FDA Lawyers Blog

by Howard E. Rosenberg, Ph.D.

Doshi et. al. ("Doshi") in a recent publication in PLoS Medicine highlighted their difficulties in obtaining full clinical trial data surrounding the approval of the influenza antiviral Tamiflu® (oseltamivir). Their interest in the drug was aroused when they began examining claims for the utility of drug and the differing ways that the World Health Organization ("WHO"), FDA and other health authorities around the globe interpreted the effectiveness and thus the recommended method of treatment plans for the drug. The information that was freely available to Doshi came from published trial data and meta-analyses but this proved to be unsatisfactory, as it did not allow them to really examine how the differing understandings of the drug's effectiveness and treatment patterns were decided upon by the world health authorities.

Widening their research into clinical trial reports and published data provided for other drugs that had subsequently been withdrawn or turned out to be unsatisfactory (e.g., rosiglitazone, rofecoxib, etc.), when it became clear to them that what they needed to see original clinical trial data without any "spin" attached. They pointed out that although published randomized clinical trials ("RCTs") are considered the "gold standard" source of synthesized evidence, their conclusions are vulnerable to distortion when the trial sponsors have strong interests that might benefit from suppressing or promoting selected data. From their point of view, a better method to independently assess drugs would be to enable the access and review of the clinical trial documentation and reports sent to the government drug regulators. However, these reports are historically treated as commercial confidential documents, impeding additional scrutiny by independent researchers. As a result, Doshi was unable to get all the data they required for their Tamiflu® project, despite putting in a great effort trying to get key documents released by government regulators.

A group of European regulators have replied to the Doshi article, agreeing that clinical trial data should not be considered commercial confidential information, particularly as most patients enrolling in clinical trials do so with an assumption of contributing to general medical knowledge, and that non-disclosure of complete trial results undermines this. They see many potential advantages in having public disclosure, for example, in enabling the development of predictive models for patient selection to appropriate treatments and the potential for better individualized therapeutic decisions.

by Brian Malkin

On 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."

by Brian Malkin

On April 4, Senator Michael Bennett (D-CO) announced that a draft Bill introduced by himself and Senators Orrin Hatch (R-UT) and Richard Burr (R-NC) on March 26 has been included a Senate Committee bipartisan plan to help advance important medical and bioscience breakthroughs through certain FDA reforms. The Committee is called the Senate Health Education Labor and Pension Committee, which seeks to implement FDA reforms as part of a larger FDA reauthorization. The Bill, now described as a "discussion draft," is called the Advancing Breakthrough Therapies for Patients Act.

The Bill amends Section 506 of the Federal, Food, Drug and Cosmetic Act ("FD&C Act") by creating a new "breakthrough therapy" designation to provide more flexibility for these types of drugs to encourage their development and approval. At the request of a sponsor, a drug, alone or in combination with one or more drugs, may be designated as a "breakthrough" drug, if intended to treat serious or life-threatening diseases or conditions and preliminary evidence suggests that the drug may demonstrate substantial improvements on one or more clinically-significant endpoints over existing therapies. Within 60 calendar days of the sponsor's request, FDA must determine whether the drug meets the "breakthrough therapy" criteria. If FDA agrees that the drug meets the "breakthrough therapy" criteria, then FDA may take appropriate actions to expedite development and review of the drug. Such actions include holding meetings with the drug sponsor throughout the drug development process and providing timely advice to the sponsor regarding the drug development plan. In addition, the Bill enables a collaborative, cross-disciplinary approach by senior managers and review staff at FDA to help craft a clinical program that minimizes the number of patients enrolled in studies, shortens the duration of studies, and reduces the number of clinical studies, when scientifically appropriate. A "breakthrough therapy" may further seek fast-track product designation, accelerated approval, and priority review to help speed the review process.

Drugs that receive accelerated approval under these provisions may be subject to either post-approval studies to verify and describe the predicted effect on irreversible morbidity or mortality or other clinical benefit, or be required to submit all promotional materials related to the product during the approval period and at least 30 days prior to dissemination of any materials. FDA may withdraw approval on an expedited basis if the sponsor fails to conduct any required post-approval study, such studies fail to verify the predicted effects or benefits, or the sponsor disseminates false or misleading promotional materials about the product.

by Brian Malkin

On March 29, Rep. Frank Pallone, Jr. (D-NJ) introduced in the House a Bill aimed at raising the reporting level of the Office of Generic Drugs ("OGD") in FDA and implementing a temporary "fix" of the 180-day exclusivity forfeiture situation affecting applicants unable to obtain tentative approvals within 30 months from filing. The Bill (H.R. 4332), co-sponsored by Rep. Brett Guthrie (R-KY) is called, "Generic Drug Application Review Fairness Act of 2012".

