Tertiary Patents: An Emerging Phenomenon

By Jonathan J. Darrow

Brand-name pharmaceutical manufacturers have long been known to try to protect and extend their market exclusivity periods by obtaining patents on a drug’s substance (“primary patents”) and also on its peripheral features, such as formulations or methods of manufacture (“secondary patents”). A new study describes an emerging phenomenon of “tertiary patents,” which have the potential to further delay and discourage market entry in the context of drug-device combination products.

Combination products are defined by the U.S. Food and Drug Administration (FDA) to include therapeutic products that combine a drug with a device, such as an inhaler or injector pen. These products can sometimes offer life-changing or life-sustaining treatment, as with naloxone (Narcan) for opioid overdose or epinephrine (EpiPen) for severe allergic reactions. In recent years, these and other similar products have been the subject of substantial controversy related to their prices and prolonged lack of generic competition.

To investigate the potential role of patents on the prices and exclusivity periods of drug-device combination products, two researchers at the Program On Regulation, Therapeutics, And Law (PORTAL) at Brigham and Women’s Hospital and Harvard Medical School (where I hold a faculty appointment) conducted a comprehensive evaluation of drug-device combination patents registered with the FDA. They found that patents related to drug delivery devices have tripled since the year 2000 and contribute a median of five years of additional market exclusivity to those products (subject, of course, to potential judicial or administrative patent invalidation). Furthermore, the researchers identified a subset of 31 products having only device patents (i.e., having no primary or secondary patents), and found that these patents were scheduled to expire a median of 17 years after FDA approval. Read More

Capsule Endoscopy Instead of Colonoscopy? The FDA Approves the PillCam COLON

By Jonathan J. Darrow

In January, the Food and Drug Administration (FDA) approved the use of the PillCam COLON 2 as a minimally-invasive means of viewing the colon, a development that is sure to be welcomed by U.S. patients who currently undergo an estimated 14 million colonoscopies each year.  While the approval represents a major step forward, the PillCam is unlikely to supplant current procedures just yet.

The colon has traditionally been examined via optical colonoscopy, a procedure perceived by many to be uncomfortable and embarrassing that involves insertion through the rectum of a 5-6 foot long flexible tube as part of an examination that can take 30 to 60 minutes. Air must be pumped in through the rectum in a process called “insufflation.” Sedatives and pain medication are generally used to help relieve discomfort. In contrast, the PillCam COLON contains a power source, light source, and two tiny cameras encapsulated in an easy-to-swallow pill that produces no pain or even sensation as it moves through the colon. Reflecting the absence of discomfort, one report from a clinical researcher noted that a few patients have insisted on X-rays to confirm that the device had passed in their stool (FDA Consumer). The pill takes about 30,000 pictures before passing naturally from the body, which usually occurs before the end of its 10-hour battery life.

The safety record of capsule endoscopy, the category to which the PillCam COLON belongs, so far appears to compare favorably with the alternatives. Capsule endoscopy may be less likely to produce accidental colonic perforations or other serious complications, which occur in less than 1% of traditional colonoscopies despite the best efforts of the treating physician. Tears of the colon wall can in turn “rapidly progress to peritonitis and sepsis, carrying significant morbidity and mortality.” (Adam J. Hanson et al., Laparoscopic Repair of Colonoscopic Perforations: Indications and Guidelines, 11 J. Gastrointest. Surg. 655, 655 (2007)). Splenic injury or other serious complications also occur rarely with optical colonoscopies. Unlike “virtual colonoscopy,” which uses computed tomography (CT) to peer into the body, capsule endoscopy does not involve bombarding the body with radiation. A leading study published in the New England Journal of Medicine reported no serious adverse events among 320 subjects given the PillCam COLON, and concluded that use of the device was “a safe method of visualizing the colonic mucosa through colon fluids without the need for sedation or insufflation.” Read More

Upcoming Talk: Pharmaceutical Efficacy, The Illusory Legal Standard

Jonathan Darrow, PFC Student Fellow and HLS SJD student, will be presenting his chapter – “Pharmaceutical Efficacy: The Illusory Legal Standard” – on Tuesday, April 23, at noon in Hauser 105, Harvard Law School, Cambridge.

If you’d like to review the chapter in advance, please be in touch with Jonathan directly: jon underscore darrow at yahoo dot com.

Branded Drugs and Generics: Reverse Payment Settlement Agreements

By Jonathan J. Darrow

Earlier this week the Supreme Court heard oral arguments in FTC v. Actavis, in which the Federal Trade Commission is asserting that it is impermissible for a brand name drug company to pay a generic drug company to stay out of the market. Normally, such collusive behavior would constitute a clear violation of antitrust laws, because it reduces competition and thereby has the potential to raise prices to the detriment of consumers. But a complication arises in the case of branded and generic drugs because a patent is involved, giving the patent holder the lawful right to exclude competitors from the marketplace.

