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.” Nevertheless, capsule endoscopy is not risk-free. According the company behind the PillCam, Israel-based Given Imaging, there have been at least eight occurrences of the high-tech capsule becoming lodged (“retained”) inside the digestive tract, although this represents less than 1% of clinical trial subjects and appears to occur more frequently in patients with obstructions or other conditions that might require intervention in any event. In patients with known Crohn’s disease and suspected small bowel obstruction, for example, retention rates of 5% and 21%, respectively, have been reported. However, capsules that are retained, even for long periods, do not necessarily pose serious health risks (see Mukai Bhattarai et al., Longest Duration of Retention of Video Capsule: A Case Report and Literature Review, 5(7) World J. Gastrointestinal Endoscopy 352 (2013)).

Another appealing aspect of capsule endoscopy is cost: At around $500, the PillCam costs less than a colonoscopy, which can run $800 to $4,000 or more. In addition, a small number of competing capsules may eventually help to exert downward price pressure, including the EndoCapsule of Japan’s Olympus, the Sayaka of Japan’s RF Co. Ltd., the MicroCam of Korea’s IntroMedic, and the OMOM of China’s Jinshan Science and Technology Co. (See also J.L. Toennies et al., Swallowable Medical Devices for Diagnosis and Surgery: The State of the Art, 224 J. Mechanical Eng’g Sci. 1397 (2009) (special issue)). Rapidly declining prices may be unlikely, however, in part because of the lack of price transparency and conflicts of interest that reportedly characterize at least some segments the medical device industry (New York Times; Health Affairs).

Despite its safety, cost advantages, and obvious appeal from the patient perspective, the PillCam COLON was approved “for use only in patients who had an incomplete optical colonoscopy.”  This labeling reflects the FDA’s judgment that the PillCam COLON should only be used in those patients for whom a traditional colonoscopy cannot be completed, which might occur in patients with histories of abdominal surgery, diverticular disease, or other colon conditions. Only about 750,000 patients, representing approximately 5% of the 14 million colonoscopies noted above, experience incomplete colonoscopies and would therefore fall within the PillCam COLON’s labeled use.  Although physicians may lawfully use medical devices “off-label” according to their best knowledge and judgment (FDA Information Sheet), use by physicians as a substitute for a colonoscopy is unlikely unless and until the label indication is broadened.

If this limited approval seems unfortunate, the FDA decision summary explains that in a trial of 700 subjects who underwent both capsule endoscopy and an optical colonoscopy, the capsule failed to identify polyps about one third of the time (the exact figure depends on the method of calculation used; see Table 4 in the decision summary and accompanying discussion).  The limited labeling, therefore, reflects concern that the PillCam COLON might fail to diagnose conditions that would be apparent from a traditional colonoscopy. A 2009 article in the New England Journal of Medicine similarly concluded that the PillCam COLON was not as good as a standard colonoscopy in detecting polyps in the colon.

Concerns over effectiveness may not be the only reason for the limited labeling, however. Colonoscopies generate the majority of revenue for most gastrointestinal physicians (See Daniel Rosenberg, Given CEO: PillCam To Compete With Virtual Colonoscopy, Dow Jones Newswire, May 17, 2005; see also New Tests, New Future for Doctors), and anesthesiologists also enjoy revenues from the procedure.  In 2013, a particularly incisive exposé in the New York Times, entitled Colonoscopies Explain Why U.S. Leads the World in Health Expenditures, explained the high costs and industry pressures surrounding high-cost colonoscopies. Widespread use of capsule endoscopy (or other techniques, such as stool testing) could upset this status quo, potentially allowing administration by general practitioners.  Images could even be transmitted over the Internet to be analyzed by trained personnel anywhere in the world. Expanded use of the PillCam COLON as a substitute for colonoscopies may indeed be the “motherlode” for capsule manufacturers, as analysts have stated, but large increases in utilization of capsule endoscopy technologies could decrease physician revenue from the procedures that are replaced. Analysts have praised Given Imaging’s management as shrewdly positioning the PillCam COLON as an additional tool for the gastroenterologist, rather than a substitute for traditional procedures.

