Category: Jonathan Darrow

Graph with number of biosimilar approvals on the X axis and years from 1970 until 2018 on the Y axis. The line on the graph represents a generally upward trend.

The Rise of Biosimilars: Success of the BPCIA? (Part III)

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By Jonathan Darrow

This is Part III in a series exploring the history, challenges, and opportunities in the regulation of biosimilars, or biologic medical products that are very similar to already approved biological medicines.  Part III considers a path forward in the regulation of biologics.  For Part I, click here.  For Part II click here.

A Path Forward

The small number of biosimilar approvals compared to generic drug approvals cannot establish the failure of the BPCIA due to differences in industry familiarity with each follow-on pathway, the number of reference products available for copying, patient population sizes, patent barriers, and drug costs. The later arrival of US laws and guidance documents—not inadequate legal design—is the most straightforward explanation of why the first US biosimilar approvals were delayed compared to those in Europe.

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Graph with number of biosimilar approvals on the X axis and years from 1970 until 2018 on the Y axis. The line on the graph represents a generally upward trend.

The Rise of Biosimilars: Success of the BPCIA? (Part II)

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By Jonathan Darrow

This is Part II in a series exploring the history, challenges, and opportunities in the regulation of biosimilars, or biologic medical products that are very similar to already approved biological medicines.  Part II covers some key considerations and factors that impact the biologics market and regulation.  For Part I, click here.

Reference Products Available for Copying in 1984

Because most post-1962 drugs enjoyed a 17-year patent term (changed to 20 years in 1995), there was little need for an abbreviated pathway in the years immediately following the Kefauver-Harris Amendments. But as patents expired, increasing numbers of post-1962 drugs became available for copying yet were ineligible as reference products under the 1970 ANDA regulations. On the eve of the Hatch-Waxman Act, Congress estimated that approximately 150 post-1962 drugs were off-patent but had no generic equivalent. This backlog of available reference products produced a surge in ANDA approvals following enactment of the new law (Exhibit 1).

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Graph with number of biosimilar approvals on the X axis and years from 1970 until 2018 on the Y axis. The line on the graph represents a generally upward trend.

The Rise of Biosimilars: Success of the BPCIA? (Part I)

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By Jonathan Darrow

This is Part I in a series exploring the history, challenges, and opportunities in the regulation of biosimilars, or biologic medical products that are very similar to already-approved biological medicines.  This Part briefly covers the history of American regulation of biologics and touches briefly on the European experience.

The Biologics Price Competition and Innovation Act (BPCIA), part of the 2010 Affordable Care Act, sought to drive down prices for biologics, much as the 1984 Hatch-Waxman Act did for small-molecule drugs. By allowing manufacturers of follow-on products to rely in part on the clinical data of the brand-name reference product, both laws were designed to lower development costs and attract competitors.

Since the BPCIA’s enactment, however, scholars have compared it unfavorably to the Hatch-Waxman Act, criticized its pathway as “obstructed” and lacking in sufficient incentives, lamented the scarce approvals it has produced, and recommended that it be “abandoned.” Although criticisms of the law are not without basis, their collective implication—that the BPCIA is irredeemably defective and will never yield robust competition—may be wrong.

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Pills spilling out of a few bills rolled in a cylinder

New Podcast Tackles Drug Pricing, Market Power, and More

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About 24 percent of adults report difficulty in affording prescription drugs, including 9 percent who report it is “very difficult” to afford them and 15 percent who report it is “somewhat difficult.” Approximately 11 percent of adults reported rationing high-priced drugs in 2017.

Recently, @Arnold_Ventures launched a new podcast, “Deep Dive with Laura Arnold,” that tackles the issue of drug prices. In its debut episode, podcast host Laura Arnold sits down with David Mitchell, founder of Patients for Affordable Drugs, who began his fight for drug pricing reform after a devastating diagnosis of an incurable blood cancer. The cost of his medicine each year: $325,000. They discuss a broken system built to serve those who make money — not those who depend on it for their health.

“Our mission is to improve people’s lives by fixing broken systems,” Arnold says. “We view drug pricing as a broken system, and not just from a theoretical perspective, but from a human perspective. We see this as a crisis in our nation. People can’t afford their drugs, and the consequences for all of us, both personally and from a societal perspective, are dire.”

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Tertiary Patents: An Emerging Phenomenon

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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

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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

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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

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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?

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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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