In a typical “reverse payment” case, the scenario unfolds as follows: First, the branded company enters the market with a new drug product that is covered by a patent. Some time later, but before the expiration of the patent, a generic drug company seeks to market a generic version of a drug, asserting that the patent is either invalid or not infringed (the assertion takes the form of a Paragraph IV certification, named for the section of the U.S. statute under which the certification arises, see 21 U.S.C. 355(j)(2)(A)(vii)(IV)).  Rather than litigate the case to completion, however, the two firms settle, with the patent holder agreeing to pay the generic company to stay off the market until some future date, such as the date that the patent is set to expire. The “monopoly” profits are thus shared between the two companies, to the detriment of consumers.

Defenders of reverse payment settlements argue that such agreements should be legal so long as they are “within the scope of the patent,” that is, so long as the restrictive agreement does not extend beyond the patent expiration date (see, e.g., Edward Stewart, Skepticism from the Court in Drug Case, N.Y. Times, Mar. 25, 2013).  The fundamental weakness of this argument—and what the N.Y. Times article does not mention—is that many drug patents (73% according to a 2002 government report (see page vi)) turn out to be invalid, not infringed, or otherwise insufficient when litigated in court. If many drug patents would be invalid or not infringed if litigated to conclusion, then the actual “scope of the patent” would be less than its nominal term would suggest, and the high cost borne by consumers would be greater than the patent law contemplates. Read More

Xolair for Chronic Itch: Magic Bullet or Marketing Hype?

By Jonathan J. Darrow

Earlier this week, the New York Times reported that Xolair (omalizumab), a monoclonal antibody approved in 2003 to treat allergic asthma, had recently shown efficacy in relieving hives patients of chronic itch (See Laurie Tarkan, Drug to Treat Asthma Could Relieve Hives Patients of a Chronic Itch, Study Says, N.Y. Times, Feb. 25, 2013, at A5).  The article noted that a Phase 3 trial (usually, the final phase before FDA approval) showed that a monthly injection of Xolair “significantly reduced hives and itchiness.” Quoting the lead author of the study, the article reported that Xolair “is the magic bullet patients have been waiting for for the last 40 years.”  Is it?

An initial concern is the large number of conflicts of interest associated with the study. An examination of the Phase 3 trial as published in the New England Journal of Medicine (NEJM), on which the New York Times article is based, reveals that the trial was “[f]unded by Genentech and Novartis,” both of which sell Xolair.  The lead author and at least one other co-author of the study have received consulting fees from one or both companies, while another of the co-authors (Karin Rosen) is the medical director for Genentech.  Conflicts of interest, however, do not necessarily mean that the drug is in fact ineffective.  To determine efficacy, one must look at the evidence.

The NEJM study reports that test subjects received either placebo or Xolair at doses of either 75 mg, 150 mg, or 300 mg.  Starting from a baseline itch-severity score of about 14, the data were as follows:

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The High Cost of Health Care: Why Some Pay $240 for a $9 Bottle of Pills

By Jonathan J. Darrow

An earlier post discussed the equivocal efficacy of Propecia (finasteride) as a baldness remedy, ending with the provocative assertion that, efficacy aside, “there is little reason for anyone ever to buy or consume Propecia (finasteride), or any doctor ever to prescribe it, since a much cheaper and identical chemical sold under the trade name Proscar (finasteride), is available.” This post continues the discussion, addressing one small component of the rising cost of healthcare—the cost of finasteride.  It explores why consumers pay as much as $240 for a bottle of Propecia (finasteride) when a $9 bottle of an equivalent, FDA-approved supply of the identical chemical is readily and legally available at nearby stores.

In the exorbitantly priced landscape of prescription drugs, there is at least one low-cost oasis: Wal*Mart.  Though some find reason to criticize the discount store, few would disapprove of the dozens of prescription medications Wal*Mart offers for an unbeatable $4 for a 30-day supply.  Cost-sensitive consumers can purchase everything from blood thinners to antidepressants to antibiotics at this price, while a 90-day supply is only $10 (and this price includes shipping to your doorstep).  A handful of drugs that cannot be sold at $4 per month sell for a still-modest $9.  For the 300 or so drugs on Wal*Mart’s list, this means there is no longer a need for $10 co-pays or snowy treks to the pharmacy in 15 degree weather.  That’s right: the Wal*Mart total price is less than most insurance company co-pays.  Finally, a major industry player seems to have put effective downward pressure on prescription drug prices.  Read More

Finasteride as an FDA-Approved Baldness Remedy: Is It Effective?

By Jonathan J. Darrow

Questionable baldness remedies have been peddled since the beginning of medicine. According to Pliny (23-79 A.D.), ashes of seahorse could cure baldness.  Almost 2000 years later, the British Medical Association warned the public of the increasing “number of preparations put forward for the cure of baldness,” particularly those which “are not applied locally but taken internally.”  The purported active ingredient? “[H]aemoglobin.”  (see Secret Remedies (1909), page 114).

While the medicinal use of a seahorse or dried blood matter may sound fanciful to modern ears, one has to wonder whether today’s public is any less credulous: Worldwide, consumers have spent over $400 million per year on a modern baldness remedy known by the trade name Propecia (finasteride).  Has science finally triumphed over a medical condition that has persisted through millennia? Today’s consumers might rationally believe that its has, given that Propecia is FDA-approved for the treatment of alopecia (baldness).  FDA-approved remedies must, according to federal law (21 U.S.C. § 355(d)), prove their efficacy in well-controlled, clinical investigations.

