Articles Posted in Bioequivalence

FDA.bmpFDA issued a draft guidance Wednesday that provides its recommendations for generic-drug makers seeking to show bioequivalence to a reference listed drug. The document–Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA–does not represent a significant change or shift in FDA policy/opinion, but it covers many approaches and revises and replaces parts of two existing FDA Guidances (see here and here). And, most notably perhaps, the document is a consolidation of many of FDA’s previous opinions and guidances on establishing bioequivalence that concludes with an attachment providing a summary of general approaches for the design and data handling of bioequivalence studies with pharmacokinetic endpoints. The document should provide would-be generic-drug applicants with a good starting place.

FDA’s advice is very general, as the Agency states that companies should see FDA’s product-specific guidances for information on individual drugs. But despite the lack of product-specific advice, the guidance provides significant detail about common study parameters. FDA starts with a general discussion of how best to establish bioequivalence. The Agency notes that applicants can establish bioequivalence using in vivo and/or in vitro methods, which include–in descending order of preference–pharmacokinetic, pharmacodynamic, clinical, and in vitro studies.

Regarding pharmacokinetic studies, FDA suggests that applicants use: (1) a two-period, two-sequence, two-treatment, single-dose, crossover-study design; (2) a single-dose-parallel-study design; or (3) a replicate-study design. To establish bioequivalence from the studies, FDA urges applicants to use the average bioequivalence method of analysis. The guidance provides that, if possible, the study population should consist of enough subjects–18 years and older and representative of the entire population, considering age, sex, and race–to provide adequate statistical power.
Continue reading

lingual.jpgOn October 31, 2013, FDA responded to a Citizen Petition filed by G. Pohl-Boskamp GmbH & Company KG (“Pohl”) on December 16, 2010. The petition requested that FDA require particular showings prior to approval of an abbreviated new drug application (“ANDA”) for a generic version of Pohl’s Nitrolingual® Pumpspray (nitroglycerin lingual spray). Nitrolingual® Pumpspray is a metered dose spray indicated for acute relief of an attack or prophylaxis of angina pectoris, i.e., chest pain, due to coronary artery disease.

In its Citizen Petition, Pohl requested that FDA require ANDA applicants to show in vivo bioequivalence studies evaluating the concentration of active ingredient (nitroglycerin or “TNG”) and its two metabolites, 1,2- and 1,3-glyceryl dinitrate (“1,2-DNG” and “1,3-DNG”, respectively) in plasma. FDA “effectively granted” Pohl’s request in 2012 with issuance of revised Draft Bioequivalence Recommendations for Nitroglycerin Metered Spray/Sublingual products (“the 2012 Revised Recommendations”). FDA recommended that data for TNG as well as 1,2-DNG and 1,3-DNG be submitted as supporting evidence since these metabolites may contribute to the pharmacological activity of Nitrolingual® Pumpspray.

Author's photo

Written by Shelly Fujikawa. Ph.D

Other Posts By This Author

FDA also effectively granted, in the 2012 Revised Recommendations, Pohl’s request for in vivo bioequivalence studies to use a confidence interval approach for TNG, the parent substance. This ruling thereby prohibited substitution for a confident interval approach only for the active metabolites, 1,2-DNG and 1,3-DNG. Pohl argued and FDA agreed that TNG can reliably and accurately be measured using analytical methods employing gas chromatography.
Continue reading

rapaflo.jpgEarlier this month, FDA denied a Citizen Petition filed by Watson Laboratories Inc. (now part of Actavis, Inc. or “Actavis”) on May 10, 2013, requesting that FDA deny any abbreviated new drug applications (“ANDAs”) it receives for a generic version of Rapaflo® (silodosin) Capsules unless the applicant demonstrates bioequivalence for both silodosin and its metabolite KMD-3213G. Watson requested that bioequivalence for both the drug and its metabolite be measured using a strict statistical evaluation of the standard pharmacokinetic measures of area under the plasma concentration-time curve (“AUC”) and peak drug concentration (“Cmax”). Watson further requested that FDA revise its draft guidance on bioequivalence testing for silodosin capsules to require a demonstration of bioequivalence for both silodosin and KMD-3213G.

On October 8, 2008, FDA approved Watson’s new drug application (“NDA”) for Rapaflo®, 4 mg and 8 mg, indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (“BPH”). BPH is a noncancerous enlargement of the prostate that makes urination difficult and uncomfortable. Sandoz Inc. (“Sandoz”) recently filed an ANDA for generic Rapaflo®.

