DNApurple.jpgYesterday, the U.S. Supreme Court held that “a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but that cDNA is patent eligible because it is not naturally occurring.” The Court’s ruling decided the question: “Are human genes patentable?” We have been blogging on this issue for some time now, see for example here, our blog on the oral arguments at the Supreme Court with links to some previous blogs.

Myriad concerns the “discover[y of] the precise location and sequence of what are known as the BRCA1 and BRCA2 genes.” Specifically, Myriad discovered that “[m]utations in these genes can dramatically increase an individual’s risk of developing breast and ovarian cancer.” Myriad subsequently obtained a patent including such claims as “[a]n isolated DNA coding for a BRCA1 polypeptide” that included a specific amino acid sequence. The isolated DNA existed in nature before Myriad found them, the Court noted, and Myriad’s principle contribution involved determining the precise location and genetic sequence of these polypeptides. The Court said that finding the location of the genes does not make the genes themselves patentable, nor does the extensive effort involved in discovering them. Additionally, the Court found that isolating certain DNA from the human genome by severing chemical bonds would be not enough to render the matter patent eligible, because the “claims are simply not expressed in terms of chemical composition, nor do they rely in any way on the chemical changes that result from the isolation of a particular section of DNA.” As a result, the Court held the claims invalid since “genes and the information they encode are not patent eligible under [35 U.S.C.] § 101 simply because they have been isolated from the surrounding genetic material.”

Another issue was whether the cDNA sequence claimed in the patent (as opposed to the full DNA sequence) would be patent-eligible. Here, the Court said that “cDNA cannot be isolated from nature, but instead must be created in the laboratory.” The Court noted that “cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments.” So, even though “cDNA retains the naturally occurring exons of DNA, [] it is distinct from the DNA from which it was derived.” For this reason, the Court concluded, “cDNA is not a ‘product of nature’ and is patent eligible under § 101, except insofar as . . . a short strand of cDNA may be indistinguishable from natural DNA.”
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spongescrub.pngOn June 4, FDA announced in the Federal Register that they were considering release of de-identified data sets in an effort to provide greater access to clinical and preclinical study data for researchers. This collaboration with the National Institutes of Health (“NIH”) would presumably work like other public databases NIH has supported over the years to provide access to medical data for research purposes. As a researcher, I (Eric) used NIH databases like the Lung Image Database Consortium (“LIDC”) and Reference Image Database to Evaluate Response (“RIDER”) sets of Lung computer tomography (“CT”) scans to gather anatomic information about the potential patient population to make product design choices. FDA’s proposal offers both potential benefits and harms to consider.

FDA recognizes that clinical study data sets are underutilized for the scientific understanding that they can provide. As a rule, preclinical and clinical studies are very expensive propositions that produce high quality data but receive limited publication, granting few in the research community with access to the raw data. This is understandable, in part, because sponsors wish to both protect their clinical data from competitors who may copy or undermine it, as well for protection of their intellectual property. This limited access prevents that data from being included in certain meta analyses studies. Meta analysis provides the numbers needed to identify lower frequency events and weaker correlations in the data. If a correlation does not reach the widely recognized p-value of 0.05 or lower, the scientific community is hard pressed to consider it a proven hypothesis. Meta analysis combines several studies and can produce “significant” results based on the increased size of the dataset. FDA has access to the raw data from clinical studies submitted with new product applications as well as other databases, however, it does not have the resources or mandate to perform this type of research.

FDA notes that there are potential hazards to this disclosure. FDA’s call for comments states that FDA is not a covered entity for the purposes of the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”). However, patients who have signed up for clinical trials generally have agreed to have their information used for certain purposes, often including publication. For the most part, patients understand that such data may be reported in the aggregate.
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pharmacy.jpgCompounding pharmacies are petitioning against a recent bill that would give FDA greater control over compounding manufacturers of sterile products. S.959, The Pharmaceutical Compounding Quality and Accountability Act, was unanimously passed by the Senate Health, Education, Labor and Pension Committee on May 22, 2013, and places compounding manufacturers that sell sterile products over state lines under FDA control.

