of which are taken into account when developing Center-specific approaches to the public disclosure of ULs.
FDA took issue with Congress’ suggestion that FDA had motives other than achieving regulatory compliance in issuing and posting some ULs. In its letter to FDA, Congress questioned whether the timing of issuing ULs was meant to advance new FDA policy or interpretation outside the routine administrative process or impact investment decisions. In its response to this issue, FDA expressly rejected the notion that it uses ULs to “announce new regulatory approaches or policy.” With respect to timing, FDA responded by stating that it does not “investigate or evaluate” whether companies receiving WLs or ULs are publicly traded on a U.S. or foreign exchange or “seek to time [the] release [of WLs or ULs] based on market considerations.” In a final point on this issue, FDA stated it “does not believe the Agency has a special expertise or a mission to change its own processes to attempt to time impacts on the stock market and determine whether impacts are desirable.”
It will be interesting to see where this goes from here. Was the Committee’s intent to take FDA to task over what FDA Centers should do, having FDA describe its existing policies regarding the issuance and posting of ULs? If so, then we may not hear more from either Congress or FDA on the subject. Or was it a more searching inquiry into what FDA Centers actually do? If it was the latter, then FDA’s response likely does not provide Congress with what it was looking for and we may see more activity from the Committee, such as a request for a public hearing on the matter.
FDA recently released a draft guidance, titled “Rare Diseases: Common Issues in Drug Development.” The fourteen-page document amounts to more of a primer than a focused discussion of technical issues. It serves as a useful reminder of the broader themes that confront orphan drug sponsors, and it is particularly helpful for those that are new to the rare disease space. In a number of ways, the Draft Guidance is similar to another draft guidance published in May 2015, entitled “Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators,” which, as the title suggests, provides a high-level overview on how to prepare and submit an IND.
By publishing the Draft Guidance, FDA may be seeking to increase the consistency and flexibility exercised in the review of orphan drugs in CBER and CDER as well as across the Centers’ various review divisions. To be certain, the Draft Guidance highlights a number of ways FDA can exercise flexibility in its review of orphan drugs. For example, the Draft Guidance discusses FDA’s views on the acceptance of historical controls, and reliance on a single trial with confirmatory evidence. FDA also notes that “[t]here is no specific minimum number of patients that should be studied to establish effectiveness and safety of a treatment for any rare disease.”
Overview
The Draft Guidance addresses the following aspects of developing a drug for a rare disease:
Adequate description and understanding of the disease’s natural history;
Adequate understanding of the pathophysiology of the disease and the drug’s proposed mechanism of action;
Nonclinical pharmacotoxicology considerations to support the proposed clinical investigation or investigations;
Reliable endpoints and outcome assessment;
Standard of evidence to establish safety and effectiveness; and
Drug manufacturing considerations during drug development.
Natural History Studies
Perhaps the most interesting aspect of the Draft Guidance document comes in its discussion of natural history studies. FDA’s Draft Guidance urges sponsors of drugs for rare diseases to develop an understanding of the natural history of the disease early in the development program so as to better inform the design and analysis of clinical trials.
Natural history has been defined as “the natural course of a disease from the time immediately prior to its inception, progressing through its presymptomatic phase and different clinical stages to the point where it has ended and the patient is either cured, chronically disabled or dead without external intervention.” Stephen C. Groft and Manuel Posada de la Paz, “Rare diseases-avoiding misperceptions and establishing realities: the need for reliable epidemiological data,” Rare Diseases Epidemiology (2010). In May 2012, FDA hosted a helpful workshop on natural history entitled, “Workshop on Natural History Studies of Rare Diseases: Meeting the Needs of Drug Development and Research.”
The Draft Guidance accepts that the natural history of rare diseases is often poorly understood. Although natural history studies are not required, FDA counsels that, for an orphan drug, “a well-designed natural history study may help in designing an efficient drug development program.” Such studies, FDA notes, can help by:
Defining the disease population, including a description of the full range of disease manifestations and identification of important disease subtypes;
Understanding and implementing critical elements in clinical study design, such as study duration and choice of subpopulations;
Developing and selecting outcome measures that are more specific or sensitive to changes in the manifestations of the disease or more quickly demonstrate safety or efficacy than existing measures; and
Developing new or optimized biomarkers that may provide proof-of-concept information, guide dose selection, allow early recognition of safety concerns, or provide supportive evidence of efficacy.
The Draft Guidance also notes that, because rare diseases are “highly diverse . . . with wide variations in the rates and patterns of manifestations and progression,” natural history studies should be broad and based on features of the disease, including those morbidities most important to patients. The Draft Guidance then sets forth a number of helpful considerations in developing a natural history study, including:
Selecting data elements that are broad and based on features of the disease, including morbidities that aremost important to patients, among others.
Because of the substantial phenotypic variability in many rare disorders, natural history studies should include patients across as wide a spectrum of disease severity and phenotypes as possible, rather than focusing too early on a particular subset;
Natural history data should be collected for a sufficient duration to capture clinically meaningful outcomes and determine variability in the course of the disease; and
The data for natural history studies can be collected prospectively or retrospectively, but prospective longitudinal natural history studies are likely to generate the most useful information about a disease.
It is important to note, however, that prospective longitudinal natural history studies can span years and even decades and waiting for the results of a such trials, prior to designing pivotal studies, may substantially delay drug development programs. As such, patients with serious and life-threatening conditions may be denied access to promising therapies. In addition, companies may find that conducting such prospective longitudinal natural history studies is not commercially viable. This is particularly true for small companies, which make up a large percentage of the orphan drug space.
While the Draft Guidance emphasizes the utility of natural history studies as “critical background information” to inform sponsors’ decision-making regarding clinical trial design and provides guidance on developing natural history registries to support that activity, when it comes to the use of natural history data as a historical comparator, the Draft Guidance minimizes the credibility of using historical controls. While the challenges associated with the use of historical controls are well recognized, FDA fails to recognize that natural history studies have been used in this way to support important approvals in the rare disease space; for example:
Myozyme (alglucosidase alfa), the first treatment for patients with Pompe disease, was approved on the basis of two studies with historical controls where a natural history database was used to create a subgroup-matched historical control based on certain prognostic factors;
Cresemba (isavuconazonium sulfate) was approved in 2015 for the treatment of invasive aspergillosis and invasive mucormycosis, rare but serious infections, with one of the two studies’ effectiveness comparisons using a combination of both matched and unmatched historical controls; and,
Cholbam (cholic acid) was approved in 2015 for both bile acid synthesis disorders due to single enzyme defects and as an adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders, which in the absence of sufficient natural history information was based largely on uncontrolled studies.
