Articles Posted in Human Drugs

Thumbnail image for Thumbnail image for Thumbnail image for Thumbnail image for gavelgold.jpgZogenix, Inc., the San Diego-based manufacturer of the extended-release hydrocodone drug Zohydro ER, has sued the Governor of Massachusetts in U.S. District Court in Boston to overturn as unconstitutional the state’s recent prohibition against prescribing and dispensing the medication.

Zohydro ER is the only FDA-approved hydrocodone drug indicated for daily, round-the-clock, long-term treatment of chronic pain for which other pain treatments are inadequate. The product, which was approved last year, is also the only available extended-release opioid drug containing hydrocodone alone, not combined with acetaminophen, which has been associated with liver damage.

The Governor of Massachusetts recently issued an “emergency declaration” establishing the ban, without consulting Zogenix, on the ground that a hydrocodone-only drug presents a greater risk of overdose and abuse than a hydrocodone combination drug. The ban would remain in place until “adequate measures are in place to safeguard against the potential for diversion, overdose and misuse.”
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multipills.jpgOn February 21, 2014, FDA issued a Draft Guidance that will now permit a fixed combination drug product containing a new active ingredient plus a previously approved active ingredient to qualify for New Chemical Entity (NCE) exclusivity, thereby preventing the filing of generic drug applications referencing the combination product for a period of 5 years. (A fixed combination drug is one containing more than one active ingredient, each in a fixed amount).

FDA’s prior approach, in effect since 1994, had denied NCE exclusivity status to a fixed combination drug product that included an already-approved active ingredient. By virtue of the new Draft Guidance, the Agency is changing its interpretation of pertinent sections of the Federal Food, Drug, and Cosmetic Act and its own regulations. Going forward, FDA will determine NCE exclusivity by considering the newness of each drug substance (active ingredient) in a fixed combination drug product. If one active ingredient is new, NCE exclusivity can be awarded to the entire product.

As reasons for the change, FDA cites: (i) the emergence of combination drug treatment as a standard of care for serious diseases such as cancer, cardiovascular disease and infectious diseases (e.g., HIV), and (ii) the need to encourage the development of fixed combinations to treat these and other diseases, because particular combinations have been shown to improve treatment response, lower risk of resistance and lower rates of adverse events.
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TVad.pngYou can hardly watch television without seeing a prescription drug advertisement. Often the most memorable part of the advertisement is the required voiceover disclosing a long list of all the risks associated with taking the drug. The problem becomes deciphering which risks are actually the serious ones. FDA seeks to find out if that long disclosure of risks results in “reduced consumer comprehension, minimization of important risk information, and potentially, therapeutic noncompliance due to fear of side effects.”

On February 18, 2014, FDA issued a notice seeking comments about its proposed collection of information – “Disclosure Regarding Additional Risks in Direct-to-Consumer (DTC) Prescription Drug Television (TV) Advertisements (Ads).” FDA proposes to investigate the impact of limiting the risk disclosure in prescription drug television advertisements to only those that are “serious and actionable” plus an alert that there are other risks associated with the drug but which are not disclosed in the advertisement.

FDA would like to hear from you by April 21, 2014 about: whether you think its investigation is necessary “for the proper performance of FDA’s functions;” whether the information will have practical utility; the validity of the methodology and assumptions its investigation will use; how the quality, utility and clarity of the information collected can be enhanced; and how the collection of information can be less burdensome on respondents.
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leerink.pngOn February 12 and 13, 2014, Leerink Partners LLC (“Leerink”) held its annual Global Healthcare Conference at the Waldorf-Astoria Hotel in New York, New York. Each year the Conference includes emerging themes in healthcare, where Leerink’s equity analysts moderate discussions with MEDACorp specialists to provide unique and timely insights.

In addition to the company presentations, this year’s line up featured the following panels or keynote speakers with some observed comments or trends:

• Panel: The Future of Medical Devices in an Evolving Landscape: A Shifting Emphasis to Patient Monitoring and Customizable Solutions

  • Patients view surgeons that incorporate robotics in their practice as the better doctors, driving more surgeons to utilize them in their practice. As surgeons become more familiar with these devices, patients may have more options for surgical procedures and implants.
  • Larger companies are looking at controlling infections caused by implanted medical devices with special coatings–either anti-infectives or antibiotics, particularly for use in higher-risk patients. There is an increasing need, however, for implants to have built-in tools for monitoring the devices. But as medical devices become more complex, such as hip, knee, or total joint replacements, these devices will require preapproval marketing applications (“PMAs”) with clinical data rather than less costly and time-consuming 510(k)-type premarket clearance applications. Since PMAs cost companies more than 510(k) applications, these newer devices will cost third party payors and patients more.
  • Hospitals continue to be under a lot of pressure not to lose patients, so they may seek lower margins by having surgeons add anti-infective coatings or antibiotics rather than purchasing more costly versions with the coatings or by importing “generic” implants from other countries that may not be as rugged as the versions cleared for use in the U.S. FDA’s new unique device identifiers and improved monitoring, however, may reduce use of such imported devices with unclear pedigrees.