The Bill, authored by Senator Tom Harkin, was a response to a deadly meningitis outbreak reported by FDA in October of 2012. The U.S. Centers for Disease Control and Prevention (“CDC”) traced the outbreak to fungal contamination in three lots of methylprednisolone acetate used for epidural steroid injections made by the New England Compounding Center (“NECC”). The CDC reported that the NECC meningitis outbreak has made 745 people sick and has caused 58 deaths in the United States. On May 24, 2013, another meningitis outbreak was announced. This recent outbreak was reportedly caused by Tennessee-based Main Street Family Pharmacy’s methylprednisolone acetate injections. The recent outbreak has sickened 24 people in Illinois, North Carolina, Florida, and Arkansas. These meningitis outbreaks have spurred the legislation that is being petitioned against.

Currently, individual States oversee their own compounding pharmacy operations. The potential shift from State to FDA control is worrisome to many pharmacists, doctors, and their patients. Specifically, there is concern that the FDA may ban compounded bio-identical hormones used to treat chemical imbalances.
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GSK FDA.pngOn June 6, an FDA’s joint Endocrinologic and Metabolic Drugs Advisory Committee (“EMDAC”) and Drug Safety and Risk Management Advisory Committee (“DSaRM”) recommended that the FDA lift restrictions on controversial drug Avandia® (rosiglitazone).

Avandia®, first approved for commercial marketing in the United States on May 25, 1999, was once the world’s bestselling treatment for diabetes. Now, it is rarely sold or prescribed. Avandia® began to lose popularity in 2007, when a Cleveland Clinic cardiologist published an aggregate study suggesting the drug caused heart problems. In response, FDA issued a warning restricting its use. A flurry of controversy followed the drug, damaging the drug’s reputation with physicians and fueling allegations in the U.S. Senate that GlaxoSmithKline (“GSK”)–the manufacturer of the drug–failed to inform patients its effect on cardiovascular risk.

In an attempt to salvage the drug’s reputation, GSK sponsored a new study on Avandia®’s cardiovascular risk in 2009, called the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (“RECORD”). This clinical study seemed to suggest that Avandia® had no measureable effect on cardiovascular risks. But the damage had already been done to Avandia®’s reputation, and other researchers criticized the trial as flawed due to missing data and alleged trial design defects. GSK failed then to improve the drug’s reputation with the RECORD trial.
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safe harbor.jpgThe Supreme Court has heard additional briefing―in the form of Amphastar Pharmaceuticals, Inc.’s Brief in Opposition and Momenta Pharmaceuticals, Inc. and Sandoz Inc.’s Reply Brief―about whether to review Momenta Pharm., Inc. v. Amphastar Pharm., Inc. and further clarify the scope of the safe-harbor provisions of 35 U.S.C. § 271(e)(1). As previously blogged on here, Momenta Pharmaceuticals, Inc. (“Momenta”) and Sandoz Inc. (“Sandoz”) petitioned the Supreme Court to determine:

Whether the use of a patented invention in the course of post-approval manufacture of a drug for commercial sale, where the FDA requires that a record of that manufacturing activity be maintained, is exempt from liability for patent infringement under Section 271(e)(1) as “solely for uses reasonably related to the development and submission of information under a Federal law which regulations the manufacture, use, or sale of drugs.

In its Opposition, Amphastar framed the issue as:

Whether the Federal Circuit correctly vacated a preliminary injunction on the ground that petitioners had no likelihood of success on the question of whether a generic manufacturer’s compliance with FDA-mandated, pre-marketing safety testing falls within the Hatch-Waxman Act’s statutory safe harbor provision, 35 U.S.C. § 271(e)(1).

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shareball.jpgOn May 10, Prometheus Laboratories Inc. (“Prometheus”) filed a Citizen Petition (FDA Docket No. FDA-2013-P-0572) requesting “complete notice and comment rulemaking establishing the standards and processes for a single, shared REMS [Risk Evaluation and Mitigation Strategies]” and waivers for the requirement for a single, shared REMS. Prometheus also requested that it be given notice and the opportunity to engage in any process used by FDA to determine whether to grant a waiver from the requirement for a single, shared REMS for Lotronex® (alosetron hydrochloride).

REMS are a type of risk management plan structure established by the Food and Drug Administration Act of 2007 (“FDAAA”) in September 27, 2007. REMS are required for a drug to be approved or post approval based on new safety information if FDA determines “it is necessary to ensure that the benefits of the drug outweigh the risks of the drug.” FDA may require a REMS to include a medication guide, patient package insert, and a communication plan. Where REMS get more complicated are when they include elements to assure safe use (“ETASU”), which generally involve more restrictive REMS, such as controlled distribution, special training for the physicians who prescribe the drug, typically to manage a serious risk, such as a severe side effect that may occur without such controls. REMS also involve a timetable for assessment to ensure that the REMS is controlling the risk for administering the drug. If a drug has a REMS, then generic version must have the same general elements and either share the same REMS with ETASU with the innovator or have its own essentially equivalent REMS with ETASU.