First, the Bill would elevate OGD to a "separate office" within the Center for Drug Evaluation and Research ("CDER") with direct reporting authority to the Director of CDER, currently Janet Woocock, M.D. OGD is presently part of the Office of Pharmaceutical Science. If enacted, this change would follow a new trend to elevate certain groups within CDER, presumably to empower the separate offices more than in the current hierarchy. A recent elevation from "Division" to "Office", for example, occurred last year for the former Division of Drug Marketing, Advertising and Communications ("DDMAC"), now known as the Office of Prescription Drug Promotion ("OPDP") within the Office of Medical Policy. As proposed, OGD would then be on equal hierarchical par with the Office of New Drugs ("OND") and presumably have more clout when it comes to issues such as resources, funding, or scientific decisions within its purview, such as bioequivalence.

As a temporary fix of OGD's backlog of abbreviated new drug applications ("ANDAs"), the Bill initially would provide 60 months for first applicants with 180-day exclusivity eligibility to obtain a tentative approval. The current forfeiture provision, enacted by the in 2003 under the Medicare Prescription Drug, Improvement, and Modernization Act ("MMA") states that a first applicant to submit a "Paragraph IV" patent challenge will forfeit its 180-day exclusivity in the following situation:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

by Brian Malkin

On March 30, FDA denied the Natural Resources Defense Council, Inc.'s ("NRDC's") Citizen Petition to remove the chemical bisphenol A ("BPA") from food packaging and other products where it comes in contact with food. NRDC said that BPA may be found in a wide variety of the liners of metal food cans and hard plastic containers such as baby bottles.

As we previously reported here, on August 19, 2011, NRDC sued FDA for declaratory and injunctive relief for FDA to grant the citizen petition and issue a regulation prohibiting the use of BPA in food packaging. NRDC's original Citizen Petition was filed in October 2008 yet remained unanswered by more than 1000 days, as of the complaint filing date. According to NRDC's complaint, FDA should have responded to its type of petition within 90 days and had a maximum time of 180 days to respond. NRDC had asserted that FDA's failure to respond to NRDC's Petition prolonged its members from unwanted exposure to BPA in food packaging. FDA's failure to respond to the Petition, NRDC further claimed, denied NRDC from seeking judicial review, if necessary.

NRDC's latest suit on this Petition resulted in a Consent Judgment, where FDA agreed to issue a final decision to NRDC's Citizen Petition "on or before March 31, 2012" as the "settlement of all claims that were asserted, or could have been asserted . . . related to the allegations in the Complaint." NRDC was also awarded $10,500 as "attorney feed and costs arising out of this Action" in a Stipulation and Order that followed the Consent Judgment.

by Julie E. Kurzrok

On March 27, the FDA approved Affymax's Omontys® (peginesatide) for use in adult dialysis patients with anemia caused by chronic kidney disease. Anemia is a condition characterized by a decrease in the level of red blood cells in the body. Healthy red blood cells carry oxygen to the body's organs and tissues, and when the level of red blood cells is decreased, the organs are not able to function properly. The kidneys produce the hormone erythropoietin, which directs the bone marrow to produce enough red blood cells to support the body. Diseased kidneys do not produce enough erythropoietin, and as a result, the bone marrow does not produce enough red blood cells, causing anemia. There are currently close to 400,000 patients on dialysis, and almost all of them have anemia.

Amgen has held a monopoly on the anemia market, yielding close to $40 billion since Epogen®'s (epoetin alfa) approval in 1989. Amgen supplies the same drug under the name Procrit® to Johnson and Johnson for use in chemotherapy patients with anemia and for non-dialysis kidney patients. Amgen also produces the drug Aranesp®, a longer-lasting anemia drug used mainly in non-dialysis patients, which has made close to $26 billion in sales since it entered the market.

Omontys® is a synthetic erythropoietin-stimulating agent that assists the body in increasing red blood cell production. Prior to the approval of Omontys®, the only treatment choice for dialysis patients with anemia was Amgen's Epogen®. Epogen® is an injection usually given between one to three times weekly. Omontys®, on the other hand, is an injection given once monthly, which has demonstrated equivalent safety and efficacy to Epogen® treatment.

by Howard E. Rosenberg, Ph.D.

