Source: http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2016/07/index.html
Timestamp: 2017-03-26 22:41:58
Document Index: 403291571

Matched Legal Cases: ['§ 505', '§ 314', '§ 505', '§ 505', '§ 505', '§ 314', '§ 505', '§ 316', 'arty 510']

FDA Law Blog: July 2016
FDA Prevails in Otsuka Challenge to Scope of ABILIFY 3-Year Exclusivity, Leaving Intact ARISTADA 505(b)(2) NDA Approval
By Kurt R. Karst – Late last week, Judge Ketanji Brown Jackson of the U.S. District Court for the District of Columbia issued a 57-page Memorandum Opinion handing FDA a victory on the scope of 3-year new clinical investigation exclusivity. The decision came in a case initiated last October when Otsuka Pharmaceutical Development & Commercialization, Inc. and Otsuka Pharmaceuticals Co., Ltd. (collectively “Otsuka”) filed a Complaint challenging FDA’s October 5, 2015 denial of a Citizen Petition (Docket No. FDA-2015-P-2482) submitted by Otsuka and FDA’s approval of Alkermes plc’s (“Alkermes”) 505(b)(2) NDA 207533 for ARISTADA (aripiprazole lauroxil) Extended-release Injectable Suspension notwithstanding unexpired 3-year exclusivity applicable to Otsuka’s ABILIFY MAINTENA (aripiprazole) for Extended-release Injectable Suspension, for Intramuscular Injection (NDA 202971). ARISTADA is a prodrug of N-hydroxymethyl aripiprazole (and which N-hydroxymethyl aripiprazole is a prodrug of aripiprazole) that FDA approved for the treatment of schizophrenia – the same use for which ABILIFY is approved – and for which a period of 5-year New Chemical Entity Exclusivity was awarded. In ruling for FDA (and intervenor Alkermes), Judge Jackson granted Motions for Summary Judgment filed by FDA and Alkermes (here and here), and denied Otsuka’s Motion for Summary Judgment (here).
As we previously reported (see our previous posts here and here), Otsuka alleged in its Complaint that FDA violated the FDC Act’s 3-year exclusivity provisions (FDC Act § 505(c)(3)(E)(iii) and (iv), and referred to as “romanette iii” and “romanette iv” in the court’s ruling), the Agency’s regulation governing 3-year exclusivity (21 C.F.R. §§ 314.108(b)(4) and (5)), and the Administrative Procedure Act (“APA”) in approving ARISTADA. All three allegations boil down to a single issue, as the court noted:
What is at issue in the instant case is the scope of the exclusivities that were conferred to Abilify Maintena and its supplement by statute. . . . In essence, Otsuka maintains that the FDA was plainly prohibited from approving Alkermes’s drug Aristada during the relevant time period, and thus the agency’s authorization of the marketing of Aristada was arbitrary, capricious, and in violation of the law, because the three-year periods of marketing exclusivity that Abilify Maintena and its supplement received under romanettes iii and iv (and their accompanying regulations) were broad enough to block the approval of subsequent drug applications that have the same “conditions of approval.” But the FDA has taken the position that the exclusivity provisions in the FDCA and the agency’s regulations only prohibit approval of a subsequent new drug application that pertains to a drug that has the same active moiety as the drug that received exclusivity, regardless of any overlap with respect to the conditions of approval, and so, the FDA argues, because Aristada and Abilify Maintena have different active moieties, the agency was permitted to approve the Aristada NDA within Abilify Maintena’s exclusivity periods. [(emphasis in original)]
Applying the familiar deference principles articulated by the U.S. Supreme Court in Chevron, U.S.A., Inc. v. Natural Resources Defense Council, Inc., 467 U.S. 837 (1984), and Auer v. Robbins, 519 U.S. 452 (1997), Judge Jackson came down on the side of FDA and Alkermes for each allegation:
First, the Court concludes that the FDCA’s terms do not unambiguously preclude the FDA from viewing the exclusivity bar as pertaining only to drugs that contain the same active moiety as the drug with exclusivity, and, in fact, the Court finds that the FDA’s interpretation of the FDCA’s exclusivity provisions is entirely reasonable. Furthermore, to the extent that the FDA reads its own implementing regulations in the same way as it has interpreted the pertinent statutory provisions, this Court concludes that the agency’s reading is not plainly erroneous and is entitled to deference. In this same vein, the Court also finds that the agency’s resolution of the regulation’s ambiguity through its active-moiety interpretation is not a “de facto” rulemaking, as Otsuka argues. Consequently, the summary judgment motions that the FDA and Alkermes have submitted must be granted; Otsuka’s motion for summary judgment must be denied; and Otsuka’s claims against the FDA will be dismissed.
Analyzing each allegation separately, Judge Jackson took great pains to parse out the so-called “eligibility” and “bar” clauses of the 3-year exclusivity provisions at FDC Act §§ 505(c)(3)(E)(iii) and (iv). Finding that the provisions are susceptible to “multiple plausible interpretations,” and thus ambiguous with respect to whether or not 3-year exclusivity blocks the approval of a 505(b)(2) NDA for a drug product containing a different active moiety for the same condition of approval as the drug product protected by 3-year exclusivity, Judge Jackson eventually moved on to Chevron Step Two. There, Judge Jackson ruled that the text of FDC Act § 505(c)(3)(E)(iii) (and later FDC Act § 505(c)(3)(E)(iv)) permits FDA’s “active moiety” interpretation, and that FDA has provided a cogent explanation that is supported by the goals of the FDC Act. [I]t makes eminent sense for the FDA to conclude that the scope of the three-year-exclusivity benefit should relate to the particular drug substance that was studied in order to give rise to exclusivity in the first place; indeed, to find otherwise would upset the “careful balance” that Congress struck in the Hatch-Waxman Amendments insofar as it would seemingly permit a drug manufacturer who made investments related to one particular drug substance to prevent the marketing of other drug products and substances that might be safe and effective as treatments for the same or similar conditions. Nothing in the statutory scheme suggests that Congress intended that result, and in fact, it appears that Congress strongly desired to affect the drug market in precisely the opposite manner. Thus, an agency interpretation that views romanette iii’s exclusivity as only extending to second-in-time applications for the marketing of drugs that are, in essence, the same as the drug that was previously studied (i.e., those that have the same active moiety) is entirely consistent with the way the statutory scheme was intended to operate and accords fully with the purposes animating Hatch-Waxman. [(emphasis in original; internal citation omitted)]
Similarly, Judge Jackson found that FDA’s interpretation of the Agency’s 3-year exclusivity regulations at 21 C.F.R. §§ 314.108(b)(4) and (5), which largely mirror the text of FDC Act §§ 505(c)(3)(E)(iii) and (iv), are not plainly erroneous or inconsistent with the text of those regulations.