Author's photo

Written by Shelly Fujikawa. Ph.D

Other Posts By This Author

Silodosin is an alpha-1 adrenergic receptor antagonist and undergoes extensive metabolism. Its main metabolite is a glucuronide conjugate, KMD-3213G, which has been shown in vitro to be active. KMD-3213G has an extended half-life (approximately 24 hours) and reaches plasma exposure approximately four times greater than that of silodosin.
Continue reading

stagehook.jpgBased on data submitted by Watson Pharmaceuticals Inc. (“Watson”) (recently merged with Actavis Inc. (“Actavis”)), FDA announced last week that Watson’s generic bupropion hydrochloride (“HCl”) extended-release (“ER”) 300 mg tablet product is not therapeutically equivalent to Wellbutrin XL® 300 mg, the reference listed drug (“RLD”). Therapeutically equivalent drugs generally may be substituted for each other with the expectation that the substituted product will produce the same clinical effect and safety profile when used according to the labeling. Watson has agreed voluntarily to withdraw this product from the distribution chain.

Last year, FDA also reviewed data indicating that Budeprion XL 300 mg (bupropion hydrochloride extended-release tablets), manufactured by Impax Laboratories, Inc. (“Impax”), and marketed by Teva Pharmaceuticals USA, Inc. (“Teva”), is not therapeutically equivalent to Wellbutrin XL® 300 mg. Impax requested that the Agency withdraw approval of Budeprion XL 300 mg extended-release tablets. Impax and Teva stopped shipping the product and issued detailed information to their customers.

Author's photo

Written by Shelly Fujikawa. Ph.D

Other Posts By This Author

FDA has changed the Therapeutic Equivalence Code in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) for the Impax and Watson products from AB (therapeutically equivalent) to BX (data are insufficient to determine therapeutic equivalence). FDA does not anticipate a drug shortage.
Continue reading

On February 20-22, 2013, the Generic Pharmaceutical Association (“GPhA”) held its 2013 Annual Meeting attracting over 600 attendees to see how the nation’s health and regulatory issues will impact the generic industry and consumers who use generic medicines. While some events are for GPhA members only, a majority of the events are open to all attendees and were held in a single room or exhibit hall. Most of the main events were held in a slickly-decorated room filled with stars, comets, and planets.

 

 

While the Meeting covered a lot of territory, recurrent themes appeared to emphasize that the generic industry has come of age, where it joins its big-pharma brothers in having an office on par level with the Office of New Drugs (“OND”) in FDA’s Center for Drug Evaluation and Research (“CDER”) and now pays user fees to speed up generic drug approvals. GPhA’s members announced that they are ready to develop high quality generic versions of specialty pharmaceuticals and biologics, some of which may require the expenditure of hundreds or more millions of dollars to develop, obtain approval for, and market. At the same time, GPhA appears to hold onto the notions that that they can continue to settle cases with reverse payments that the Federal Trade Commission (“FTC”) views as so-called “pay-for-delay” settlements that are presumptively anticompetitive. GPhA also believes that manufacturers should be allowed to sell generic versions of products with the same labeling as the innovator, when the innovator or generic companies that manufacture and sell the product are aware of safety information not presently included in the FDA-approved labeling.

Kicking off the meeting with a “State of the Association”, GPhA President and CEO Ralph G. Neas described generic drugs as the “backbone of the pharmaceutical industry.” Neas expressed the Association’s confidence that FDA will “come through” and help the industry understand what will be expected of it to develop biosimilars and interchangeable biosimilars, which are the future to save lives and money.
Continue reading

sleepingperson.pngLast week, FDA denied a Citizen Petition filed by Jazz Pharmaceuticals, Inc (“Jazz”). The May 18, 2012 Petition concerned bioequivalence studies relating to Xyrem® (sodium oxybate), Jazz’s oral solution indicated for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. Before issuing its decision, FDA received and considered public comment from Roxane Laboratories (“Roxane”), who had an Abbreviated New Drug Application (“ANDA”) referencing Xyrem accepted for review in late 2010.

Jazz asked FDA to take three actions. First, Jazz asked FDA to immediately publish in The Orange Book bioequivalence requirements specifying whether in vitro or in vivo bioequivalence studies, or both such studies, are required for ANDAs referencing Xyrem®. Jazz claimed that FDA’s failure to have done so within the first 30 days of Xyrem®’s approval was a violation of the Federal Food, Drug, and Cosmetic Act (“FD&C Act”) (See 21 U.S.C. § 355(j)(7)(A)(i)-(ii).) and the Administrative Procedure Act (“APA”) (See 5 U.S.C. § 706.). FDA disagreed; the Agency found several flaws with Jazz’s arguments. First, requiring the publication of bioequivalence data type for ANDAs within 30 days of new drug approval would be inconsistent with other sections of the FD&C Act, as well as certain FDA regulations. Second, adopting Jazz’s arguments would require the Agency to generate and evaluate the scientific data needed to understand bioequivalence characteristics at the time the reference listed drug (“RLD”) was approved. FDA disfavored this position, because it would prevent FDA from gaining insight into the characteristics of the RLD during its marketing. Many products never face generic competition, or only do so after the development of acceptable bioequivalence methodologies. As such, FDA reasoned it would be a waste of Agency resources to determine what types of bioequivalence studies are needed within the first 30 days of the RLD’s approval. Third, there is no indication Congress meant the statute to require what Jazz sought, and no court has construed the statute as requiring as much. Finally, FDA noted that Jazz’s interpretation would actually prejudice those who the statute was meant to protect, i.e., the ANDA sponsors. Requiring FDA to publish bioequivalence requirements within 30 days of the RLD approval would diminish FDA’s ability to provide ANDA sponsors with information about the best ways to demonstrate bioequivalence.