Lotronex® was approved on February 9, 2000 to treat irritable bowel syndrome in women whose predominant bowel syndrome is diarrhea. Soon after Lotronex® was marketed, FDA received reports of obstructed or ruptured bowels as a complication of severe constipation and sudden swelling/inflammation of part of the colon that occurs when there is a temporary loss of, or reduction in, blood flow to the colon. On November 28, 2000, Lotronex® was voluntarily withdrawn by its then sponsor GlasxoSmithKline (“GDK”).
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Thumbnail image for mortar and pestle.jpgOn May 10, FDA denied a Citizen Petition submitted on behalf of Endo Pharmaceuticals Inc. (“Endo”). The Petition requested that FDA: (1) determine that Opana® ER (oxymorphone hydrochloride) Extended-Release Tablets (“OP”) were discontinued for safety reasons, (2) refuse to approve any pending abbreviated new drug application (“ANDA”) for a generic version of OP, and (3) suspend and withdraw the approval of any ANDA referencing OP as the reference listed drug. By statute, if a drug was withdrawn from sale for reasons of safety or effectiveness, FDA must refuse to approve any pending ANDA and suspend or withdraw any approved ANDA referencing the drug.

FDA initially approved the New Drug Application (“NDA”) for OP held by Endo on June 22, 2006. The approved label advised that the product should be swallowed whole and warned against crushing, chewing, snorting, or injecting the dissolved product to prevent uncontrolled delivery, overdose, and death. FDA approved two ANDAs referencing OP in December 2010. Generic versions of the product entered the market in July 2011 and January 2013, respectively.

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Written by Shelly Fujikawa. Ph.D

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FDA approved an NDA for a reformulated version of OP, also called Opana® ER (oxymorphone hydrochloride) Extended-Release Tablets (“OPR”), held by Endo on December 9, 2011. FDA found that OPR could still “dose dump” and approved a label for ORP that was virtually identical to the approved label for OP. Endo ceased shipping OP on May 31, 2012 and submitted the present petition in August 2012 which was subsequently supplemented with preliminary postmarketing data and analysis concerning the abuse of OP, generic versions of OP, and OPR.
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plan b.pngThe fight over whether versions of the emergency contraceptives Plan B and Plan B One-Step (collectively “Plan B”) should be available without a prescription to all women continued yesterday. Lawyers for FDA appeared before Judge Edward Korman of the Eastern District of New York urging him to stay his April 4 Order requiring the Agency to lift age restrictions on access to emergency contraceptives by May 10. FDA has appealed that ruling to the Second Circuit. The Agency has yet to implement the court’s directive, but in late April it approved a supplemental new drug application (“sNDA”) that lowers the age at which women can obtain these drugs without a prescription from 17 to 15. Judge Korman expressed skepticism as to the timing of the approval and criticized the Agency for not following his order. A ruling on the stay is expected by the end of this week.

FDA’s actions have received mixed reviews. Last week, President Barack Obama reiterated his support of FDA’s and the Department of Health and Human Services’ (“DHHS’s”) determination that the age-restriction should be fifteen. He said that he was “very comfortable with the decisions they’ve made.” Others have been more critical. Nancy Northup, President and CEO of the Center for Reproductive Rights, speaking after the Department of Justice’s appeal to the Second Circuit said, “We are deeply disappointed that just days after President Obama proclaimed his commitment to women’s reproductive rights, his administration has decided once again to deprive women of their right to obtain emergency contraception without unjustified and burdensome restrictions.”