[T]he regulations clearly permit the agency to employ the same reasoning that it applies when it interprets the statute, which means that “the conditions of approval of the original application” language is permissibly viewed as, in effect, incorporating the nature of the drug in the original application itself. . . . All that the Court has said before with respect to its analysis of romanettes iii and iv applies and leads inexorably to the conclusion that the FDA has not committed plain error or acted inconsistently with its regulations, and indeed, the fact that these regulations involve “a complex and highly technical regulatory program, in which the identification and classification of relevant criteria necessarily require significant expertise and entail the exercise of judgment grounded in policy concerns” makes deference to the FDA’s interpretation “all the more warranted[.]” These ambiguous regulations do not preclude the conclusion that an active-moiety overlap is needed in order for a second-in-time application to be “for” the “conditions of approval” of an earlier NDA regarding a drug, or “for” a “change approved” in a supplement regarding a drug with exclusivity. [(internal citation omitted)]
Having ruled for FDA on Otsuka’s first two allegations, it was relatively easy for Judge Jackson to dispense with the third allegation. (In fact, Judge Jackson wrote that the “final claim can be resolved in mercifully short order.”) “[T]his Court’s prior rejection of Otsuka’s argument that the three-year exclusivity regulations have an unambiguous meaning that foreclosed the FDA’s “active moiety” interpretation and consequent approval of Aristada, also compels the rejection of Otsuka’s contention that the FDA transgressed the APA by improperly ‘amending’ an unambiguous regulation,” wrote Judge Jackson. As we’ve noted before, disputes concerning the metes and bounds of 3-year exclusivity have been plentiful over the past few years. And we may very well see more in the months and years ahead as the countours of the statutory 3-year exclusivity provisions are further elucidated through approvals, exclusivity determinations (particularly in the context of abuse-deterrent drug products), and in guidance that FDA is expected to issue, tentatively titled “Three-Year Exclusivity Determinations for Drug Products.” And while there may be plenty to argue about in the shades of gray, Judge Jackson’s opinion seems to be one clear bookend on the scope of 3-year exclusivity: in order for 3-year exclusivity to have an effect against a competitor’s product, both drug products must share the same conditions of approval and share an active moiety.
Posted at 05:52 PM in Hatch-Waxman, Prescription Drugs and Biologics | Permalink
The UDI rule was finalized in September 2013, and FDA accredited the first issuing agency soon thereafter. Since then, the issuing agencies have been working with labelers to issue UDIs for Class III and Class II devices. Though FDA does not state in the draft guidance that it is aware of the issuance of any non-compliant UDIs, that seems to be the implication of the draft guidance. For example, the draft guidance states: “It is critical that each FDA-accredited issuing agency develop and operate a system for the assignment of UDIs that allow labelers to confidently use the FDA-accredited issuing agency’s system to develop UDIs that are compliance with the UDI labeling requirements . . . . Therefore, the FDA-accredited issuing agencies’ systems for issuing UDIs should align with the UDI labeling requirements.”
For a labeler that has already obtained a UDI from an accredited issuing agency, this language in the draft guidance may cause some concern, as it seems to imply that the issuing agencies have in fact been issuing UDIs that are not in compliance with the UDI labeling requirements. Yet the draft guidance does not advise labelers to confirm compliance of the issued UDIs, nor does it explicitly state that FDA is aware the issuance of non-compliant UDIs. If FDA is aware of the such UDIs, it should so state, and should provide more direct guidance to labelers and issuing agencies about steps to take the remedy the non-compliance.
The draft guidance also introduces new concepts not discussed in the rule or in guidance issued by FDA since the rule was finalized. It is not clear if these concepts, such as “data delimiter” and “UDI carrier,” were already being used by the issuing agencies, or if they are entirely new ways of developing the form and content of a UDI. It may also be that these concepts are now being introduced as a means of remedying whatever concerns FDA may have about compliance of the UDIs that have been issued. The draft guidance simply does not say.
FDA should more explicitly discuss why the guidance was issued at this late stage, concerns about potential non-compliant UDIs, and why new terms are being introduced now. If labelers obtained non-compliant UDIs from issuing agencies, FDA should allow a grace period to come into compliance, and should not take enforcement actions against labelers that acted in good faith in obtaining a UDI.
Posted at 04:36 AM in Medical Devices | Permalink
“ACE” Is Here. Are You Ready? How FDA Intends to Help
By Dara K. Levy –
The Automated Commercial Environment (ACE), which went into effect for FDA-regulated products on June 15, 2016 (after several delays), is an electronic system operated by Customs and intended to automate import processing and expedite reviews for electronic import filings. It replaces the Automated Commercial System (ACS) and is intended to implement the “single window” electronic submission requirement outlined in the International Trade Data System (ITDS) for import and export data provided to the U.S. Government. The ITDS is “a partnership of government agencies committed to the modernization and facilitation of international trade.” In February 2014, President Obama issued Executive Order 13659, Streamlining the Export/Import Process for America’s Businesses, which required this “single window” to go into effect by December 31, 2016 for all partner government agencies involved with the ITDS, which includes FDA.
The purpose of ACE, generally, is to improve the information flow to the U.S. Government about imports and exports and, ultimately, ease the burden on importers/exporters by reducing redundant submissions required by the different agencies that may review the entries. As importers of FDA-regulated products already know, Customs may often release goods only for those goods to be held for substantial periods of time by FDA while it reviews entry information submitted. FDA has acknowledged that the ACS system had allowed for incomplete and inaccurate data to be transmitted to FDA, which then required FDA to manually review entry information. FDA estimates that it took approximately 28 hours for FDA to ultimately release an entry when it conducted a manual review under the legacy ACS system. Not surprisingly, when complete and accurate information was submitted in ACS, and an automated review was sufficient, the release time was significantly quicker, taking approximately 24 minutes. FDA has estimated that with the implementation of ACE, and inclusion of the required (and optional) data elements, manual reviews of information are completed over 30% faster than previously with ACS. The expectation is that review times will only improve. Ultimately, the goal is to prioritize FDA resources for products that represent a greater public health risk, while automating the release of lower risk products.