The use of natural history data as a historical control remains an area where a greater understanding of FDA’s flexibility in previous approval decisions would benefit the rare disease community.
Comments on the Draft Guidance are due by October 16, 2015 here.
*Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.
On August 17, 2015, FDA announced the availability of an update to its 11 year old guidance on botanical drug development. Botanicals are plant materials, algae, macroscopic fungi, and combinations of those things that can be regulated as a food (including a dietary supplement), drug/biologic, medical device, or cosmetic under the Federal Food, Drug, and Cosmetic Act. The updated guidance covers the development of those botanicals that are that are regulated as drugs (i.e., under an investigational new drug application to support a future new drug application submission, as part of over-the-drug monograph system). While the general approach to botanical drug development has remained unchanged in the updated guidance, FDA has primarily modified and expanded the 2004 draft guidance to address late-phase development and NDA submission. The updated guidance still covers these topics in drug development:
Description of the product and documentation of prior human experience;
Chemistry, manufacturing, and controls (CMCs);
Nonclinical safety assessment, including pharmacology and toxicology;
Clinical pharmacology and bioavailability; and,
Clinical considerations.
Therapeutic Consistency
While there are a number of smaller changes to what FDA requests of sponsors when embarking on clinical trials for botanical drugs, the Agency significantly expanded the quality control measures. Given the heterogeneous nature of botanical drug products, and that it can be technically challenging to determine a botanical drug’s identity and ensure its consistency, the draft guidance maintains a “totality-of-the-evidence approach” to demonstrate that the commercial batches will be therapeutically consistent with those batches observed during premarket clinical development. Such quality controls still consist of a combination of (a) botanical raw material controls (e.g., agricultural practice and collection), (b) quality controls by chemical tests, and (c) manufacturing controls. However, it seems that FDA would like to see additional evidence that supports therapeutic consistency. As such, the updated guidance includes two new quality control aspects: biological assays and clinical data.
Biological Assays.While raw material controls and other CMC measures can help establish the identity and ensure the quality of botanical drug products, the draft guidance states that in certain cases information on correlations between such quality parameters and the pharmacological activity or clinical effect may be warranted to ensure that variations in raw materials and drug substance will not affect the product’s therapeutic consistency. For a biological assay, FDA prefers one that reflects the drug’s known or intended mechanism of action. At a minimum, FDA would like to see an appropriately validated biological assay that demonstrates accuracy, precision, specificity, linearity, and range.
Clinical Data.The updated guidance requests clinical data beyond the primary efficacy analyses to show that clinical response to a botanical drug will not be affected by variations of different batches in two ways. The first approach is to conduct multiple batch analyses, looking at batch effects on clinical endpoints. This allows quantification of potential heterogeneity in clinical outcomes for subjects who receive different batches in the study. This is in principle similar to other types of subgroup analysis. The second approach is to show that clinical response is not sensitive to dose, while also demonstrating that the studied doses are more effective than placebo or control, or not inferior to active treatment.
Applicability of Combination Drug Regulations
Another major expansion to the updated guidance is the addition of a discussion on the applicability of FDA's combination drug regulations. For a fixed-dose combination drug product, current regulations require sponsors to demonstrate each component’s contribution toward overall efficacy and/or safety. However, the draft guidance clarifies that these regulations generally do not apply to naturally derived mixtures, such as those found within a single botanical raw material. Therefore, botanical drug products derived from a single botanical raw material are generally not considered fixed-dose combination drugs because FDA considers the entire botanical mixture to be the active ingredient.
On the other hand, botanical drug products derived from multiple botanical raw materials are currently considered by FDA to be fixed-combination drugs. Since demonstrating each botanical raw material’s contribution to efficacy and safety in such a botanical product is not always feasible, FDA is reviewing the requirements for fixed-combination drugs and how they should be applied to botanical drugs. For now, FDA is requesting nonclinical data from animal disease models or pharmacological in vitro assays to help show the contribution of individual components to the claimed effects.
Other Modifications
In addition, the guidance document’s discussion of Phase 1 and Phase 2 clinical studies for botanical drugs is no longer split into separate recommendations and requirements for (a) marketed products without safety concerns and (b) non-marketed products or products with known safety concerns. The new document has blended these requirements. For example, the nonclinical pharmacology and toxicology information needed to support Phase 1 and Phase 2 clinical studies of botanical products still depends on the extent of previous human use, and if currently lawfully marketed in the United States as a dietary supplement, initial clinical studies may still be allowed to proceed without further nonclinical testing. In the updated guidance, FDA has now further explained that regardless of whether the drug is currently lawfully marketed in the United States, if the anticipated exposure in the proposed clinical trials exceeds that in prior human use (e.g., higher doses or a longer duration), an additional nonclinical pharmacological/toxicological assessment is warranted to adequately address the difference between the prior human use and the proposed clinical trial.
Comments on the draft guidance can be submitted to the public docket through October 16, 2015 here.
*Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.
As we previously reported, FDA and FTC are reviewing their regulation of homeopathic drugs. In March 2015, FDA issued a notice requesting comments on the current use of homeopathic drugs, and that agency’s approach to regulation of the category. In June 2015, FTC announced a workshop in September to discuss advertising of over-the-counter (OTC) homeopathic products.
Last week, FTC staff announced that it has submitted a comment to FDA. The comment was approved by the Commission by a vote of 5-0. Not surprisingly, FTC staff takes the position that claims for homeopathic drugs must be supported by competent and reliable scientific evidence. The comment suggests that FTC believes that its position is compromised by FDA’s current conflicting policy that allows marketing of homeopathic drug products without proof of efficacy. FTC staff suggests that it has been “reluctant” to pursue action against homeopathic products because of this conflict.
FTC staff puts forward three possible approaches for FDA to resolve the conflict between FDA’s policy and FTC’s substantiation doctrine:
FDA discontinues its current policy and requires that homeopathic products meet the same standard as other conventional OTC drug products;
FDA removes the requirement for an indication for homeopathic drug products so that the inclusion of the indication becomes voluntary and, therefore, is no longer “sanctioned” by FDA but remains subject to FTC’s standard of competent and reliable scientific evidence;
FDA amends the current policy to require that the indication be supported by “competent and reliable scientific evidence.”
The FTC staff’s comment includes data from two studies – a focus group and copy test – to support its contention that consumers are confused about the nature of homeopathic products. These studies and their interpretation will undoubtedly be a topic of discussion at FTC’s September workshop.
The comment confirms that FTC is intent on holding homeopathic drug products to the same standard as conventional drug products. The question now is whether FDA will accept the comment’s recommendations in furtherance of that objective or if FDA will continue to recognize the uniqueness of homeopathic drug products.