Next, Jazz asked FDA not accept for review, review, or approve any ANDA referencing Xyrem® unless and until FDA has published bioequivalence requirements in the Orange Book specifying whether in vitro bioequivalence studies, in vivo bioequivalence studies, or both such studies, are required for ANDAs referencing Xyrem®. Jazz argued that to do so would violate the APA. The drug company reasoned that an ANDA must reference an RLD, and an RLD does not become an RLD until FDA issues the bioequivalence requirements. As such, Jazz concluded that an ANDA can only be accepted for review after FDA issues bioequivalence requirements. Accordingly, Jazz asked FDA to set aside its acceptance of Roxane’s ANDA because this was “agency action . . . without observance of procedure required by law,” “not in accordance with law,” “in excess of statutory jurisdiction, authority, of limitations,” and “short of statutory right.” Again, FDA declined. The Agency claimed that refusing to accept an ANDA on those grounds would conflict with various FD&C Act sections, including Section 505(j)(2)(A), which delineates what information is required in an ANDA and does not list the bioequivalence requirements, as well as certain FDA regulations. It also refused to accept an interpretation of the statute that would punish ANDA applicants, even if in compliance with the statutory requirements, for FDA’s failure to publish the bioequivalence requirements.
Continue reading

Thumbnail image for Thumbnail image for pills.jpgOn May 17, Osmotica Pharmaceutical Corp. (“Osmotica”) filed a somewhat unusual citizen petition requesting that FDA refuse to approve Sun Pharma Global Inc.’s (“Sun’s”) 225 mg Venlafaxine Hydrocholoride Extended-Release Tablets because of the size of Sun’s tablets.

Wyeth Pharmaceuticals Inc. (“Wyeth”) (now Pfizer Inc. (“Pfizer”) first obtained FDA approval for Venlafaxine Hydrochloride, an antidepressant sold under the trade name Effexor®, in 1993. Wyeth’s patent for the compound expired in 2008, although it still holds Orange Book-listed patents for methods of using extended release venlafaxine. In 1997, FDA approved Wyeth’s Extended-Release Capsules, 37.5 mg, 75 mg, 100 mg, and 150 mg, under NDA No. 020699. As an aside, Wyeth’s decision to list the method-of-use patents in the Orange Book and to assert them against generic competition has led to allegations of antitrust violations.

Osmotica’s 505(b)(2) application (NDA No. 022104) for Venlafaxine HCl Extended Release Tablets, 37.5 mg, 75 mg, 150 mg, and 225 mg, received FDA approval in 2008, referencing Wyeht’s Effexor XR® capsules. Later the same year, FDA granted Osmotica’s citizen petition requesting that FDA require ANDA applicants, specifically Sun, to submit new ANDAs and conduct new bioequivalence studies using Osmotica’s tablets, rather than Wyeth’s capsules, as the reference listed drug (“RLD”), because it is the most similar pharmaceutical equivalent (i.e., an extended-release tablet). Sun, an Indian Corporation, subsequently obtained FDA approval for tablets on three of Ostmotica’s four dosage strengths, 37.5 mg, 75 mg, and 150 mg. Sun’s Venlafaxine HCl Extended Release Tablets have an AB-therapeutic equivalence rating to Osmotica’s product (i.e., a generic substitute product).
Continue reading

Thumbnail image for thethinker.bmpOn March 27, FDA granted final approval to 10 drug companies for their generic versions of AstraZeneca’s Seroquel® (quetiapine fumarate) tablets. Seroquel® is used to treat the symptoms of schizophrenia and to treat and prevent mania or depression in patients with bipolar disease. Seroquel® is AstraZeneca’s second-best selling drug, generating $5.83 billion in revenue in 2011.