On July 1, 2016, FDA published a proposed rule to establish certain data requirements for FDA-regulated import entries electronically filed in ACE. Because ACE has already been implemented, much of the proposed rule is practically in effect. FDA has confirmed that all but four ACE-required elements were previously captured in the legacy ACS system. The four new elements include the following: 1) name, telephone number, and email address for one of the persons related to the importation of the product, which may include the manufacturer, shipper, importer of record, or Deliver to Party; 2) a telephone number and email address for the importer of record; 3) name and address of the ACE filer; and 4) brand name for tobacco products.
Where things may be different with ACE is in the level of detail that is now being requested as “optional” submission information. FDA is strongly encouraging ACE filers to include certain “optional” information that will better enable FDA to make automatic admissibility determinations. FDA is seeking comments on the advantages, disadvantages, and feasibility of requiring the submission of data elements currently identified as “optional,” such as the approval or clearance status of the product and intended use. Comments are due August 30, 2016.
FDA has implemented a number of outreach programs to assist industry with the transition to ACE. In addition to webinars, FDA has implemented the FDA ACE Support Center, staffed 24/7 and available to answer questions regarding the FDA Supplemental Guide, required data elements, and general ACE submissions. FDA is also prioritizing assistance to industry through “Production Calls.” A production call is a “meeting between the FDA, the entry filer and the entry filer’s software vendor (preferably) to walk through an entry that is being submitted via ACE. These production calls allow FDA and the entry filer to talk about the entry submission in real time.” While not mandatory, FDA encourages these calls and, upon request, will assist with a filer’s first ACE submission. More information about ACE and FDA’s Facilitation of the ACE Transition can be found here and here.
Posted at 07:33 PM in Import/Export | Permalink
Striking the Right Balance – Comprehensive Addiction and Recovery Act of 2016
By John A. Gilbert Jr. & Alan M. Kirschenbaum –
On Friday, July 22, 2016, President Obama signed into law the Comprehensive Addiction and Recovery Act (“CARA” or “Act”) of 2016, which is intended to help reverse the serious prescription drug abuse trend in the United States. Although the Act’s primary objective is to address the serious problem of prescription drug abuse, CARA also includes several provisions related to pain management that reflect a recognition of the important need to treat pain. We hope that the implementation of CARA will strike the right balance between these two objectives so as to ensure a successful outcome on both fronts.
The following are some notable elements of the new law: The Act requires the Department of Health and Human Services (“HHS”) to convene a Pain Management Best Practices Inter-Agency Task Force. The goals of the Task Force are to update the best practices for pain management and prescribing pain drugs and to review medical alternatives to opioids. The Task Force is to include representatives of HHS, the Department of Defense (“DOD”), the Department of Veterans Affairs (“VA”), and the Office of National Drug Control Policy (“ONDCP”) as well as practitioners, pharmacists, and other experts. The Act also requires HHS, along with other agencies, to advance education and awareness of prescription drug abuse among providers and the public. The Act identifies specific issues to be addressed, including the link between heroin and prescription opioids and the dangers of mixing fentanyl and heroin.
A significant part of the law is directed at addressing the issue of opioid abuse at VA facilities by improving the Opioid Therapy Risk Report tool and generally improving the education and training on pain management and safe opioid prescribing practices. For example, the VA is required to designate a pain management team at each facility to coordinate pain management therapy for patients.
The Act also authorizes HHS to establish a grant program to support prescribing of opioid overdose reversal drugs such as naloxone. This program would be available to Federally qualified health centers, opioid treatment programs or other practitioners authorized to dispense narcotic drugs for office based treatment. HHS is also authorized to make grants available to states to implement programs for pharmacists to dispense an FDA approved drug or device for “emergency treatment of known or suspected opioid overdose, as appropriate, pursuant to a standing order.” CARA also provides for grants to states to allow first-responders to administer such drugs and for a GAO review of so-called state “Good Samaritan” laws that allow individuals to administer overdose drugs in emergency situations.
Section 705 of the Act removes a financial disincentive that currently discourages drug manufacturers from developing new abuse-deterrent formulations of pain medications. Under the Medicaid Drug Rebate Program, line extensions of existing oral dosage form innovator drugs may be subject to a higher Medicaid rebate than other newly introduced innovator drugs. (See p. 21 of our summary of CMS’s implementing regulation here.) The Act amends the Medicaid Rebate statute to specifically exclude a new abuse deterrent formulation from the definition of a “line extension” that may be subject to higher rebates.
CARA also amends the federal Controlled Substances Act to allow a pharmacist to partially fill a Schedule II controlled substance prescription based on the request of the prescriber or patient. The prior law and regulations allowed a partial fill of a Schedule II drug only where the pharmacy did not have enough to dispense the entire quantity prescribed. Under the new provisions, either the prescriber or patient can request that the prescription be partially filled at first. The remainder can then be dispensed within 30 days of the original prescription. The objective of this provision appears to be an attempt to limit the amount of pain medicine received by the patient to no more than necessary. However, the new provisions will also require more diligence on the part of pharmacists to ensure that they monitor dispensing, especially if the partial filling is directed by the practitioner rather than requested by the patient. In this case, the pharmacist may need to consult with the practitioner should the patient request to fill the remainder of the prescription.
The Act also authorizes nurse practitioners and physician’s assistants to administer, prescribe, and dispense narcotics in office-based opioid treatment programs. Previously, this practice was limited to physicians. It also authorizes HHS to increase the patient limit for office-based treatment from 30 to 100.
Finally, the Act contains provisions to expand the reporting requirements and access to state prescription drug monitoring programs by practitioners as well as law enforcement. This will likely not only increase access by practitioners to assist in treating patients, but also expand the use of monitoring programs as tool for law enforcement to investigate practitioners, pharmacies, and patients.
Posted at 08:37 PM in Controlled Substances, Drug Enforcement Administration | Permalink
The Third Time’s the Charm for RAVICTI and Orphan Drug Designation: Another “Greater Safety” Clinical Superiority Precedent
By Kurt R. Karst – We recently posted on an orphan drug clinical superiority precedent we came across: PURIXAN (mercaptopurine) Oral Suspension, 20 mg/mL, for the treatment of Acute Lymphoblastic Leukemia in pediatric patients. It’s the sixth “greater safety” orphan drug clincial superiority precedent we know of (see our scorecard of precedents here). Today we give you the seventh precedent, as promised in our previous post: Hyperion Therapeutics Inc.’s (“Hyperion’s”) RAVICTI (glycerol phenylbutyrate) Oral Liquid, 1.1 grams/mL, which FDA approved on February 1, 2013 under NDA 203284 “for use as a nitrogen-binding adjunctive therapy for chronic management of adult and pediatric patients ≥2 years of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone.”