We’ve all been told that consistency is a virtue and some recent developments have AbbVie’s consistency on display while that company questions FDA’s biosimilar labeling morality, or at least decision-making. In a citizen petition supplement recently submitted to FDA, AbbVie renewed its efforts to change FDA’s policies on biosimilar labeling by assailing the logic behind FDA’s reliance on the Purple Book in response to a Congressional inquiry, by citing FDA’s own recent statements in the Amarin off-label matter and by continuing to assert the needs of prescribing physicians to be fully informed about biosimilars.
AbbVie’s specific requests are that the labeling of all biosimilars contain “clear statement[s] that the product is a biosimilar, that the biosimilar is licensed for fewer than all the reference product's conditions of use (if applicable), … that the biosimilar's licensed conditions of use were based on extrapolation (if applicable), [and] that FDA has not determined that the biosimilar product is interchangeable with the reference product (if applicable).” AbbVie also asks for “[a] concise description of the pertinent data developed to support licensure of the biosimilar, along with information adequate to enable prescribers to distinguish data derived from studies of the biosimilar from data derived from studies of the reference product.”
The original AbbVie citizen petition was submitted by AbbVie in June in reaction to the Agency’s removal from a final guidance document on “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product” of requirements that the labeling of a biosimilar biological product indicate that it is biosimilar to a reference product, and also to call out whether or not it is interchangeable with a reference product, two requirements that did appear in the 2012 draft version of the document (see our previous posts here and here).
AbbVie’s supplement references FDA’s response to an April 30th letter from Lamar Alexander and eight other Republican senators that questioned FDA’s decision to make the labeling of the first approved biosimilar, Sandoz Inc.'s Zarxio (filgrastim-sndz) almost identical to that of its reference product, Amgen Inc.'s Neupogen (filgrastim). The letter noted that Zarxio’s labeling “does not even include the word "biosimilar," which could further increase consumer confusion about how this product relates to the reference biologic.”
AbbVie zeroes in on FDA’s June 22 response to that letter, in which FDA stated that information about biosimilarity and interchangeability did not need to be included in biosimilar labeling because it was in the Purple Book: “The Purple Book enables a user to see whether a biological product has been determined by FDA to be biosimilar to, or interchangeable with, a reference product.” The Purple Book is the biologics analog to the Orange Book drug listing guide (see our post here). The Purple Book lists licensed biological products and contains information about reference product exclusivity, biosimilarity and interchangeability.
AbbVie notes that FDA also states in the June 22nd letter that "health care professionals should have product labeling that includes the essential scientific information necessary to make informed prescribing decisions for their patients," while the 2012 draft guidance said that information "regarding biosimilarity or interchangeability" is needed for informed prescribing decisions. This leads AbbVie to conclude that “The proposition that the Purple Book could cure a material omission in the labeling for a biosimilar is indefensible, FDA regulations explicitly state that prescription drug labeling found "on or within the package" (in other words, the package insert) must contain all of the information that prescribers require to administer the drug to their patients safely and effectively. For decades, FDA, industry, and the medical profession have all understood that package inserts must provide ‘full disclosure.’ If information is necessary for prescribing decisions, it must appear in the package insert. That is a foundational principle of FDA law—and one that FDA fought long and hard to vindicate.”
AbbVie also notes two other pieces of information that are not in the Purple Book but are needed to make informed prescribing decisions- information about the indications and routes of administration for which a biosimilar has been found to be biosimilar to its reference product. AbbVie asserts that this information will become increasingly important as more biosimilars are approved and the market evolves into “a highly complicated landscape of products with varying scopes of biosimilarity and interchangeability," and concludes that “The only way to convey that nuanced information to prescribers is through product-specific disclosures in the labeling of each biosimilar.”
In a separate section of the citizen petition, AbbVie cites FDA’s own statements in support of AbbVie’s position that biosimilar labeling should make clear which supporting clinical studies were conducted by the reference sponsor and which by the biosimilar sponsor. In the Amarin case, which involves a challenge to FDA’s regulation of off-label statements by drug companies, (see our post here), Amarin included a letter to it from Janet Woodcock, the Director of FDA’s Center for Drug Evaluation and Research, concerning what Amarin could and could not say, in FDA’s opinion, about its Vascepa (isocapent ethyl) product. Dr. Woodcock states: “[A] communication should not state or imply that studies conducted using products other than Vascepa were studies of Vascepa itself …. Rather, to ensure that your communications are not false or misleading, we recommend that they expressly disclose when studies were conducted using products other than Vascepa (in particular when those other products contain active ingredients that are different from the isocapent ethyl—an ester of EPA—that is contained in Vascepa) and that the results of the studies may not be applicable to Vascepa.
AbbVie also quotes the government brief in the Amarin case as saying that it would be "misleading for Amarin to suggest or imply … that studies using products other than Vascepa were studies of Vascepa itself."
AbbVie points out that these FDA statements stand in contrast to FDA's current approach to biosimilar labeling, at least in the case of Zarxio. “As explained in the Petition, a biosimilar and its reference product are – like Vascepa and related products — similar, but not the same active ingredients or products. But, the labeling that FDA approved for Zarxio relies entirely on studies involving a different product without acknowledging that the studies were not conducted with Zarxio. As both FDA and DOJ have now represented to a federal court, a failure to "expressly disclose when studies were conducted using [other] products" is misleading.”
A third section of the AbbVie supplement concerns growing “stakeholder support for more transparent biosimilar labeling.” AbbVie' cites three recent letters to FDA’s Acting Commissioner, an important conference on Capitol Hill, additional survey evidence, and a recent statement from the biosimilar industry.
Our two earlier posts on this topic analogized the issue of whether biosimilar labeling should or should not indicate that a product is a biosimilar to the affixing of a scarlet letter to Hester Prynne in Hawthorne’s classic novel. Having completed a blog trilogy and seeing no end in sight for the issue of biosimilar labeling issues, we may need to move on to new references – perhaps Fast and Furious 8 will suffice.
On July 24, 2015, FDA issued a proposed rule amending the Agency’s previously issue proposed rule on Accreditation of Third-Party Auditors/Certification Bodies (see our prior posts here and here) and establishing user fees for the Agency’s proposed accreditation program (hereinafter “User Fee Proposed Rule”). On the same day and in a related publication, FDA issued a draft guidance for Model Accreditation Standards (hereinafter “Draft Guidance”).