On March 28, 2012, the majority, if not all, of the ANDA filers launched their products. Also on March 28, 2012, AstraZeneca filed a complaint against FDA stating that it is entitled to exclusive rights for Seroquel® until December 2, 2012, and FDA’s approval of these ANDAs was unlawful and will cause AstraZeneca irreparable harm. AstraZeneca had filed another law suit against FDA prior to the ANDA approvals, but this suit was dismissed without prejudice on March 23, 2012 based on a lack of ripeness (see our blog on this here). The Court held that AstraZeneca could seek a new action “[s]hould the FDA ever give final approval to a competing generic in a manner that is not to AstraZeneca’s liking.” Four days later, FDA provided Astrazeneca with notice of approval of the ANDAs for Seroquel®, and AstraZeneca filed the current suit on March 28, 2012.

Author's photo

Written by Julie E. Kurzrok

Other Posts By This Author

Similar to the arguments made in the first suit, AstraZeneca claims that it is entitled to a three-year new-patient- population exclusivity period as a result of a labeling change that FDA mandated in the supplemental NDAs that were approved on December 2, 2009. AstraZeneca argues that it is improper for FDA to approve any ANDAs prior to December 3, 2012, because AstraZeneca has exclusive rights to the clinical data that FDA required to be added to its Seroquel® and Seroquel XR® labels.
Continue reading

by Andrew S. Wasson

Thumbnail image for FDA.jpegAs promised, ViroPharma filed a complaint in the United States District Court for the District of Columbia for a declaratory judgment and injunctive relief, as well as a motion for a temporary restraining order and/or preliminary injunction against FDA. ViroPharma’s lawsuit responds to FDA’s decision to mostly deny ViroPharma’s Citizen Petition with regard to its Vancocin® (vancomycin hydrochloride) product and the simultaneous approval of three generic vancomycin hydrochloride capsule products (Akorn, Strides Arcolabs Ltd., and Watson Pharmaceuticals) (see our blog here. ViroPharma previously sued FDA in September 2010, only to have the court dismiss ViroPharma’s suit for a lack of standing.

In the present action, ViroPharma alleged that: (1) FDA violated the Section 706(A) and (D) of the Administrative Procedure Act (“APA”) by adopting and applying in vitro dissolution testing as the bioequivalence method in approving the generic vancomycin products, and (2) FDA violated Section 706 of the APA and the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(c)(3)(E)(iv) and (j)(5)(F)(iv)) by denying ViroPharma’s request for the three-year period of regulatory exclusivity. ViroPharma alleged that FDA’s actions have been arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law.

In particular, ViroPharma characterized the use of in vivo testing as the “traditional” approach to testing for bioequivalence. ViroPharma stated that, “[e]xcept in very limited circumstances, regulations adopted by FDA to implement the statute requires ‘bioequivalence’ to be demonstrated through in vivo testing, i.e., clinical testing on humans.” What is more, ViroPharma alleged that drugs that act locally in the gastrointestinal tract should be treated differently for bioequivalence standards (clinically efficacy and safety endpoints). According to ViroPharma, prior to 2006, FDA consistently held that it would require generic applicants to demonstrate bioequivalence through the use of in vivo studies with clinical endpoints.
Continue reading

by Brian Malkin

FDA.jpegOn April 9, FDA simultaneously denied ViroPharma’s Citizen Petition regarding bioequivalence and labeling requirements for generic Vancocin® capsules (vancomycin hydrochloride)
and approved three generic applications to Akorn, Strides Acrolabs Ltd. and Watson Pharmaceuticals. In an unprecedented 87-page response (with index), FDA responded to a myriad of arguments presented in ViroPharma’s original Citizen Petition dated March 17, 2006, as well as its 20 additional supplements and 16 submissions to a public docket for FDA’s Draft Vancomycin Bioequivalence Guidance.

FDA’s response provides numerous insights into FDA’s decision-making process for bioequivalence determinations in addition to FDA’s affirmation of its draft generic Vancocin recommendation as “scientifically sound” and “the most accurate, sensitive, and reproducible approach for demonstrating bioequivalence for generic vancomycin capsules.” For generic Vancocin® FDA will continue to permit in vitro dissolution data alone to demonstrate bioequivalence for generic Vancocin® capsule versions that contain the same active and inactive ingredients in the same amounts (“Q1/Q2”). Non-Q1/Q2 formulations must perform clinical endpoint studies in patients with Clostridium difficile Associated Diarrhea.

FDA’s decision secondarily answered an issue raised in a later supplement regarding certain labeling changes to Vancocin® that was supported with clinical data, which FDA determined would not be eligible for 3 years of clinical data exclusivity because it is not a new indication. According to FDA, “old” antibiotics, such as vancomycin, may only obtain 3-year new data exclusivity for a significant new use or new indication, not for “refinements in labeling related to previously approved used for Old Antibiotics.”
Continue reading