We’ll spare you all of the legal background – you can refer to our previous posts (linked to above) for that – and cut right to the chase. . . .
Hyperion initially requested orphan drug designation of RAVICTI, which is also referred to as “GT4P,” in March 2005 for “maintenance treatment of patients with deficiencies in enzymes of the urea cycle.” But FDA’s Office of Orphan Products Development (“OOPD”) didn’t grant designation – at least not initially. FDA’s previous approvals of BUPHENYL (sodium phenylbutyrate) under NDA 020572 (Tablets; approved on May 13, 1996) and NDA 020573 (Powder; approved on April 30, 1996) for use “as adjunctive therapy in the chronic management of patients with urea cycle disorders” were an obstacle to obtaining orphan drug dersignation. Although BUPHENYL and RAVICTI contain different active ingredients, glycerol phenylbutyrate is an esterified prodrug of phenylbutyrate, and is considered by OOPD to be the same drug under FDA’s orphan drug regulations. As such, Hyperion needed to provide a plausible hypothesis of clinical superiority to obtain orphan drug designation. In September 2006, OOPD informed Hyperion that the company failed to provide a plausible hypothesis of clinical superiority to BUPHENYL under any of the three available bases (i.e., greater efficacy, greater safety, or a major contribution to patient care):
We find no reason to believe that GT4P may confer greater safety or greater effectiveness than Buphenyl in the treatment or urea cycle disorders. Moreover, we find a lack of objective evidence to support your claim that GT4P, at the proposed dosages, would have comparable safety and effectiveness profiles as those of Buphenyl. . . .
You indicate that GT4P is clinically superior to phenylbutyrate since it can be administered in smaller daily dosing volume, is odorless and tasteless, and lacks the inherent sodium load. At issue is whether these advantages, in light of the current lack of preclinical and/or clinical evidence showing that the drug is as safe and effective as Buphenyl, are sufficient for considering that GT4P makes a major contribution to patient care for purposes of orphan-drug designation under § 316.3(b)(3)(iii), or they just simply render the drug an acceptable alternative to Buphenyl. First, with respect to the daily dosing volume, while four teaspoons of liquid GT4P may be better received than 40 Buphenyl tablets, it is difficult to believe that they really represent a significant advantage over four tablespoons of Buphenyl powder per day. Second, while the sodium burden and the objectionable taste and odor of phenylbutyrate are obvious drawbacks, we find no evidence that these disadvantages prevent the use of phenylbutyrate in an extraordinary number of patients, nor is there any evidence to show that a substantial proportion of patients discontinue treatment as a result. Hence, it is not readily apparent that these advantages of GT4P, per se, rise to the level of a major contribution to patient care to be considered a different drug than Buphenyl for purposes of orphan-drug designation.
Therefore, for us to consider your request to designate GT4P on the basis of a major contribution to patient care, you should first demonstrate with reasonable certainty that GT4P, at the proposed dosages, would offer at least comparable safety and effectiveness profiles as those of Buphenyl, and that it would be well tolerated by most patients in chronic use. Second, you need to present clear and convincing evidence that Buphenyl, due to its taste, odor, and sodium load, cannot be used, or is so poorly tolerated that its effectiveness is significantly compromised, in a substantial number of patients with urea cycle disorders.
Hyperion got back to OOPD several months later, in May 2006, with new information and clinical superiority arguments. But OOPD shot Hyperion down for a second time, in October 2006, saying, among other things, that “no clinical evidence [supports] your suggestion that the currently recommended doses of Buphenyl produce too high a level of [phenylacetate] in UCD patients.”
Some time passed, and Hyperion eventually went back to OOPD (in December 2008) for a third time, but armed with new data and analyses. According to Hyperion:
HPN-100 is not just a re-formulation of sodium phenylbutyrate. It is a new chemical structure, a triglyceride that exhibits delayed release characteristics. It is a nearly odorless and tasteless, more concentrated drug (providing three 4-phenylbutyrate molecules for every mole of drug), which enables the overall drug volume to be reduced and eliminate the need for G-Tubes that are placed solely for drug administration. It will ease the comfort of drug administration thereby reducing the emotional/psychological trauma that patients/caregiver deal with on a daily basis due to drug administration issues. Because it is a triglyceride, it should the symptoms consistent with oral mucositis and the upper GI side effects patients struggle with on a regular basis due to BUPHENYL® (sodium phenylbutyrate). In addition HPN-100 removes the noxious excipient sodium. Finally, data suggests that has the potential to offer more effective nitrogen-scavenging and superior ammonia control compared to BUPHENYL.
Out of all of this, OOPD latched on to the last point above: sodium load. OOPD states in an April 2009 Memorandum:
The sponsor claims that HPN-100 is different than the approved product because it is more efficacious, safer, and a major contribution to patient care. However, the only salient aspect of the amendment that is relevant to the potential designation of HPN-100 for the maintenance treatment of patients with deficiencies in enzymes of the urea cycle is the difference in the sodium content of the approved product, Buphenyl, compared to HPN-100. The approved labelingfor Buphenyl states that each tablet contains 62 mg of sodium (corresponding to 124 mg of sodium per gram of sodium phenylbutyrate) and that Buphenyl powder contains 11.7 gm of sodium, corresponding to 125 mg of sodium per gram of sodium phenylbutyrate. The recommended total daily dose of Buphenyl is 9.9 to 13.0 g/M2/d in patients weighing more than 20 kg. For an average size adult (1.7M2), this means that a person would need to take as many as 44 tablets per day which would contain 2.728 g of sodium. This is a significant sodium load and in the Warnings section of the labeling for Buphenyl, it states that “Buphenyl should be used with great care, if at all, in patients with congestive heart failure or severe renal insufficiency, and in clinical states in which there is sodium retention with edema.” In contrast, HPN-100 contains no sodium. The current recommended daily allowance of sodium is less than 2.4 g per day. When dietary intake of sodium is added to the sodium intake from Buphenyl, a person could be taking over 5 gm of sodium every day.