On their face, the User Fee Proposed Rule and the Draft Guidance might seem to be of interest only to those who might participate in the Voluntary Qualified Importer Program (see our prior post here). However, FDA’s accreditation standards can be expected to influence the content of similar standards currently used by third-party auditors and their certifiers. In addition, because the accreditation program set up by FDA might not be revenue neutral, administration of the program could divert resources from other program areas – one of the several issues on which the Agency has requested comment. Comments on both the User Fee Proposed Rule and the Draft Guidance are due October 7, 2015. Below we provide summaries of both documents.
User Fee Proposed Rule.Section 808(c)(8) of the FDC Act (which was added by FSMA) requires FDA to establish a user fee program to set up and administer the Agency’s proposed accreditation program. FDA explains the costs associated with establishing and maintaining the accreditation program in the User Fee Proposed Rule in a Q&A format. The Questions are presented as follows: (1) Who would be subject to a user fee; (2) What user fees would be established; (3) How will FDA notify the public about the fee schedule; (4) When must the user fees be submitted; (5) What are the consequences for not paying a user fee on time; and (6) What are the possible exemptions?
(1) Who would be subject to a user fee?
Accreditation Bodies (ABs) and third-party auditors/certification bodies (CBs) would be subject to user fees. As presented in the proposed § 1.700, FDA identifies four main groups subject to a user fee:
ABs submitting applications or renewal applications for recognition in the third-party accreditation program;
Recognized ABs participating in the third-party accreditation program subject to FDA monitoring activities;
CBs submitting applications or renewal applications for direct accreditation; and
Accredited CBs (whether accredited by recognized ABs or by FDA through direct accreditation) participating in the third-party accreditation program subject to FDA monitoring activities.
(2) What user fees would be established?
The proposed language in § 1.705 establishes application fees and annual fees for ABs and CBs in the four categories listed in the above section “Who would be subject to a user fee?” FDA bases the costs for this proposed User fee program on other established User fee programs such as the Prescription Drug User Fee Act (PDUFA) and the Medical Device User Fee Act (MDUFA). These exiting User fee models show that every seven full-time federal employees (FTEs) who perform direct FDA work require three indirect and supporting FTEs. FDA calculates the base unit for the hourly fee rate of an FTE as $202. The base unit for the hourly fee rate of an FTE requiring foreign inspection travel is calculated at $305, and the hourly fee rate of an FTE requiring domestic inspection travel is $217.
In the User Fee Proposed Rule, FDA estimates the amount of time it will take to perform the functions necessary to establish and maintain the accreditation program. For example for FDA to accredit an AB applying for recognition, FDA estimates that it will take approximately 60 person-hours to review a submitted application, 48 person-hours to perform an onsite performance evaluation, and 45 person-hours to prepare a written report. Therefore, the total estimated average cost for FDA to review an application submitted by an AB is $35,850.
Using similar hourly estimate calculations, FDA provides user fee costs for the following functions:
AB Applying for Recognition, $ 35,850 (as discussed in the example)
AB Renewal Application, $18,853
CB Applying for Direct Accreditation from FDA, $35,850
CB Renewal Application, $26,930
Annual Fees for Recognized ABs, $7,928 over 5 years
Annual Fees for CBs Directly Accredited by FDA, $21,104
Annual Fees for CBs Accredited by a Recognized AB, $7,928 over 4 years
FDA states that the proposed fee structure for ABs and CBs is consistent with the current industry model. FDA is requesting comment on whether these fees should be paid as a flat fee or billed on an hourly basis. FDA proposes that the alternative approach of an hourly bill may incentivize ABs and CBs to submit higher quality applications, in other words, applications that are faster to review because of the substantive quality of the application. FDA also requests comment on a proposed flat fee, hourly fee, or whether a hybrid approach of flat fee and hourly would be appropriate.
(3) How will FDA notify the public about the fee schedule?
Under the proposed § 1.710, FDA intends to notify the public annually in the Federal Register prior to the beginning of the fiscal year for which the fee will apply. As an example, MDUFA fee rates were published on July 30, 2014 for fees beginning in 2015.
(4) When must the user fees be submitted?
Application and renewal fees will be submitted concurrently with an application or renewal. FDA will not review an application or renewal until the fee has been submitted. FDA also notes that user fees are not refundable. FDA tentatively concludes that this is the simplest approach to encourage high quality applications for ABs and CBs who have made a thoughtful decision to stay in the program for subsequent years.
(5) What are the consequences for not paying a user fee on time?
Annual fees will be paid within 30 days of the due date. After 30 days, the entity (AB or CB) will face suspension. After 90 days, the status of the entity will be revoked.
(6) What are the possible exemptions?
In the proposed rule, FDA does not provide an exemption or reduced fee for small businesses or entities. FDA is requesting comment on whether the final rule should account for small businesses by offering an exemption or fee reduction. FDA also proposes to charge user fees to foreign governments that are participating in the program as either an AB or CB. FDA requests comment on whether for trade reasons, or other reasons, they should consider a different approach.
Draft Guidance.Section 808(b)(2) of the FDC Act requires FDA to develop Model Accreditation Standards for recognized accreditation bodies (ABs). Pursuant to the statute, ABs shall use these model standards to qualify third-party auditors/certification bodies for accreditation. FDA noted that the Draft Guidance, “if finalized, will constitute the model accreditation standards referred to in section 808(b)(2) of the FD&C Act. In instances where this draft guidance provides different or more specific recommendations than are contained in the ISO/IEC 17021:2011, or conflicts with ISO/IEC 17021:2011, the recommendations of this guidance apply.” As is the case with any guidance, alternative approaches may be used to the extent that they meet the requirements of the statute, and in this case, the proposed rule.
Authority and responsibility: A third-party auditor/certification body must demonstrate the authority, as a governmental entity or through legally enforceable contractual rights, to exert any authority necessary to perform credible audits and certifications of the program. Specifically, a third-party auditor/certification body must have authority to (1) Review relevant records; (2) Conduct onsite audits; and (3) Suspend or withdraw certification for failure to comply with requirements of the program.
Capacity and competence: A third-party auditor/certification body must demonstrate that it has the adequate number of competent personnel to implement the program, as well as sufficient finances to operate in compliance with the program. Competent personnel must have relevant knowledge, skills, and experience to audit and assess compliance with FDA requirements under the program. Competency is based on education, industry experience, ongoing training, and professional development in the area of food safety. A third-party auditor/certification body should have a documented process to ensure that audit agents and managers meet the requirements for competency.
Conflicts of interest: A written program must be in place to prevent conflicts of interest between a third-party auditor/certification body and entities seeking certification. The written program should include measures for promoting independence, objectivity, and impartiality and procedures for effectively identifying, investigating, and resolving potential conflicts.