Yet one need only walk through a crowded street to see that, if a baldness cure has truly arrived, a surprising number of people have not availed themselves of it. Is Propecia, then, not effective? Let us take a look at the official data. Read More

At $28,000 a Dose, How Effective Is Acthar?

By Jonathan J. Darrow

In a well-researched, recent post, Patrick O’Leary addresses the FDA’s efficacy requirements as applied to an old drug, Acthar (corticotropin), that was first approved in 1952 and granted an orphan designation in 2010 for the treatment of infantile spasms. The initial approval therefore occurred before the Drug Amendments of 1962, which instituted a “new” statutory requirement of efficacy (more on this below). O’Leary points out that Acthar’s “grandfather” status does not entirely exempt it from the FDA’s efficacy requirements, and that the drug did survive an efficacy evaluation under the DESI program. But how effective is Acthar?

Neither O’Leary nor the New York Times article on which his post is based dig very far into the clinical trial data accepted by the FDA as supporting the efficacy of the drug as a treatment for infantile spasms, and I was curious to know what the evidence says about Acthar in this regard. Clinical trial data is presented—or perhaps more accurately, “buried”—in Section 14 of a drug’s FDA-approved label; in the case of “H.P. Acthar Gel” (NDA 022432), that label can be found here. What does the clinical trial data reveal?  The section is brief, just half a page, and notes that of “[t]hirteen of 15 patients (86.7%) responded to Acthar Gel as compared to 4 of 14 patients (28.6%) given prednisone (p<0.002).”  Nonresponders were then given the other treatment, with the following results. “Seven of 8 patients (87.5%) responded to H.P Acthar Gel after not responding to prednisone,” while “[o]ne of the 2 patients (50%) responded to the prednisone treatment after not responding to Acthar.”  As the p-value (0.002) indicates, the first figures, at least, are statistically significant.  These figures were also better than I expected: 86.7% efficacy with Acthar does seem much better than 28.6% efficacy with prednisone.  Read More

Pharmacy Compounding: Federal Law in Brief

by Jonathan J. Darrow

Until recently, most ordinary people had never heard of “pharmacy compounding.”  Then, a number of deaths and illnesses caused by a drug that was compounded in a Framingham, Massachusetts pharmacy propelled drug compounding to the national spotlight (see, e.g., Denise Grady et al., Scant Oversight of Drug Maker in Fatal Meningitis Outbreak, N.Y. Times, Oct. 6, 2012).

Compounding is the practice of preparing a drug for an individual patient’s needs, and is used when those needs cannot be met by a mass-produced drug.  See Thompson v. Western States Medical Center, 535 U.S. 357, 360 (2002).  For example, if a patient is allergic to a particular excipient (inactive ingredient) in an FDA-approved medicine, a doctor may order a special compounding pharmacy to prepare the medicine without that excipient. Because of the very small scale of compounding, Congress in 1997 attempted to exempt (via 21 U.S.C. § 353a) the industry from a number of provisions of the Food Drug and Cosmetic Act, including the requirement to submit a new drug application prior to interstate sale (21 U.S.C. § 355), the requirement that the drug labeling bear “adequate directions for use” (21 U.S.C. § 352(f)(1)), and the need to strictly follow good manufacturing practices, or GMP (see 21 U.S.C. § 351(a)(2)(B)).  A number of controls on compounding were included, however, such as the requirement that there be a valid prescription from a licensed practitioner (21 U.S.C. § 353a(a)(1)), that the drug be compounded by a licensed pharmacist (or physician) (21 U.S.C. § 353a(a)(1)), and that the drug be compounded from ingredients that meet certain quality standards (21 U.S.C. § 353a(b)(1)(A)–(B)).

However, § 353a—and with it, all of the provisions and exemptions just mentioned—was held unconstitutional in its entirety in Western States Medical Center v. Shalala, 238 F.3d 1090 (9th Cir. 2001), aff’d 535 U.S. 357 (2002), on the basis of certain restrictions on free speech that were also contained within the statute and which, according to the Ninth Circuit, could not be severed from the remaining provisions because “Congress intended to exempt compounding from the FDCA’s requirements only in return for a prohibition on promotion of specific compounded drugs.” See 535 U.S. at 366. Thereafter, the FDA promulgated a policy by which it would primarily “defer to state authorities regarding less significant violations” but would enforce a number of provisions relating to ingredient standards, unapproved substances, commercial scale production, adulteration, and promotion.  The FDA made clear that its enforcement activities “need not be limited to” these or any particular areas, however, thus negating any expectations that Congress’ now-invalidated exemptions might nevertheless provide a safe harbor through the weight of influence, if not law. Since then, the FDA has in fact exercised oversight of compounding pharmacies, as is evident from the handfuls of warning letters that it sends to non-compliant facilities each year.  These letters have addressed, for example, promotion that made unsubstantiated efficacy claims, contamination, and the large-scale manufacture of what were essentially copies of FDA-approved drugs.

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