Source: http://blog.petrieflom.law.harvard.edu/author/jdarrow/
Timestamp: 2019-04-21 20:15:35+00:00

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Available March 26, 2019, a new course “FDA and Prescription Drugs: Current Controversies in Context” will be offered at no cost via the HarvardX online platform (part of the non-profit EdX consortium). It is designed around a 6-week, self-paced schedule, and features expert guest speakers including former FDA commissioner Margaret Hamburg.
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.
Xolair for Chronic Itch: Magic Bullet or Marketing Hype?
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.
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.
Finasteride as an FDA-Approved Baldness Remedy: Is It Effective?
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.
At $28,000 a Dose, How Effective Is Acthar?
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?
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.
On October 3, 2012, the FDA’s Division of Professional Drug Promotion issued an untitled letter to Genentech in connection with its cancer drug Tarceva. Tarceva (erlotinib) was approved in 2004 for the treatment of non-small cell lung cancer, and has since been approved, in combination with Gemzar (gemcitabine), for the treatment of pancreatic cancer. Its approval letter reported a tumor response that was 9 times greater with Tarceva than with placebo (0.9% in placebo versus 8.9% in Tarceva), but relatively modest improvements in 1-year survival rates: approximately 8 of 10 patients on placebo did not survive 1 year, while about 7 of 10 patients on Tarceva did not survive (see page 6, line 102 of the approval letter). A 2005 New York Times article was less than enthusiastic about Tarceva’s efficacy, noting that it (along with several other cancer drugs that were new at the time) “help[s] most patients only marginally . . . .” Despite its modest efficacy, Tarceva was reported in the same New York Times article to cost almost $31,000 per year. A number of patents are listed in the FDA’s Orange Book as covering Tarceva until 2020.
The recent untitled letter accused Genentech’s promotional materials of misleadingly indicating that Tarceva in combination with gemcitabine extended overall survival by 3.7 months in comparison with gemcitabine alone, when the actual increase in survival was only about 12 days. The FDA characterized the discrepancy as “drastically overstat[ing] the efficacy of Tarceva.” (The figure of 3.7 months was derived, according to the FDA, “from a retrospective, exploratory subgroup analysis that does not provide substantial evidence to support the efficacy claims cited . . . .”). In addition, the front cover of one of the promotional materials in question contained an image of an hourglass positioned on its side, presented with the claim: “Extending survival for moments that matter.” Although the claim with its associated image may be literally true (“moments” is left undefined), the FDA characterized the image and claim as “drastically overstat[ing] the overall survival benefit for patients” because it “strongly suggests that time is standing still for the cancer patient because of Tarceva therapy.” The FDA noted a number of other instances of misleading overstatement of efficacy or minimization of risk.
The October 3 Tarceva letter brings to 23 the total number of Drug Marketing and Advertising Warning Letters (and untitled letters) listed by the FDA’s Office of Drug Promotion as having been sent this year.

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