Quality assurance: A third-party auditor/certification body must implement a written program to conduct periodic self-assessment, implement corrective actions, and prepare a report written in English documenting the results of the self-assessment. FDA recommends that the third-party auditor/certification body establish procedures to conduct annual reviews for their self-assessment. The annual review would include areas of improvement for deficiencies, corrective action taken to address deficiencies, assessment of the effectiveness of the corrective action, an evaluation of personnel compliance with conflict of interest measures, and an identification of resource needs.
Records: A third-party auditor/certification body must maintain written procedures to establish, control, and retain records. The written procedures must include requirements that records must be written in English and retained electronically for four years. A third-party auditor/certification body should also have legal authority to grant FDA access to relevant records.
Regulatory audit reports: Within 45 days of completing a regulatory audit, an accredited auditor/certification body must prepare and submit a report written in English to FDA and to its accreditation body. In the case of direct accreditation, an accredited auditor/certification body would only submit the report to FDA. The audit report should include the name and address of the facility; the FDA food facility registration number, if applicable; the date and scope of the audit; the processes and foods observed during the audit; the identity of the person responsible for compliance at the facility; deficiencies observed, and the reasonable probability that the deficiency poses a serious adverse consequence to public health; corrective action for any deficiency; whether sampling or analysis was used at the facility; whether a food-safety recall has been issued in the last 2 years, and the reason for the recall; whether significant changes have been made to the facility, processes, or products in the last 2 years; and a list of any food or facility certifications issued to the entity in the last 2 years.
Miscellaneous: A third-party auditor/certification body must maintain an updated list of eligible entities on its website. For each eligible entity listed, the website should identify the duration and scope of the certification and the date the entity paid, or was reimbursed for, a fee associated with their certification. Also, a third-party auditor/certification body must issue food or facility certifications electronically in English.
*Admitted only in Maryland. Practicing under the supervision of the Firm.
The GAO was asked to review DEA registrants’ and others’ interactions with DEA. The GAO Report, released at the end of July examines the following: (1) To what extent registrants interact with DEA about their Controlled Substances Act (CSA) responsibilities and registrants’ perspectives on those interactions; (2) how state agencies and national associations interact with DEA; and, (3) stakeholders’ perspectives on how DEA enforcement actions have affected prescription drug abuse, diversion, and access to drugs for legitimate medical needs. To conduct its study, GAO administered web-based surveys to DEA-registered pharmacies, distributors, corporate offices of chain pharmacies, and practitioners. GAO interviewed DEA employees, individuals from 26 national associations including non-profit associations, and 16 government agencies in four states. Set forth below are some of the GAO’s conclusions.
Registrants’ Interactions with DEA. The Report notes that registrants vary in the extent of their interaction with DEA, and their awareness of DEA resources available to assist registrants in complying with the CSA and DEA’s implementing regulations. Page 19 of the Report notes that although DEA has made available various resources to assist registrants, such as guidance manuals and registration validation tools, registrants are not utilizing these resources because they are unaware they exist. (Report at 20). Registrants also want DEA to provide them with additional information. GAO indicated that distributors may have more communication with DEA given the fact that their renewal cycle is on an annual basis, while pharmacies and practitioners renew their DEA registrations every three-years, and are not subject to scheduled, cyclical regulatory investigations. Report at 17 (… although we note that DEA has been inspecting pharmacies on a more frequent basis than it did in the past).
The survey also showed that many registrants are not utilizing these DEA information resources. For example 70% of practitioners are not aware of the Practitioner’s Manual, and 53 percent of pharmacies are not aware of the Pharmacist’s Manual. Although the survey interestingly refers to “Know Your Customer” guidance for distributors, that information is not generally available, to our knowledge, on DEA’s website or otherwise; instead DEA provides the “Know Your Customer” guidance to distributors when it visits the registered location or otherwise meets with the registrant. GAO states that the “lack of awareness among registrants of DEA resources and conferences suggests that DEA may not have an adequate means of communicating with its registrant populations.” Report at 21.
The GAO also noted, surprisingly, that while DEA has promoted some industry conferences by email, DEA generally does not have current, valid email addresses for all of its registrants. GAO stated that DEA should “ensure that there are adequate means of communicating with stakeholders who may have a significant impact on the agency achieving its goals.” Report at 22. DEA officials responded that despite the lack of awareness noted by GAO, DEA indicated that they do not believe they need to “take any additional steps to improve communication or raise registrants’ awareness of the agency’s conferences and resources.” Id.
GAO concluded that given the state of industry unawareness of available resources, DEA “lacks assurances that registrants have sufficient information to understand and meet their CSA responsibilities.” Among the registrant groups that communicate with DEA, a common theme contained in the responses to the GAO survey was that they desired more and clearer communications from the Agency, as well as a more collaborative and proactive relationship. Pharmacies and distributers responded in particular that they wanted increased guidance and communications with the Agency.
Although State Agencies are Satisfied, Associations Want Improved Communications with the Agency. GAO described different communications that state agencies had with DEA, such as through joint enforcement activities, joint task forces, or otherwise working collaboratively to reduce diversion and abuse. State agencies reported general satisfaction with interactions with the Agency. However, twenty four national associations reported various levels of interactions with DEA, typically through meetings where they have hosted DEA at events to discuss regulations or trend data on prescription drug abuse.
Some associations noted that DEA interactions were insufficient in terms of both communication and collaboration. Five reported that as prescription drug abuse has increased, DEA has been less collaborative; officials from two organizations noted that DEA refused to meet with them to clarify issues related to their members’ CSA responsibilities. Report at 35. DEA responded that registrants should communicate directly with DEA to the extent they have questions related to “roles and responsibilities.” GAO noted that improved communications with and guidance for registrants may address associations’ concerns.
DEA’s Enforcement Actions may have Decreased Diversion and Abuse but Also May Have Limited Legitimate Access to Controlled Substances. Many of the survey responders reported that DEA’s actions have resulted in decreased drug abuse and diversion. However, over half of DEA registrants reported changing certain business practices as a result of DEA enforcement actions, or the business climate the actions have created. Many reported these changes limit access to prescription drugs for patients with legitimate medical needs.
As for enforcement actions, GAO reports that many stakeholders believe that the Agency’s enforcement actions have helped to decrease drug diversion and prescription drug abuse. A review of DEA enforcement actions from 2009 through 2013 showed that certain types of administrative enforcement actions — enforcement hearings, letters of admonition, and memoranda of agreement – increased across all registrant types. However, other administrative enforcement actions including orders to show cause and immediate suspension orders decreased. This shows that DEA’s enforcement efforts are being resolved by methods that involve increased cooperation between registrants and DEA. However, there is no available data to show the link between DEA enforcement actions and a decrease in diversion. Report at 38.