The general public's expectation for transparency in the regulation and assessment of the safety of medicines is characterized by the number of Freedom of Information Act ("FOIA") requests to FDA asking for detailed information regarding this data and the multitude of blog articles covering this subject matter. To some extent, public postings on FDA's website, particularly Drugs@FDA, has quelled the need for some FOIA requests. In Europe there is the same public pressure and an increasing trend for the release of information contained in the Marketing Authorization Applications ("MAAs") after they are granted. For example the release of clinical and safety data is regularly requested.

Feedback from initial European proposals found that in general the pharmaceutical industry had concerns regarding the release of contractual arrangements between companies, personal data of experts, and clinical and non-clinical data. Pharmaceutical companies also raised special concerns with regard to the disclosure of non-clinical data, while the release of clinical data was supported by most stakeholders.

The European Medicines Agency ("EMA") and the Heads of Medicines Agencies ("HMA") have now adopted a joint guidance document, providing, for the first time, a consistent Europe-wide approach to the identification of commercially-confidential information and personal data in a MAA. This "major step for transparency," will apply in the future to identify which parts of an application dossier can or cannot be released in response to requests throughout the regulatory authorities in the European Economic Area ("EEA"). This policy applies regardless of whether the product concerned was authorized using the centralized, mutual recognition or decentralized procedures.

by Kyle Deighan

FDA is currently exploring the possibility of allowing additional drugs for common health conditions to be sold over-the-counter ("OTC") without a prescription. FDA held public hearings last week to gather input from various groups on the issue, including consumers, pharmacists, and health care community members. Janet Woodcock, M.D., Director, Center for Drug Evaluation and Research ("CDER"), explained, "What we are asking is, should there be more flexibility in the concept of nonprescription drugs? Can we broaden the assistance a consumer gets and increase the types of medicines that might be available over-the-counter?" Drugs that may soon be available OTC without a prescription include cholesterol, asthma, migraine and blood-pressure medications.

FDA may require special conditions to apply before a drug may be sold OTC. These could include requiring patients to speak with a pharmacist before obtaining a medication or undergoing some form of diagnostic test. Or patients may be required to first see a physician to obtain a prescription, but then could obtain refills without needing subsequent prescriptions. FDA has also discussed the use of kiosks in pharmacies or questionnaires on the Internet to help consumers determine whether or not to take a certain drug. Woodcock noted that "the rules for nonprescription status were established in an age when widespread access to information technology did not exist. The world is evolving. It is clear there are now many interactive mechanisms that can help consumers through the process of self-diagnosis and medication selection in a much more comprehensive manner than a few worlds on a fact box."

Supporters argue that making more drugs available OTC would give patients the access they need to necessary medications. According to FDA, the time and cost required to visit a doctor, obtain a prescription, and then fill that prescription may deter patients from ever obtaining medications. An estimated 20 percent of patients with prescriptions do not even bother getting them filled, for example. Proponents argue that more OTC offerings would provide these patients with easier access to necessary drugs. Other benefits highlighted by FDA include "an increase in the appropriate use of medication, decreases in health costs, greater access to health screening ... and better, more consistent treatment of common conditions."

PIV Disputes 2012

Each spring, leading pharmaceutical patent litigators for brand name and generic drug companies gather in New York City at American Conference Institute's (ACI's) Paragraph IV Disputes conference to discuss, debate, and analyze the latest trends, judicial rulings and legislative developments affecting Hatch-Waxman litigation. Come and be part of this industry-leading think tank: meet with the leading legal minds in this area and access the information which will help you master the critical competencies needed for the new era of Hatch-Waxman litigation.

An experienced faculty comprised of respected and renowned counsel for brand name and generic pharmaceutical companies will help you develop your new plan of attack for 2012 and beyond. They will provide insights on all facets of Paragraph IV litigation: pre-litigation concerns - the commencement of suit - final adjudication - and every step in between. Sessions will address the key elements of Paragraph IV litigation in addition to some of the most pressing and recent controversies surrounding Paragraph IV cases, including:

• The impact of the AIA on Hatch -Waxman litigation
• Carve-outs, use codes and labeling
• Claim construction conundrums
• Prior art obviousness and obvious-type double patenting
• Inducement of infringement and divided infringement
• Inequitable conduct
• Damages

by Richard F. Kurz

On March 26, the United States Supreme Court granted the certiorari petition in Association for Molecular Pathology v. Myriad Genetics, Inc., and remanded the case to the Federal Circuit for reconsideration in light of its newly-issued holding in Mayo Collaborative Services v. Prometheus Laboratories, Inc.