As noted by the sponsor, there are no reports of the clinical effects of the high sodium content of Buphenyl in patients with urea cycle disorders. However, Buphenyl has been used to treat other diseases in which the sodium content of the drug adversely impacted patient health. . . . Although [reports provided by Hyperion] are not in patients with urea cycle disorders, the clinical effects attributed to the sodium content in Buphenyl highlight the risk associated with the drug. The risk of high sodium intake leading to hypertension and eventual heart disease is well recognized in the medical community. Therefore, HPN-100, with no sodium in the formulation, is safer than Buphenyl and should be considered a different drug for purposes of orphan designation.
Hyperion’s persistence paid off. FDA approved RAVICITI on February 1, 2013 and granted a period of orphan drug exclusivity that expires on February 1, 2020.
Posted at 08:04 PM in Orphan Drugs, Prescription Drugs and Biologics | Permalink
By McKenzie E. Cato* and Jeff N. Gibbs -
As we reported previously (see previous post here), FDA has issued two long-awaited draft guidances on next generation sequencing (NGS) diagnostic tests. The first, “Use of Standards in FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases,” provides recommendations for designing, developing, and validating NGS in vitro diagnostics (IVDs) and discusses the use of standards as part of the regulatory controls. The second, “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics,” describes how publicly available databases can be used as a source of valid scientific evidence to support the clinical validity of an NGS IVD. These topics have been extensively discussed already. NGS is playing an increasingly prominent role in research and diagnosis. Prior to releasing these draft guidances, FDA held three public meetings and released a discussion paper on regulation of and standards relating to NGS IVDs (see previous post). Further efforts by FDA on this front include the creation of “precisionFDA,” an online research and development portal “that allows for testing, piloting, and validating existing and new bioinformatics approaches to NGS processing.”
The key features of each draft guidance are outlined below.
Use of Standards in FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases
The scope of this draft guidance is limited to targeted and whole exome human DNA sequencing (WES) NGS-based tests for suspected germline diseases. The recommendations are not intended to apply to NGS-based tests for stand-alone diagnostic purposes, screening, microbial genome testing, risk prediction, cell-free DNA testing, fetal testing, pre-implantation embryo testing, tumor genome sequencing, RNA sequencing, or use as companion diagnostics. In other words, the proposal covers only a small subset of potential applications. Furthermore, this draft guidance addresses only analytical validity, not clinical validity. Both analytical and clinical validity are required to demonstrate a reasonable assurance of safety and effectiveness of an NGS-based test. (FDA has also just issued a draft guidance on co-development of companion diagnostics which stresses this point for diagnostics.) The few cleared NGS-based tests are single-gene, disease-specific, and targeted. Because FDA has not yet classified NGS-based tests with a broad intended use for suspected germline diseases, they are automatically classified into class III as a matter of law. However, FDA notes that it believes an NGS-based test for germline disease would be a suitable candidate for de novo classification, and encourages applicants to use the pre-submission process to discuss anticipated de novo requests. Since FDA cannot guarantee that any particular device will be granted de novo status, this is about as strong endorsement as FDA can give of the de novo pathway. The draft guidance states that if FDA were to classify NGS-based tests as class II in response to a de novo request, it would consider exempting the tests from premarket notification requirements. The factors FDA considers in determining whether a class II device may be exempt from premarket notification are outlined in a 1998 guidance. Once finalized, this guidance will supersede the 1998 guidance with respect to NGS-based tests for germline diseases.
FDA explains in the draft guidance that one way to show the analytical validation of an NGS-based test is through conformity to FDA-recognized standards or special controls. In order for a standard to be recognized by FDA, it should at a minimum include the design, development, and validation activities outlined in this draft guidance.
Test Design Considerations: Satisfying FDA’s data requirements will not be a trivial task. Test developers are advised to prospectively define and document the indications for use statement, the features necessary to address specific user needs, the acceptable specimen types, and the region(s) of the genome that will be tested. To demonstrate performance, FDA recommends that test developers define and document the test metrics, performance thresholds for the metrics, the degree to which interrogated regions that do not meet test run quality metrics can be included, the use of secondary procedures, and possible limitations to test performance.
In addition, FDA recommends that developers specify and document all test components, set technical specifications for each step of an NGS-based test, and document the limitations of each component for critical factors. The draft guidance identifies several specific test design considerations for the sequencing platform, controls and reference materials, and bioinformatics components.
Developers are advised to develop and document methods for each step of the test; procedures for using instruments, consumables, reagents, and supporting methods; any limitations for each step; and the type of sequencing that will be used. The draft guidance includes specific recommendations for sample preparation and input, multiplexing (i.e., simultaneous testing of multiple samples), library preparation and target enrichment, and follow-up procedures to be used when a test run fails.
Test Performance Characteristics: The draft guidance recommends the following performance metrics for analytical validation of NGS-based tests for germline diseases:
Accuracy: Demonstrate accuracy by measuring positive percent agreement, negative percent agreement, technical positive predictive value, and the rate of “no calls” or “invalid calls.”
Precision: Evaluate precision (i.e., reproducibility and repeatability) for both variant and wild type calls.
Limit of Detection: Establish and document the minimum and maximum amount of DNA that will enable the test to provide expected results in 95% of test runs with an acceptable rate of “no calls” or “invalid calls.”
Analytical Specificity: Document any interfering substances, the potential for cross-reactivity of known cross-reactive alleles and homologous regions, and methods to detect cross-contamination between samples.
Test Run Quality Metrics: Test developers are advised to establish and document performance thresholds for average and minimum depths of coverage, uniformity of coverage, and percentage of bases in the target region(s) above the minimum depth of coverage for the test. The draft guidance states that FDA will not recommend specific thresholds for coverage metrics. However, FDA indicates that thresholds should not be set below the levels specified in the draft guidance.
The draft guidance includes a list of factors for establishing test run metrics and performance thresholds for the following test elements: specimen quality, DNA quality and processing, sequence generation and base-calling, mapping or assembly metrics, and variant calling metrics.
General Recommendations for Performance Evaluation Studies: The draft guidance includes an extensive list of features that FDA recommends incorporating into performance evaluation studies. This list includes recommendations regarding performance test design and configuration, recommendations for evaluating NGS-based test accuracy, and recommendations for documenting the results of validation studies. If test developers deviate from, delete, or add to these recommendations, FDA requests that they provide a “detailed justification.” As always, companies that deviate from the “guidance” should do so thoughtfully and for non-trivial reasons.