GAO recognized that some changes in business practices may help drug abuse and diversion, and cited specifically to pharmacy calls to verify prescriber prescriptions. The Report noted, though, that stricter distributor thresholds, or limits on the quantity of controlled substance ordering, which were influenced by DEA’s enforcement actions against distributors, limit supplies of controlled substances to those with legitimate medical needs. Of the national associations interviewed, more than half expressed concern that DEA’s enforcement actions have limited access to controlled substances that serve legitimate needs. DEA responded that enforcement actions do not have any bearing on access issues, and they have rarely heard about concerns with patient access to needed medications. GAO suggested that if access is an issue, then DEA and registrants should communicate more regularly, including with clearer guidance, which could mitigate registrants’ fears of DEA action.
GAO Recommendations.GAO concludes by making three recommendations – each in an effort to strengthen DEA’s communications, guidance, and interaction with registrants:
Identify and implement means of cost-effective, regular communication with distributor, pharmacy, and practitioner registrants, such as through listservs or web-based training.
Solicit input from distributors, or associations representing distributors, and develop additional guidance for distributors regarding their roles and responsibilities for suspicious orders monitoring and reporting.
Solicit input from pharmacists, or associations representing pharmacies and pharmacists, about updates and additions needed to existing guidance for pharmacists, and revise or issue guidance accordingly.
DEA raised concerns about the second recommendation. DEA specifically stated that it cannot provide more specific information to distributors about suspicious order monitoring systems because those systems differ depending on the distributor. DEA noted it can educate through proactive interaction during inspections. GAO responded that inspections do not provide registrants with a “neutral education setting in which to obtain a better understanding of their CSA roles and responsibilities.” GAO also stated that DEA could provide better written guidance for distributors. Note that those that represent distributors likely believe that such guidance is only appropriate to the extent that it is promulgated through notice and comment rulemaking; otherwise it is not necessarily widely disseminated, well known, or generally available; nor does it provide enforceable obligations among registrants.
With respect to the third conclusion concerning soliciting input from pharmacists, DEA responded that it would update its Pharmacist Manual to address rescheduling of hydrocodone and new disposal rules, but it did not comment whether it would provide any additional guidance to pharmacies. GAO stated that any update should address a pharmacist’s corresponding responsibility under CSA. Industry would likely agree with GAO’s recommendation, especially given the recent (and significant) enforcement actions) DEA has taken against chain and independent pharmacies based on corresponding responsibility violations.
Back in September 2013, when FDA’s Office of Generic Drugs (“OGD”) was gearing up for significant implementation of the Generic Drug User Fee Amendments of 2012 (“GDUFA”) (and the associated Performance Goals and Procedures), the Office issued a Manual of Policies and Procedures (“MAPP”) – MAPP 5200.3 – titled “Responding to Industry Inquiries with respect to Abbreviated New Drug Applications in the Office of Generic Drugs.” The MAPP was intended to clarify “the general principles for handling inquiries with respect to [ANDAs] from the authorized representative for an applicant with an ANDA submission (the authorized inquirer) by Regulatory Project Management (RPM) staff in [OGD].” At the time, this blogger, channeling concern from some in the generic drug industry, was pretty critical of the MAPP (see our previous post here). Our friend Bob Pollock (from Lachman Consultants) even turned a nice phrase, calling the document “The MaPP to Nowhere.” (Bob's post on the revised MAPP, which we discuss below, harkens back to that old post: “MaPP to Nowhere Now has Coordinates to Find the Treasure.”)
A LOT has happened in the nearly two years since FDA issued MAPP 5200.3. OGD has undegone a significant transformation, becoming a “Super Office” with a permanent Director and instituting a new organizational structure. OGD has churned out numerous new and revised policies and guidance documents (see our previous post here). In early 2014, OGD announced a massive and unprecedented undertaking (presumably to address, in part, an outpouring of concern about MAPP 5200.3) to conduct a complete inventory of all original ANDAs in OGD’s queue, and to provide each applicant with an update regarding the status of their ANDAs (see our previous posts here and here). Earlier this year, at the Generic Pharmaceutical Association’s (“GPhA’s”) annual meeting, OGD Director Kathleen (“Cook”) Uhl provided an update on the status of GDUFA implementation and included some positive numbers (see our previous post here). (Recent figures published by FDA show some progress with achieveing the goals of GDUFA, as does the latest GDUFA Performance Report. Indeed, we understand that OGD recently approved the first GDUFA cohort year 3 ANDA way ahead of the scheduled action date: ANDA 207955 for Tretinoin Gel, 0.05%, approved on August 13, 2015.) Dr. Uhl also announced at the GPhA meeting that OGD would be assigning Target Action Dates (“TADs”) to pre-year 3 cohort applications (i.e., ANDAs submitted in the year 1 cohort [Fiscal Year 2013] and year 2 cohort [Fiscal Year 2014] – the so-called “GDUFA donut hole”), and indicated that a revision to MAPP 5200.3 was in the works and would address industry concerns.
Earlier today, FDA announced the publication of a revised and renamed MAPP 5200.3. Titled “Communications with Industry with respect to pre-GDUFA Year Three Abbreviated New Drug Applications,” the revised MAPP, “[d]ue in part to stakeholder feedback,” “substantially expands and sets forth responsibilities and procedures for communications between generic drug program staff and Authorized Representatives concerning the review status of pre-Year 3 submissions.” Pre-Year 3 submissions include not only the GDUFA donut hole (i.e., applications not approved or withdrawn as of the close of business on September 30, 2014), but pre-GDUFA backlog submissions (i.e., applications not approved or withdrawn as of October 1, 2012). The Revised MAPP continues OGD’s emphasis on RPM empowerment and responsibility for ANDAs, but also promises a greater depth and improved frequency in communication with ANDA applicants.
In an email memo “To All Staff Working with ANDAs” (reprinted below), CDER Director Janet Woodcock, M.D., stated that OGD RPMs “will communicate Target Action Dates, periodically update applicants and/or respond to applicant queries concerning the review status of submissions, communicate when certain major deficiencies may be forthcoming, and provide certain advance notifications of regulatory correspondences.” These goals are stated in greater detail in the revised MAPP, first in a Background section:
Although GDUFA requires FDA to take action on 90% of the submissions in the pre-GDUFA backlog cohort by September 30, 2017, individual pre-Year 3 submissions lack goal dates. This makes it hard for applicants to plan product launches and conduct other business planning that affects generic drug availability. To facilitate launch planning – and help ensure public access to affordable, quality generic medicines at the earliest legally available date – we intend to provide information concerning the review status of pre-Year 3 submissions down to the discipline and sub-quality discipline levels. [(Emphasis in original)]
. . . and then in a Policy section:
Our policy is to provide prompt and accurate responses to any inquiry regarding review status from the Authorized Representative while maintaining appropriate confidentiality related to other stakeholders in the generic review process, including the existence of and information contained in other ANDAs and information contained in a referenced Drug Master File. Generally, inquiries should be responded to within two business days of receipt.