In Myriad, the Federal Circuit previously considered whether certain composition and method claims relating to human genetics were patentable subject matter. The composition claims cover two "isolated" human genes, BRCA1 and BRCA2, and certain alterations, or mutations, in these genes associated with a predisposition to breast and ovarian cancers. An example of one of the composition claims is:

An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2.

All but one of the challenged method claims cover methods of "analyzing" or "comparing" a patient's BRCA sequence with the normal, or wild-type, sequence to identify the presence of cancer-predisposing mutations. An example of one of the method claims is:

A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 gene or BRCA1 RNA from a human sample or analyzing a sequence of BRCA1 cDNA made from mRNA from said human sample with the proviso that said germline alteration is not a deletion of 4 nucleotides corresponding to base numbers 4184-4187 of SEQ ID NO:1.

by Brian Malkin

On March 14, FDA's Office of Prescription Drug Promotion ("OPDP") issued its first Warning Letter this year to Teva for its branded product Copaxone® (glatiramer acetate injection) (solution for subcutaneous injection based on promotional materials sent to FDA on a Form FDA-2253 (pre-dissemination form) as well as its Team Copaxone®" webpage and several associated webpages for "David Kyle" and "Karen Stewart" for Copaxone®.

Team Copaxone

OPDP states in the letter that Teva's promotional materials are false and misleading because they overstate the efficacy, present unsubstantiated claims, broaden the indication of Copaxone®, omit and minimize risk information associated with the drug, present unsubstantiated superiority claims, and omit material facts. OPDP says it finds the violations "concerning from a public health perspective because they suggest that Copaxone is safer or more effective than has been demonstrated by substantial evidence or substantial clinical experience."

Copaxone® is indicated for reduction of the frequency and relapses in patients with Relapsing-Remitting Multiple Sclerosis ("RRMS"), including patients who have experienced a first clinical episode and have magnetic resonance imaging ("MRI") features consistent with multiple sclerosis. MRI is considered one of the best ways to diagnose multiple sclerosis.

by Brian Malkin

On March 23, U.S. District Judge Colleen Kollar-Kotelly for the District of Columbia dismissed without prejudice AstraZeneca Pharmaceuticals LP's ("AstraZeneca's") suit against FDA requesting declaratory and injunctive relief to prevent FDA from granting final approval to generic versions of Seroquel® (quetiapine fumarate) or Seroquel XR® (extended-release quetiapine fumarate). As we reported here, AstraZeneca asserted that FDA could, based on FDA's denial of AstraZeneca's citizen petitions, approve generic versions of both products as early as March 27, 2012 (tomorrow), after the pediatric exclusivity associated with the product expired.

Judge Kollar-Kotelly agreed with AstraZeneca that the Agency's denial of AstraZeneca's two related citizen petitions constituted "final agency action" but disagreed that AstraZeneca's claims were ripe. As the Judge stated in her Memorandum Opinion:

Long has it been established that even a "purely legal challenge" to "final agency action" may not be fit for judicial review. Indeed, the Court of Appeals found that a challenge to the FDA's denial of a citizen petition raising an abstract question that could affect the approvability of related ANDAs [abbreviated new drug applications] submitted by generic competitors, although constituting final agency action, may not be ripe until the agency makes a concrete determination on the related applications. (citations omitted).

FDA had denied AstraZeneca's petitions "without comment on whether [FDA] will take the actions that [AstraZeneca] request[s]." While FDA's actions on citizen petitions are typically considered final agency action, in this case, FDA only has tentatively approved several generic applicants referencing both Seroquel® and Seroquel XR®. FDA has not approved any generic applications to date.

by Richard F. Kurz

On March 20, the United States Supreme Court delivered its long awaited opinion in the Mayo Collaborative Services v. Prometheus Laboratories, Inc. case. The question in the case was whether a patent claiming a method of optimizing therapeutic efficacy for treatment of a disorder is patentable subject matter under 35 U.S.C. § 101. For the specific claims in Prometheus's patents, the answer was "no."