It is difficult to know whether or to what extent these financial and political dynamics have delayed the approval of the PillCam for use in the colon. Predecessors to the PillCam COLON were FDA approved in 2001 for imaging the small intestine, and in 2004 for imaging the esophagus. But in 2008, the FDA rejected the manufacturer’s application to commercially market the PillCam COLON in the United States, even though a similar device had been approved in Europe in 2006 and was eventually classified by the FDA as a class II (moderate risk) device. (See generally Regulation of Medical Devices in the United States and European Union, NEJM.) Eight years passed between the European approval and the FDA’s decision last month. According to a press release, eighty countries allowed commercial sale of the PillCam COLON by the time of US approval, including Japan, Canada, and Australia.

Although lower sensitivity in detecting polyps warrants caution when expanding the PillCam COLON’s labeling, the superior sensitivity of colonoscopy over capsule endoscopy improves public health outcomes only to the extent that patients actually undergo the diagnostic procedure at all.  The creation of better odds is illusory if the approach used (i.e., insisting that patients try colonoscopy first) causes patients to stay on the sidelines. Considering the patient perspective is particularly important with respect to prevention, where delays in undergoing diagnostic tests can be deadly. Colorectal cancer is the second-most deadly cancer in the United States, killing 52,000 annually (See Centers for Disease Control), but is often curable if detected early. Yet only about two-thirds of those who should undergo colonoscopies actually receive one as recommended. The percent screened may be even lower for those of lower socio-economic status and those without insurance. For obvious reasons, patients in general will be far less reluctant to ingest a painless and lower-cost pill-camera than to undergo a traditional colonoscopy.

Health authorities should also consider the extent to which lower sensitivity might be offset by more frequent administration. Current guidelines from the U.S. Preventive Services Task Force call for colonoscopies every 10 years for those aged 50 to 75, but a pill could easily be administered more often (although doing so would increase cost). The guidelines already acknowledge that more frequent screening with fecal occult blood testing or sigmoidoscopy is “approximately equally effective in life-years gained” compared to decennial colonoscopies. Moreover, as with other disruptive technologies, technical gains are likely to improve capability over time. As just one possibility of how this might happen, the 30,000 or so images taken by capsule endoscopy might eventually be analyzed using automated software rather than, or as a supplement to, the fallible and inconsistent human eye (See Docs Can Miss Abnormalities Captured by Pill Cameras, Reuters).

The potential gains that capsule endoscopy offers with regard to safety and patient comfort are unlikely to disappear, while cost advantages and effectiveness will likely improve over time. In as little as a generation from now, patients may look back to the days of dreaded but routine colonoscopy screening with sympathy for the millions of healthy individuals who had to undergo so uncomfortable a procedure.

Acknowledgment: The author wishes to thank Aaron Kesselheim and Ameet Sarpatwari for their helpful contributions.

Jonathan Darrow

Dr. Jonathan J. Darrow is a an Assistant Professor at Harvard Medical School and the Program on Regulation, Therapeutics, and Law (PORTAL) at Brigham & Women's Hospital. He received his research doctorate (SJD) in pharmaceutical policy from Harvard University, where he completed an LLM program in intellectual property (waived), as well as degrees in genetics (BS), law (JD), and business (MBA) from Cornell University, Duke University, and Boston College. After qualifying for the California and Patent bars in 2001 and 2002, Dr. Darrow served as a senior law clerk at the U.S. Court of Appeals for the Federal Circuit, worked in private law practice at Cooley LLP and Wiley Rein LLP, taught on the faculties of four universities and for the World Intellectual Property Organization, authored several law textbooks, supported the intellectual property divisions of WHO and WTO, lectured widely on issues of FDA regulation, and published numerous articles on issues such as expanded access, the breakthrough therapy designation, competition policy, pharmaceutical patenting, gene therapies, drug efficacy, biological products, therapeutic vaccines, and expedited development and approval programs. He is an author of several textbooks, including Cyberlaw: Management & Entrepreneurship (Cengage 2012; Aspen 2015), The Legal and Ethical Environment of Business (Aspen 2014 and Wolters-Kluwer 2d ed. 2018), and Business Law and Management for Entrepreneurs (Edward Elgar, forthcoming). He has lectured widely on issues of FDA regulation, and published numerous articles on issues such as expanded access, the breakthrough therapy designation, competition policy, pharmaceutical patenting, gene therapies, drug efficacy, biological products, therapeutic vaccines, and expedited development and approval programs.

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