. . . . and then in a Responsibilities section with very specific responsibilities laid out for OGD Division of Project Management Discipline Project Managers, Division of Filing Review Project Managers, and (most importantly) OGD RPMs.
OGD RPMs bear the greatest responsibilities, being tasked with ensuring application flow, timely responding to applicant (authorized representative) inquiries, and communicating with applicants (including initial TADs and revised TADs, that a newly filed pre-year 3 submission – yes, there are still about 250 ANDAs for which a filing/receipt communication has not yet been sent – has been assigned to that RPM, and advance notice of Complete Response actions).
Of course, the proof is in the pudding. There will undoubtedly be some initial bumps in the road. In the long term, however, we’re hopeful that OGD follow-through on the policies and points articulated in revised MAPP 5200.3 will significantly enhance “the user experience” and provide the greater level of clarity the generic drug industry needs and craves.
To All Staff Working with ANDAs
I am pleased to announce the issuance of the revised, joint Office of Generic Drugs-Office of Pharmaceutical Quality MAPP 5200.3, “Communications with Industry with respect to pre-GDUFA Year 3 Abbreviated New Drug Applications” (available on FDA’s Web site []). It will substantially expand our communications with applicants concerning pre-GDUFA backlog, GDUFA Year 1 and GDUFA Year 2 submissions (collectively, “pre-Year 3 submissions”).
Although GDUFA requires us to act on 90% of the submissions in the pre-GDUFA backlog cohort by September 30, 2017, individual pre-Year 3 submissions lack GDUFA goal dates. This makes it hard for industry to plan product launches and conduct other business planning that affects generic drug availability. To facilitate launch planning, we will provide information concerning the review status of pre-Year 3 submissions down to the discipline and sub-quality discipline levels. This will help ensure that quality, affordable generic medicines reach the public at the earliest legally available date.
For example, OGD Regulatory Project Managers will communicate Target Action Dates, periodically update applicants and/or respond to applicant queries concerning the review status of submissions, communicate when certain major deficiencies may be forthcoming, and provide certain advance notifications of regulatory correspondences.
OGD Discipline Project Managers and OPQ Regulatory Business Process Managers will issue Informational Requests for their respective disciplines. Informational Requests are letters sent to request further information or clarification that is needed or would be helpful to allow completion of the discipline’s review. The purpose of these communications is to assure that FDA has all the information necessary to evaluate if the application is approvable or must receive a Complete Response Letter.
To facilitate meaningful communications, we are asking review staff members to refer all questions about the overall status of applications to the appropriate OGD Regulatory Project Manager.
We appreciate all of the ANDA discipline reviewers and project managers working together to expand communications with applicants. Implementing these changes will help us achieve a robust generic drug program.
It seems that hardly a week passes (and sometimes, hardly a day or two) without news of a new merger or acquisition in the pharmaceutical or biotechnology industries. Indeed, 2015 may be a record-breaking year for such deals (see here, here, and here). Whether we’re talking about generic-on-generic, brand-on-brand, or brand-on generic acquisitions, however, there are exclusivity considerations companies must keep in mind to avoid inadvertently losing (or triggering) exclusivity. We highlight a couple of those considerations below.
We’ll start on the generic drug 180-day exclusivity side of the fence, and, specifically, with the triggering event to start the 180-day period: commercial marketing. The statute, at FDC Act § 505(j)(5)(B)(iv)(4), provides that subject to the statutory forfeiture provisions, if an ANDA from a non-first applicant (i.e., a subsequent applicant) contains a Paragraph IV certification, approval of such ANDA “shall be made effective on the date that is 180 days after the date of the first commercial marketing of the drug (including the commercial marketing of the listed drug) by any first applicant.” This provision of the FDC Act was added by the 2003 Medicare Modernization Act (“MMA”) and incorporates FDA’s previous determination (Docket No. 2000P-1446) that commercial marketing of an authorized generic by a first-filer eligible for 180-day exclusivity triggers that exclusivity.
Back in 2012, FDA applied the Agency’s pre-MMA interpretation of the statute with respect to Teva’s claim to 180-day exclusivity for a generic version of Cephalon’s PROVIGIL (modafinil) Tablets, 100 mg and 200 mg. Teva had acquired Cephalon on October 14, 2011, and on March 20, 2012, Cephalon announced the launch of an authorized generic version of PROVIGIL by Teva. FDA determined that Teva’s commercial marketing of the PROVIGIL authorized generic triggered Teva’s 180-day exclusivity such that it would expire 180-days later on September 26, 2012 (see our previous post here).
But FDA could have determined that 180-day exclusivity had been triggered months before, on October 14, 2011 when Teva acquired Cephalon. It was at that time that “Teva immediately began marketing PROVIGIL under Cephalon’s NDA.” FDA laid out this option in a footnote to an April 4, 2012 Letter Decision:
We have considered finding that Teva’s marketing of PROVIGIL upon its acquisition of Cephalon triggered its 180-day exclusivity, and believe that there is a strong argument for finding so. We have refrained from adopting that interpretation in this case, however, because that exclusivity, if it were triggered by Teva’s acquisition of Cephalon, would expire on April 11, 2012 and, given the multiple uncertainties in this case, Teva had no notice that FDA considered it to be running. Because of the potential for collusion between NDA holders and captive first generics, and the subversion of the statutory scheme that could result, the agency may in the future provide guidance on the effect of such a relationship between NDA holder and first applicant upon any claim for 180-day exclusivity.
We’re not aware of any further guidance from FDA on this issue, or whether or not the Agency has applied this position in other circumstances, but it’s clearly an issue FDA has considered and believes is consistent with the law. With complex merger and acquisition deals, companies should not forget about this possibility . . . and ANDA applicants that might otherwise be blocked by 180-day exclusivity should also be aware of this FDA position in case it needs to be argued to FDA.
Moving on to biological products, we note a provision added to the PHS Act by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”). Specifically, PHS Act § 351(k)(7), which concerns Reference Product Exclusivity (“RPE”), includes certain “anti-evergreening” provisions. One of those provisions provides that the 12-year and 4-year RPE periods do not apply in the case of:
a subsequent application filed by the same sponsor or manufacturer of the biological product that is the reference product (or a licensor, predecessor in interest, or other related entity) for— (I) a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength; or (II) a modification to the structure of the biological product that does not result in a change in safety, purity, or potency. [(Emphasis added)]
In other words, for purposes of determining the start of the 12-year and 4-year RPE periods – i.e., the date of first licensure of a reference product – FDA must take into consideration corporate relationships between sponsors.