Supplemental Procedures: The draft guidance recommends including any applicable supplemental procedures (i.e., procedures that are not a part of the main process for generating variant calls from input specimens) whose reflex use will be directed in the test’s instructions in design, development and validation activities, and documentation.
Variant Annotation and Filtering: Test developers are advised to select filtering algorithms appropriate for the indications for use, establish and document filtering thresholds, and document how and when filtering will be used. The draft guidance recommends documenting any filtering criteria and their purpose.
Presentation of Test Performance: The draft guidance provides a list of recommendations for the presentation of test performance and design. Of note, the draft guidance recommends providing public access to the test’s indications for use statement, limitations, and summary performance information “via a prominent link on the company website.” This, of course, is not a typical expectation for a device.
Test Reports: The draft guidance recommends that the following information be included in test reports: the relationship between reported variants and the clinical presentation of the patient, a description of genomic and chromosomal regions detected by the test, a summary of the results of performance studies, a “prominently-placed” list of pathogenic or actionable variants on the first page of the report, test limitations, and risk mitigation elements. One of the recurring issues in the Laboratory Developed Test debate has been the extent to which FDA could regulate test reports.
Modifications: Finally, the draft guidance addresses modifications to NGS-based tests. It states that, in order to stay within the scope of the guidance, any modifications to targeted and WES NGS-based tests should retain the intended use of aiding in the diagnosis of suspected germline diseases. FDA offers the following recommendations for sponsors when making modifications: document all modifications to the test; prepare a detailed standard operating procedure (SOP) for revalidation; conduct revalidation using a sufficient number of well-characterized samples; document the types of validation studies that will be conducted after modification; where appropriate, revalidate the test end-to-end, not just the modification; assess each modification separately and in aggregate; when adding new genes to an existing panel, evaluate test performance for the original genes on the panel; and include a procedure to account for updates to internal and external databases and their potential impact on clinical interpretation of variants. Undoubtedly questions will arise over the regulatory obligations, including the need for a new submission, when FDA germline tests are modified – which they will be.
Unlike the other draft guidance, this draft guidance addresses clinical validity, albeit in one specific manner. It describes FDA’s considerations in determining whether a publicly available genetic variant database can serve as a source of valid scientific evidence to support the clinical validity of an NGS-based test in a premarket submission and the process by which administrators of such databases can voluntarily apply to FDA for recognition. The draft guidance notes that, depending on the sufficiency of the evidence from genetic variant databases, FDA may determine that the submission of additional valid scientific evidence is not necessary. That, of course, would substantially facilitate an application that could use a database. The devil, though, is in the details.
Recommendations to Support Recognition of Genetic Variant Databases as Sources of Valid Scientific Evidence Supporting Clinical Validity of NGS Tests:
FDA believes that a genetic variant database which could serve as a source of valid scientific evidence to support clinical validity of a test would have the following characteristics:
Provide sufficient assurances regarding the quality of the source data;
Provide transparency regarding its data sources and operations;
Collect, store, and report data in compliance with all requirements regarding protected health information, patient privacy, research subject protections, and data security; and
House sequence information generated by validated methods.
The draft guidance recommends that genetic variant databases make sufficient information regarding data sources and SOPs publicly available. Asking that SOPs be made publicly available is unusual, and may not be well-received. The draft guidance further states that the SOPs should define how variant information is aggregated, curated, and interpreted. Database administrators are advised to have processes in place for assessing database stability and to back up the database on a regular basis. Additionally, the draft guidance recommends that database administrators use commonly accepted data formats.
To promote data quality, the draft guidance recommends that databases use consistent nomenclature that is widely accepted by the genomics community. The draft guidance also states that all variant data should be accompanied by metadata, including the number of laboratories or studies reporting the variant classification, the names of the laboratories that reported the variant, the name of the test used to detect the variant, variant characteristics, and details of the technical characteristics of the test used. The draft guidance recommends that database operations include methods to ensure that individual data points are not represented more than once.
The draft guidance recommends that all SOPs for curation and variant interpretation be publicly available. Additionally, FDA recommends that the SOPS include validated decisions matrices, such as those based on well-recognized professional guidelines. FDA recommends that databases define the types of evidence that personnel interpreting variants may use for an interpretation. The draft guidance states that assertions (i.e., assessments of a genotype-phenotype correlation for a particular variant) should be adequately supported and appropriate for the level of certainty and nature of the genotype-phenotype relationship. However, the draft guidance cautions that in order to be FDA-recognized, a genetic variant database should not include and recommendations regarding clinical treatment or diagnosis.
Database administrators are advised to ensure that all personnel who are interpreting variants have adequate training and expertise. The draft guidance also recommends that there be methods in place, such as proficiency testing, to make sure that personnel continue to maintain high quality standards over time. In order to be considered for FDA-recognition, database administrators should make efforts to minimize and make transparent any potential conflicts of interest regarding the database or its personnel. FDA’s proposal to provide guidance to database administrators represents an intriguing potential expansion of FDA’s reach to a new class of entities.
Genetic Variant Database Recognition Process:
The draft guidance states that FDA intends for the recognition process to involve three steps: (1) voluntary submission of detailed information about the database; (2) FDA review of genetic variant database policies and procedures for obtaining and maintaining data and making variant assertions; and (3) maintenance of FDA recognition of a database.
Database administrators who are seeking to have their variant assertions recognized by FDA as valid scientific evidence to support clinical validity of NGS-based tests can make a voluntary submission to FDA which demonstrates that the database conforms to the recommendations in the guidance. The draft guidance includes a list of the types of documents which can be included in this submission (e.g., policies, data preservation plans, validation studies for interpretation SOPs). The draft guidance states that, where appropriate, FDA may verify variant assertions to make sure they are supported and that the database is following its SOPs. FDA will treat these voluntary submissions as confidential prior to recognition. FDA intends to post on its website a list of all FDA-recognized genetic variant databases “and other relevant, public information about those databases.”
FDA stated that it plans to review FDA-recognized databases regularly to verify that they continue to follow their SOPs and the recommendations in this guidance. FDA will consider the following factors when evaluating whether a genetic variant database for NGS-based tests may maintain FDA recognition:
Processes should incorporate multiple lines of scientific evidence with appropriate weights.