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drugs.pngOn January 6, 2014, FLH Partner Brian J. Malkin was quoted in an article by Derrick Gingery in The Pink Sheet entitled “Generic Drugs 2014: OGD Creates Internal Review Goals, May Make OND-Inspired Changes”.

Gingery’s article focused on FDA’s Office of Generic Drugs (“OGD”) taking steps to meet review deadlines that will be imposed by the Generic Drug User Fee Act (“GDUFA”), and enacted by the Food and Drug Administration Safety and Innovation Act (“FDASIA”) of 2012. For example, sixty percent of all applications accepted for filing in fiscal year 2015 must be reviewed within 15 months, which is included in a GDUFA commitment letter. According to the article, as of December 1, 2013, OGD’s project managers started setting internal goals to help reviewers get used to a review clock–a new concept for OGD but something that has been around since the Prescription Drug User Fee Act (“PDUFA”) first implemented in the 1990s for FDA’s Office of New Drugs (“OND”). Acting OGD Director Kathleen Uhl, M.D. (“Cook”) commented there, “We need to have all the reviewers practice the review to a goal date and then we need to monitor what’s our predictability of meeting those goal dates.” Uhl also told Gingery that the “primary purpose” of the goal dates was to help OGD determine the time it will take to complete various parts of the abbreviated new drug application (“ANDA”) reviews and would not be shared with sponsors.

Malkin was asked to comment on the internal goals, which appeared in the article as follows:

Attorney Brian Malkin, of Frommer, Lawrence and Haug LLP, agreed that the internal goals likely would not be helpful to sponsors.

“They’re not going to be able to react to FDA’s deadlines unless FDA shares additional information with them, except perhaps to set some of their own timetables for what FDA may be doing on their end,” Malkin said in an interview.

Malkin said the aim appears to be finding areas where the process can become more efficient.

“It’s tied to FDA’s realistic expectations of what they can do to meet their timeframes, but also … it may not be exactly what industry thought they were getting,” he said. “The concept would suggest shorter review times, but we’ll have to see.”

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petition.pngIn a previous post, we covered Gilead’s Citizen Petition to the FDA requesting FDA change its policy on how it allocates five years marketing exclusivity. Gilead argued that the current ruling whereby the five year exclusivity cannot be granted if even one active ingredient in the new drug application (“NDA”) has been previously approved should be altered. Stribild®, which has two previously-approved active ingredients and two new active ingredients, is currently precluded from obtaining the five years new chemical entity (“NCE”) exclusivity.

Mylan filed a Comment in Response, supporting FDA’s current FDA interpretation, arguing against the various points raised in Gilead’s Citizen Petition. First, Mylan points out that FDA’s interpretation is not a matter of policy but governed by the plain language of the statute passed by Congress. The relevant statute is “The Drug Price Competition and Patent Term Restoration Act of 1984” (“Hatch-Waxman” or “the Act”) which states in the section dealing with allocation of the five-year new chemical entity (“NCE”) marketing exclusivity: “[I]f an application submitted under subsection (b) of this section for a drug, no active ingredient … of which has been approved in any other application under subsection (b) of this section.” Mylan argued that: (i) despite Gilead’s attempts at re-interpreting the meaning of “drug” and “active ingredient”, the statute still plainly says that there must be no active ingredient in the NDA that has been previously approved for the five year exclusivity to be granted and (ii) when Congress wrote “an application submitted under subsection (b) for a drug”, it reasonably understood the word “drug” as used in this phrase to mean drug product and, not as Gilead would like to believe, a single component of the drug, such as the active ingredient.

As further support, Mylan pointed to the language of the three-year new clinical data marketing exclusivity provision:

Section 505(j)(5)(F)(iii) states:
If an application submitted under subsection (b) for a drug, which includes an active ingredient (including any ester or salt of the active ingredient) that has been approved in another application under subsection (b), is approved after the date of the enactment of this subsection and if such application contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the application and conducted or sponsored by the applicant, the Secretary may not make the approval of an application submitted under this subsection for the conditions of approval of such drug in the subsection (b) application effective before the expiration of three years from the date of the approval of the application under subsection (b) for such drug.
Thus, Mylan argued, taken together the plain language of the statute for both exclusivities leads to the conclusion that the current FDA interpretation is correct.