FDA provided insight on how the Agency intends to apply the “licensor, predecessor in interest, or other related entity” criterion in draft guidance issued in August 2014 (see our previous post here). FDA explained that:
With respect to 351(k)(7)(C), the Agency intends to interpret the term “predecessor in interest” as it does in the 3-year new drug product exclusivity context. It will consider any entity that the sponsor has taken over, merged with, or purchased, or that has granted the sponsor exclusive rights to market the biological product under the 351(a) application, or had exclusive rights to the data underlying that application to be a predecessor in interest for purposes of the first licensure provisions at section 351(k)(7)(C) of the PHS Act.
The Agency intends to consider a “licensor” under the BPCI Act to be any entity that has granted the sponsor a license to market the biological product, regardless of whether such license is exclusive. This term would include, for instance, entities that continue to retain rights to develop, manufacture, or market the biological product, and/or rights to intellectual property that covers the biological product.
Although the BPCI Act does not define the term “other related entity,” the Agency generally will consider an applicant to be a “related entity” in this context if (1) either entity owns, controls, or has the power to own or control the other entity (either directly or through one or more other entities) or (2) the entities are under common ownership or control. The Agency also may find that two parties are related entities for purposes of the BPCI Act if the entities are or were engaged in certain commercial collaborations relating to the development of the biological product(s) at issue. In analyzing whether the relationship between the parties would result in a finding that they were “other related entities,” the Agency expects to consider not only ownership and control of the investigational new drug application (IND) and the BLA, but also the level of collaboration between the entities during the development program as a whole.
What this seems to indicate is that RPE determinations may very well be fluid because of after-the-fact happenings between companies. Thus, FDA might determine, after granting two sponsors each a period of RPE for essentially the same biological product, that after a merger of the two sponsors (or the acquisition of one by the other), there is now, post-hoc, a different date of first licensure for the later approved product. Such a post-hoc decision could significantly alter the landscape for biosimilar competition and affect how companies strategize about the BPCIA’s “patent dance” procedures. Similarly, if a sponsor with RPE files a patent infringment lawsuit against a competitor developing essentially the same product, any settlement of the lawsuit that involves a license would presumably shorten the RPE of the competitor’s product.
As the merger and acquisition rage continues, buyers and sellers should take note of the potential effects on exclusivity: caveat emptor (and caveat venditor)!
In the latest Biologics Price Competition and Innovation Act of 2009 ("BPCIA") patent dance development, Amgen filed a lawsuit alleging that Apotex’s biosimilar of Neulasta (pegfilgrastim) infringes two Amgen patents, one about to expire composition of matter patent and one process patent expiring in 2031. This is the first lawsuit in which the parties at least initially engaged in the “intricate and carefully orchestrated set of information exchanges” known as the patent dance. But alas, this beautiful pas de deux has been marred, according to Amgen, by Apotex’s providing notification of commercial marketing prior to FDA approval of its Section 351(k) application, or Abbreviated Biologics License Applications ("ABLA"). And Amgen isn’t relying solely on its interpretation of the BPCIA – the judges of its last dance contest, also known as the Federal Circuit, have already ruled in Amgen v. Sandoz that notification of commercial marketing must come after approval (see our earlier post here). Although it is anticipated that an en banc or Supreme Court appeal will be granted in that case, while it stands, the Federal Circuit opinion should govern this case. But how that will play out in the current litigation remains to be seen, as it appears that Amgen has filed a complaint that partially follows the patent dance and partially does not.
Amgen filed suit against Apotex in the Southern District of Florida on August 6th, alleging infringement of U.S. Patent Nos. 8,952,138 and 5,824,784. Amgen states in the Complaint that Apotex and it began exchanging the information and statements required by the BPCIA in December 2014 and agreed that the two above-referenced patents would be included in patent dance litigation.
Amgen received a letter from Apotex purporting to be a notification of commercial marketing on April 17, 2015. Note that this date is roughly a month after the ruling by the U.S. District Court for the Northern District of California in Amgen v. Sandoz that notification of commercial marketing could occur before approval (the ruling that was subsequently reversed by the Federal Circuit).
Although Amgen doesn’t reveal at which stage the rest of the patent dance was at when it received the April 17th letter, from the timing it was likely somewhere in the middle. The Apotex ABLA was apparently accepted by FDA in December (see Apotex press release here) and patent dance exchanges with Amgen began that month. These patent dance exchanges take quite a bit of time – 20 days permitted for Apotex to supply the ABLA to Amgen, 60 days for Amgen to provide a patent list, 60 days for Apotex to supply its own patent list, 60 days for Amgen to respond, an unspecified amount of time for good faith negotiations on which patents to litigate over (agreed to here, at least according to Amgen), and then 30 days for Amgen to bring a lawsuit.
Amgen thus appears have allowed the patent dance to proceed otherwise unimpeded after it received the April 17th notification of commercial marketing. Nothing in the complaint indicates that Amgen told Apotex upon receipt of the letter that it was ineffective or otherwise took steps to stop the patent dance. But with the Federal Circuit opinion now in hand, Amgen appears to be hedging its bets, filing a Complaint that acts as if the patent dance is and is not still on. In other words, the complaint asks for both findings of infringement under the BPCIA patent dance (artificial acts of infringement of both patents by virtue of the filing of the ABLA) and for declaratory judgements outside of the patent dance. Amgen makes two distinct declaratory judgment requests: (1) that the court declare that Apotex will infringe the later to expire process patent (No. 8,952,138) if it manufactures, uses, offers to sell, sells or imports its pegfilgrastim product; and (2) that the court declare that Apotex’s April 17th letter is not effective notice of commercial marketing and that the Court declare that Apotex will violate 42 U.S.C. § 262(l)(8)(A) by not providing Amgen with a notice after its ABLA is approved and at least 180 days before marketing commences. Amgen also asks that the court to enjoin Apotex from taking these actions.
It will be fascinating to see how Apotex responds to the nimble steps taken by Amgen, and how this case will change in reaction to possible further developments in Amgen v. Sandoz. And with Neulasta ringing up about $4.6B of annual sales in 2014, we can be pretty certain that we will see some more interesting positions taken in this litigation, and that the FDA Law Blog will find more dance puns to use to comment upon them. According to Big Molecule Watch Blog, the case has been scheduled for a two-week trial beginning on July 11, 2016. Meanwhile, the user fee date for the Apotex product should be sometime this month, although the absence of notice of an advisory committee meeting to review the application suggests that approval may not be imminent.