Processes should use a tiered system of assertions and adequately describe the meanings of each tier.
Databases should implement a decision matrix based on validated SOPs or rigorous professional guidelines that incorporate details of the gene or disease evaluated.
Databases should include validations of the decision matrix.
Guidelines, decision matrices, and details supporting each variant’s interpretation should be publicly available.
FDA does not discuss what happens to applicants who are in the midst of the review process of the database they are relying upon to keep its recognition.
The draft guidance notes that FDA may consider using third parties to assist with genetic variant database recognition in the future, as it does with the third party 510(k) review program. This, too, is intriguing, because it would entail use of third party review beyond the statutorily enumerated categories.
In theory, the ability to use curated databases in lieu of clinical validity studies is appealing to would-be applicants. A separate question is whether undergoing FDA scrutiny will be sufficiently appealing to database administrators.
Posted at 05:39 PM in Medical Devices | Permalink
FTC Announces Settlement with Herbalife; Consent Decree Sets Parameters for a Legal Multilevel Marketing Business
By Riëtte van Laack – Last week, FTC announced a settlement agreement with Herbalife International of America Inc., Herbalife International, Inc. and Herbalife Ltd. (Herbalife) under which Herbalife is to pay 200 million dollars and restructure its business (see FTC press release here).
In the Complaint filed on the same day, FTC asserts that Herbalife deceived consumers into believing that they could earn substantial amounts of money selling Herbalife products. FTC claims that Herbalife was presented as a multilevel marketing (MLM) business opportunity. The advertising represented the opportunity as one in which participants could earn money through sale of dietary supplements and personal care products and recruiting new participants. However, according to FTC, Herbalife’s compensation structure was based primarily on participants recruiting others to join and purchase product, rather than on sale of products. Allegedly, Herbalife misrepresented the business opportunity as an opportunity to get substantial income. Yet, the FTC claimed that, in reality, the business was not about selling product; allegedly profit from retail sale of product was negligible. According to FTC, the small number of participants that made significant amounts of money did so not by retail sale of product but by recruiting large numbers of new members. Those new members would pay a fee, purchase training materials, and goods at wholesale price. Although led to believe otherwise, most of the distributors/members made little to no money through sale of product. FTC claimed that the compensation structure incentivized distributors to purchase (not sell) product and to recruit new participants apparently resulting in overrecruitment of participants and an oversupply of product, making it even more difficult for participants to sell product. According to FTC, there was no or limited possibility to make money from retail sales of the product. FTC obtained a permanent injunction that includes reorganization of Herbalife’s marketing structure (and associated contractual relationships), restitution, disgorgement etc. Herbalife settled for $200 million.
In particular, Herbalife must restructure its marketing system to comply with certain parameters laid out in the consent decree. The new marketing system may no longer primarily reward participants for recruiting distributors, but only for sale of products. The consent decree details the requirements for the new MLM program and compensation structure. In addition, it specifies that Herbalife is enjoined from making misrepresentations regarding business opportunities, such as the likelihood of earning substantial income and the amount that can be earned. Herbalife is also enjoined from advertising the business opportunity as likely to result in “lavish lifestyle.” For example, claims that participants can ‘quit [their] job,’ are ‘set for life,’ can ‘earn millions of dollars,’ and images showing expensive cars and other indicators of wealth are prohibited.
A third party compliance auditor will be appointed. For seven years, this compliance auditor has the “duty and responsibility to diligently and competently review, assess, and evaluate Defendants’ compliance with [various] provisions” of the consent decree and report its findings to FTC. In addition, Herbalife is subject to certain compliance reporting requirements.
Multilevel marketing is a popular business model in the dietary supplement industry. Any company involved in this type of business should review the complaint and consent decree and consider the structure of its own MLM business.
Posted at 04:50 PM in Advertising and Promotion (Federal Trade Commission), Dietary Supplements | Permalink
FDA Releases “Notice” Advising of a Change in Inspections of Pharmacies Compounding Drug Products within FDCA Section 503A: Let’s Watch What Happens Next.... By Karla L. Palmer –
FDA posted a “Notice” on July 12, 2016, advising compounding pharmacies regulated under Section 503A that, effective August 1, 2016, FDA is changing inspection procedures for Section 503A pharmacies (see Notice here). FDA announced that it now will make a “preliminary assessment” whether compounders are compounding in accordance with the conditions in Section 503A. If a FDA Form 483 is issued upon completion of the inspection, then FDA will not include those observations including a violation of FDA’s current good manufacturing practices (“cGMP”), unless (importantly), based on the investigator’s preliminary assessment, the pharmacy is operation outside the scope of Section 503A. In past inspections, FDA has more often than not inspected compounding pharmacies (deemed a “producer of sterile drug products”) in accordance with a cGMP standard used for drug manufacturers and from which (lawful) compounders are statutorily exempt. FDA has at times held a compounder to this standard because, for example, it (unlawfully) compounded preparations for office use, or not solely for individually identified patients. For other compounders, FDA determined that they were not exempt from cGMP for the circular reason that they may have engaged in compounding under allegedly insanitary or filthy conditions in violation of Section FDCA Sections 501(a)(1) and (a)(2) -- based on an inspection conducted pursuant to cGMP. For still other compounders, FDA would not articulate at the exit interview exactly what standard – USP<795>, USP<797>, cGMP or any other standard – it had relied on during the pharmacy inspection. FDA states that it is changing its inspection procedures based on “stakeholder input.” That “input” could be the position set forth in the 2017 House Agriculture Appropriations Committee Report (April 2016) related to inspections. The statement directed FDA not to inspect state licensed pharmacies under cGMP. The text of that directive is as follows: Drug Compounding Inspections.—The Committee understands that the FDA is interpreting provisions of Section 503A of the FDCA to inspect state-licensed compounding pharmacies under current Good Manufacturing Practices (cGMPs) instead of under the standards contained in the United States Pharmacopeial Convention (USP) for sterile and non-sterile pharmaceutical compounding or other applicable pharmacy inspection standards adopted by state law or regulation. The Committee reminds the FDA that compounding pharmacies are not drug manufacturers, but rather, are state licensed and regulated health care providers that are inspected by state boards of pharmacy pursuant to state laws and regulations that establish sterility and other standards for the pharmacies operating within their states. Compounding pharmacies are more appropriately inspected using USP standards or other pharmacy inspection standards adopted by state law or regulation in the state in which a pharmacy is licensed. Notwithstanding this directive, FDA states at page 2 of the Notice that, “Importantly,” drug compounders remain subject to all other FDCA provisions “that apply to conventional drug manufacturers. Because FDA “does not contain an exemption from the prohibition on insanitary conditions,” investigators will continue to include observations related to these conditions without regard to the preliminary assessment of the firm’s “status” under Section 503A. But what remains unclear from FDA’s Notice is whether FDA’s “preliminary assessment” of “insanitary conditions” itself will be pursuant to cGMP, USP, or standards otherwise applicable to a compounding pharmacy. It is similarly unclear exactly what standard, other than cGMP, FDA investigators will use for pharmacy inspections generally after August 1. For example, will FDA hold pharmacies to certain state board of pharmacy requirements, USP<795> and USP<797>, or another inspection standard? We are curiously awaiting the wave of FDA Form 483 observations issued after August 1, 2016 to see whether the changed inspection standard actually results in changes in FDA’s Form 483 observations issued to Section 503A pharmacies. Posted at 03:14 PM in Drug Development, Enforcement | Permalink
GMO Labeling Bill Is A Pen Stroke Away From Becoming Law: What Comes Next?