At issue were two patents concerning the use of thiopurine drugs in the treatment of autoimmune diseases, such as Crohn's disease and ulcerative colitis. When a patient ingests thiopurine, the body metabolizes the drug, causing metabolites to form in the bloodstream. Different people metabolize the drug differently, however, which makes it difficult for doctors to determine the proper dose--too high a dose risks harmful side effects, too low and the drug is ineffective. Those in the field did not know the precise correlations between metabolite levels and the likely harm or ineffectiveness of the dose. But, in the research leading to these patents, correlations were identified with some precision. The patents' claims set forth processes that embodied the researchers' findings. An example of one of the claims is:

A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising: (a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and (b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder, wherein the level of 6-thioguanine less than about 230 pmol per 8 x 10(8) red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and wherein the level of 6-thioguanine greater than about 400 pmol per 8 x 10(8) red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.

by Howard E. Rosenberg, Ph.D.

Apotex, Canada's largest generic drug manufacturer, claims that as a consequence of action taken by FDA with respect to two Canadian facilities operated by Apotex-Canada, Apotex-U.S. incurred a loss of income exceeding $520 million. Apparently these two facilities produce about 80 percent of the products sold by Apotex-U.S. and an FDA-imposed import alert raised in August 2009 prevented Apotex-U.S. from receiving any drugs produced by these two facilities until the import alert was fully lifted at the end of July 2011.

Apotex alleged that during the relevant time period, FDA accorded more favorable treatment to other U.S. investors and U.S.-owned investments having issues similar to Apotex, in that these other investors were not subjected to a measure as severe as the import alert imposed on the Apotex companies. The problems began for Apotex when their two manufacturing facilities were inspected by FDA that uncovered quality system problems. These issues and the resolution of the issues by a FDA re-inspection were far more protracted to resolve than say those by Teva who, according to Apotex, appeared to have similar or analogous problems. Teva's re-inspection by FDA and the resolution of their quality failures proved to be far quicker than that for Apotex.

According to Apotex, the import alert violated North American Free Trade Agreement ("NAFTA") Article 1102 (National Treatment), Article 1103 (Most-Favored-Nation Treatment) and Article 1105 (Minimum Standard of Treatment). Article 1102 provides, in part, that each Party shall accord to investors of another Party treatment no less favorable than that it accords, in like circumstances, to its own investors with respect to the establishment, acquisition, expansion, management, conduct, operation, and sale or other disposition of investments. Apotex claim that the Import Alert put Apotex Holdings and Apotex-Canada at a clear disadvantage compared to U.S. investors in like circumstances, who were not prevented from applying for authorization of new generic drugs or from benefiting from sales thereof.
Article 1103 extends 1102 by referring to the treatment afforded to third-country investors in like circumstances. Here Apotex pointed to the apparent favorable treatment given to Teva being in stark contrast to what they themselves received. Article 1105 provides that each Party shall accord to investments of investors of another Party treatment in accordance with international law, including fair and equitable treatment and full protection and security.

by Brian J. Malkin

Last week, the U.S. Sentate unanimously passed a bill sponsored by Patrick Leahy (D-VT), S. 1886, the Counterfeit Drug Penalty Enhancement Act of 2011. The Bill increases penalties for trafficking counterfeit drugs.

Currently, it is illegal to introduce counterfeit drugs into interstate commerce, but the penalties are the same as for illegal trafficking other goods, such as electronics or other merchandise. In essence, the penalties for copying a company's logo on a prescription bottle were more severe than for making and selling counterfeit drugs. The Bill targets violators who knowingly manufacture, sell, or traffic counterfeit medicines in the United States.

Senator Leahy was clearly pleased with the result and is urging the House to act quickly on the Senate's lead, stating:

We cannot allow the counterfeiting of life-saving medicine to be just one more low-risk venture from which international organized criminals can profit . . . While we should not expect that enactment of this or any legislation will completely deter the serious problem of counterfeit medication entering the American supply chain, it is an important step in the fight. I urge the House of Representatives to act quickly on this legislation.

Worldwide counterfeit medicines are a multi-billion dollar industry, and growing at an alarming pace, especially over the internet. These medicines pose a serious threat to the health and safety of unsuspecting Americans . . .The House should act as quickly as possible to ensure that counterfeit drug traffickers are punished accordingly for putting people's lives at risk with this serious crime.