The approval of Plan B has a long history. Originally approved in 1999 for prescription-only use, Plan B became the United States’ first emergency contraceptive. In February 2001, sixty-six organizations filed a Citizen Petition with FDA urging the Agency to switch Plan B, as well as any other emergency contraceptives, from a prescription-only drug to an over-the-counter (“OTC”) drug and remove all age and point-of-sale restrictions. Despite repeated claims that it would address the outstanding petition, the Agency waited over five years to rule–denying the Petition in June 2006. FDA claimed that the petitioners had failed to provide sufficient data or information to meet the statutory and regulatory requirements of an OTC switch to any age group.
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future.pngOn May 3 and 4, the Petrie-Flom Center for Health Policy, Biotechnology, and Bioethics at Harvard Law School presented a conference, “The Food and Drug Administration in the 21st Century”. The Conference drew about 240 attendees but surprisingly very few FDA staff, especially given FDA’s revived interest in regulatory science–only five were listed on the official registration list. During these two days, FDA and its policies were looked at largely from an academic perspective, and new viewpoints were presented for changing how FDA has done its business. A wealth of resources from the Conference may be found at the Conference Dropbox, including many speaker papers and slides.

Peter Barton Hutt, Partner at Covington & Burling LLP, kicked off the conference with a historical perspective of FDA over the past 50 years. Hutt traced back to 1962, when FDA focused on foods and was an obscure, unknown agency. At this time, the Commissioner made all the decisions, largely from a purely management-type analysis, and no issue “lasted longer than a week.” Hutt recounted the incredible increase in FDA staff over the years, particularly in recent years, where he views there are increased opportunities for FDA losing control and making inconsistent decisions and mistakes, as policy is made at the bottom of the agency, not the top. Hutt described how over the years, FDA has made creative use of its regulatory authorities. Initially, FDA first explained itself in extensive preambles to regulations proposed and promulgated in the 1970s. When issuing new regulations became too cumbersome, FDA took to issuing its policies in guidances.

Hutt noted how despite FDA’s increasing regulatory responsibilities, most recently including tobacco and biosimilars, Congress has continued to inadequately fund FDA, especially in recent years, which has resulted in certain regulatory distortions. In the 1990s, the innovator drug industry agreed to pay user fees to reduce review times, first from innovator drugs in the 1990s and now encompassing biologics, medical devices, and animal drugs and just last year biosimilars and generic drugs. Hutt observed that despite FDA’s growth and new user fees, historically there were more enforcement actions when FDA was much younger back in 1938, suggesting that other factors are at work making the process less efficient. Adding to that, Hutt described FDA’s budget as “essentially flat” except for the influx of more user fees, which permits program with user fees to “thrive” while other programs are hurt, languish, or are forgotten. For example, the Drug Efficacy Study Implementation (“DESI”) program begun in 1962 to review efficacy for all drugs on the market is still not complete, the over-the-counter drug program begun in 1972 is only 75% complete, medical device reviews of all class III devices begin in 1976 is not complete, and FDA gave up without explanation on the food ingredient program begun in 1969 to review ingredients generally recognized as safe (“GRAS”). Meanwhile, programs funded by user fees (but not other programs) get a chance every five years to get additional statutory support from Congress, when the user fees and timelines for FDA review cycles are up for discussion.
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On May 2, Algorithme Pharma, an early-stage clinical contract research organization (“CRO”) based in Laval, Canada, hosted a Science Symposium, “Innovative Solutions to Common Clinical & Bioanalytical Challenges“. First, Catherine Konidas, Vice President, Global Business Development, Algorithme Pharma, , presented a comparison of clinical trials in the U.S. versus Canada. The group explained the benefits of conducting Phase I clinical trials (early stage studies in healthy human subjects to determine a proposed therapy’s safety) in Canada. For each Phase I research to be conduced in Canada, Health Canada, the FDA equivalent regulatory agency, requires Health Canada forms including a clinical trial agreement (“CTA”), an investigator brochure, a protocol, informed consent, CTD summaries, and an overall quality summary. Unlike FDA, Health Canada does not require quality, non-clinical, and clinical reports (only summaries are required) as well as new related publications. In the opinion of Algorithme Pharma, these differences may save time. On the other hand, unlike FDA, Health Canada requires one CTA per clinical trial versus an open investigational new drug exemption for FDA that permits protocol amendments. Similar to FDA, there is a 30-day default for Health Canada to review a CTA, but in Algorithme Pharma’s experience, it usually takes 21 days before Health Canada reviews and permits each study to begin. Also, while an ethics committee review is required for approval, it can be conducted in parallel, which may also save time. In Algorithme Pharma’s experience, it usually takes 58 days via FDA’s procedures before a Phase I study may begin versus 33 days via Health Canada’s procedures, which may be of value for sponsors.