By Riette van Laack and Ricardo Carvajal –
On Thursday July 14, the House approved legislation authorizing USDA to establish and administer a National Bioengineered Food Disclosure Standard. The bill, S.764, was previously approved by the Senate. The bill had been promoted as an urgent and necessary compromise by its supporters. Upon enactment, it will immediately preempt any state GMO disclosure laws, thereby preventing a state-by-state patchwork of such requirements. Among the state laws preempted will be Vermont’s Act 120, which went in effect on July 1, 2016. The disclosure requirement will apply to many food products for human consumption, except for food served in restaurants or similar retail establishments. The disclosure requirement appears to apply broadly to food subject to FDA labeling requirements; there is no explicit exemption for subcategories of food such as dietary supplements and infant formula. The disclosure requirement will also apply to foods subject to FSIS labeling requirements if (1) the most predominant ingredient in the food is subject to FDA labeling requirements, or (2) the most predominant ingredient is broth, stock, water, or a similar solution, and the second most predominant ingredient is subject to FDA labeling requirements. Thus, products that contain meat, poultry, or egg products as the most predominant ingredient will not be subject to the disclosure requirement. Not surprisingly, this can be expected to result in anomalies familiar to anyone accustomed to navigating the dividing line between FDA and FSIS jurisdiction (e.g., a cheese pizza containing bioengineered ingredients may be required to bear a disclosure, whereas a similar pizza containing meat as the most predominant ingredient would not be required to bear the disclosure). Although FDA and USDA-FSIS are the two federal agencies that generally regulate mandatory labeling requirements for foods, the bill gives the USDA Agricultural Marketing Service (AMS) the responsibility for establishing the disclosure standard within 2 years of enactment. Among other things, AMS will be charged with determining the threshold of bioengineered content that triggers the disclosure requirement, establishing a process for determining whether a product is bioengineered, and defining “small food manufacturers” and “very small food manufacturers” (the latter would be exempt). The AMS regulations must provide various options for disclosure, including the use of a symbol denoting genetically engineered ingredients, a “quick response” (Q.R.) code that people with smartphones can scan to retrieve the information, and for certain labels, a 1-800 number. The regulations must also provide other reasonable disclosure options for food in small or very small packages. With respect to enforcement, the bill makes it a prohibited act to knowingly fail to make a required disclosure. Also, the bill requires a company subject to the disclosure requirement to keep records demonstrating compliance, and authorizes USDA to examine or audit those records. USDA must provide the company notice and an opportunity for a hearing on the results of any examination or audit, after which USDA must make public a summary of that examination or audit. Thus, companies that fail to comply can expect to have that failure made public. Also, the bill disclaims preemption of “any remedy created by a State or Federal statutory or common law right.” However, recalls are off the table; the bill makes clear that USDA has no authority to recall a food that does not provide a required disclosure. In comments to Congress, FDA and USDA put forward different interpretations of certain provisions in the bill. See FDA’s comments here and USDA’s comments here. For example, FDA commented that the definition of bioengineering seems to be limited to foods that include genetic material, and therefore would not apply to foods from which all such material has been removed, such as soybean oil. In apparent disagreement – but without explanation – USDA stated that the definition authorizes the inclusion in the national disclosure program “all of the commercially grown GMO corn, soybeans, sugar, and canola crops used in food today and reviewed and approved by USDA’s Biotechnolgy Regulatory Service.” USDA also asserted that the definition authorizes inclusion in the national disclosure program of “products of certain gene editing techniques,” including “novel gene editing techniques such as CRISPR when the are used to produce plants or seeds with traits that could not be created with conventional breeding techniques.” However, FDA noted that “[i]t may be difficult to demonstrate that a particular modification could not be obtained through conventional breeding” (emphasis in original).
Once the bill becomes law, USDA will have the opportunity to put forward its interpretations in the context of rulemaking to establish the national disclosure standard. That rulemaking is likely to be contentious, given the tenor of the GMO labeling debate over the past couple of years. Thus, the Congressionally mandated 2-year timeframe for establishment of the disclosure standard could prove unduly optimistic. Posted at 01:27 PM in Foods and Dietary Supplements | Permalink
The Mutual Reliance Initiative was announced by FDA a couple of years back. It has as its goal “…to increase…[FDA’s]…exchange, with the European Commission and the European Medicines Agency, of information that is critical to making decisions that protect our public health.” What this cryptic statement is actually describing is FDA’s interest in exploring the possibility of relying on Europe’s inspections of EU drug facilities so that the agency will not have to inspect these facilities themselves, in the hope of economizing a significant fraction of its inspection budget. According to Howard Sklamberg, FDA’s Deputy Commissioner for Global Regulatory Operations and Policy, “…we cannot be the inspectors for the world. Hence, we need to effectively direct our resources in a risk-based manner as we grapple with this tremendous volume of imported goods.”
Posted at 04:34 PM in cGMP Compliance | Permalink
FDA SOT Colloquium Explores Determination of Adversity in Food Chemical Safety Evaluations
HP&M’s Frank Sasinowski and Kurt Karst Highlight Regulatory Innovations in Neurotherapeutics at the ASENT 19th Annual Meeting 180-Day Exclusivity Tracker