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handsoap.jpgOn December 17, 2013, the FDA issued a Proposed Rule for consumer antiseptic wash drug products. Prior to this Proposed Rule, the last Tentative Final Monograph (“TFM”) issued for antiseptic active ingredients was in 1994 (59 Fed. Reg. 31,402), which classified 22 active ingredients for over-the-counter (“OTC”) antiseptic handwash use.

The new Proposed Rule affects manufacturers of antibacterial hand soap and hand and body wash products containing OTC antiseptic active ingredients for repeated daily use, to be used with water. Those products do not include hand sanitizers or wipes. Additionally, the Proposed Rule is only to evaluate consumer antibacterial products and not health care setting antibacterial products, which have distinct proposed use settings, target populations, and risks for infection.

The Proposed Rule requires manufacturers of antibacterial soaps and washes to: (1) demonstrate the products are safe for long-term daily use; and (2) demonstrate with clinical data that the products are more effective than plain soap and water in the prevention of illness and the spread of infection. The manufacturers have one year to submit new data demonstrating that safety and effectiveness. If a manufacturer cannot demonstrate those two requirements, then it will have to reformulate the product (remove the antibacterial active ingredient).
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troubleswallowingpills.pngOn December 9, 2013, FDA issued a new draft guidance: Size, Shape, and Other Physical Attributes of Generic Tablets and Capules. FDA said that it issued the guidance because it is concerned that patients perceive differences in the physical characteristics (e.g., size and shape of a tablet of capsule) of generic drugs in relation to its referenced listed drug (“RLD”) counterpart. FDA believes that these perceived differences are “important” and “may affect patient compliance and acceptability of medication regimens or could lead to medication errors.” FDA does not plan for the Guidance to apply to generic drugs that are already on the market, unless there are safety issues, or other oral dosage forms.

According to the Guidance, many individuals have difficulty swallowing tablets and capsules, perhaps as many as 40 percent of Americans. Of these individuals, most blamed the dosage form size as an issue. In some instances, the larger tablets or capsules have been “shown to prolong esophageal transit time,” which may lead to disintegration of the product in the esophagus or cause injury to the esophagus, or more general adverse events such as pain, gagging, choking, and aspiration. In the industry, these larger tablets or capsules have been called “horse pills.” Some tablet and capsule shapes are known to be easier to swallow and have faster esophageal transit times than similar dosage forms with the same weight, e.g., oval sizes are easier to swallow than round. In turn, patient compliance may be affected by the size and shape of a tablet or capsule. Other physical attributes that affect ease of swallowing include coatings, weight of the tablet or capsule, and surface area of the dosage form.

As a result, FDA recommends that as part of its quality initiatives for generic drug products, generic oral tablets and capsules should be of a similar size to their corresponding RLD. In particular:

  • If the RLD is less than or equal to 17 mm in it largest dimension, the generic product should be no more than 20 percent larger than the RLD in any single dimension (resulting dimention not to exceed 17 mm) and no more than 40 percent larger than the RLD in volume.
  • If the RLD is greater than 17 mm in its largest dimension, the generic product should be no larger than the RLD in any single dimension or volume.
  • We recommend the largest dimension of a tablet or capsule should not exceed 22 mm and that capsules should not exceed a standard 00 size

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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.
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genericdrug.jpgFDA is proposing to amend its regulations to permit generic drug companies to add or strengthen safety warnings in labeling of their products on the basis of newly acquired safety information, even before the Agency has approved this safety information in the labeling of corresponding brand name drugs.

Under current rules, a generic drug must have the “same labeling” as its reference listed drug. This prevented an ANDA holder from inserting or altering a safety communication unless and until FDA has approved this information in the labeling of the brand name drug.

The purpose of the amendment is to “level the playing” field for generics, which arises from two conflicting Supreme Court decisions involving Federal preemption of safety warnings in prescription drug labeling. In Wyeth v. Levine, the Court held that a failure to warn claim in a Vermont personal injury action was not preempted by FDA labeling regulations, because the brand name drug company could have voluntarily amended its labeling to include a stronger safety warning even if FDA had not approved it. In contrast, the Court subsequently held in Pliva v. Mensing that a state failure to warn claim was preempted by FDA-approved labeling, since the generic company could not unilaterally add or strengthen its warning due to the same labeling requirement.
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