Have You Been Smoking Something That Is Biologically Active?

Up in smoke… . That’s where my money goes.

—Cheech and Chong

Physicians worldwide are currently spending millions of dollars of other people’s money for endovascular coils that are commonly called “biologically active.” I fear that too few of these physicians have paused to consider what the term “biologically active” actually means and why they are spending so much money for these coils. I therefore suggest that we critically examine the term “biologically active.” Let us start with “biologically.” After consulting several dictionaries, I propose that we define “biologically” as “in a manner related to a living organism.” I will similarly propose that we define “active” as “causing change.” Clearly, these terms are extremely broad. When the words are combined to form “biologically active,” we are still left with an extremely broad term that might be most simply defined as “causing change in a living organism.” That definition would lead me to conclude that an enormous number of objects in the universe are biologically active, ranging from my college roommate’s stash, a Grateful Dead song, the sun, a cup of coffee, and the journal you are reading to any material implanted in an animal, plant, fungus, bacteria, or virus. The term “biologic activity” is thus so broad as to be almost useless.

When the term “biologically active” is used in reference to endovascular coils for cerebral aneurysm therapy, I think that it is intended to mean “eliciting more of a tissue response than platinum.” Although this definition of biologic activity is a bit less broad, it is still so broad that it is nearly useless as a scientific term. Yet, it appears to be rather useful as a marketing term.

It remains unknown exactly what the tissue response to a biologically active coil should ideally be to make it more efficacious than platinum. It will only be known post hoc—that is, after a device is shown to safely reduce aneurysm recurrence and rehemorrhage, we will know that it generates a favorable tissue response. In the meantime, theoretically beneficial “biologic activities” such as inflammation, fibrosis, neointima formation, and endothelialization are proposed.1–6

Detachable platinum coils were certainly a major advance in the treatment of cerebral aneurysms.7,8 Contrary to popular opinion, platinum coils are “biologically active.” When implanted in a biologic system (eg, human cerebral aneurysm), they elicit a tissue response (eg, thrombosis and fibrosis). Platinum coils disturb blood flow within an aneurysm and thereby promote thrombosis. Thrombosis then progresses to fibrosis in many cases. The major weakness of platinum coils is that the rate of aneurysm recurrence is about 14%–21% overall,9–12 which is about 10 times higher than the recurrence rate following surgical clipping.13 Theoretically, this recurrence rate may be related to the relatively biologically “inert” or “inactive” nature of platinum. This “inactive” nature of platinum made it an attractive material for coil construction during the development of coils for cerebral aneurysm therapy because biologic activities such as thrombosis, fibrosis, and inflammation might lead to clinical complications. This relative biologic inactivity, however, is now hypothesized to be causative of aneurysm recurrences following endovascular coil therapy.1–3,5,6 The hypothesis is that aneurysm recurrences are due to a failure of platinum coils to induce an adequate biologic response to the coils rather than to a mechanical failure of the coils. The hypothesis leads us logically to theorize that aneurysm recurrences can be reduced by changing the biologic response to the chemistry of the device. Thus, coil modifications have been proposed that are directed at the biologic response to the chemistry of the device rather than the physical properties of the device. This hypothesis is widely discussed and has led to the introduction of multiple devices for aneurysm therapy; however, the hypothesis remains unproved. Indeed, much of the research published in this area would fail to pass the basic standards of a high school science project.

What we seek with biologically active coils is a nearly perfect balance between promotion of an effect that reduces aneurysm rehemorrhage and recurrence—which is primarily how we would measure efficacy—and avoidance of negative clinical effects, especially promotion of aneurysm rupture and/or excessive thrombosis—which is primarily how we would measure safety. The choice of biologically active materials, however, is as much related to regulatory issues as it is related to biologic issues. The first priority of development of such a device has been to get the device past regulatory hurdles and onto the market, with proof of efficacy of biologic activity as a secondary priority. Before biologic activity is addressed, “regulatory inactivity” is established.

The combination of platinum and polyglycolic acid/polylactic acid (PGLA) polymer in Matrix coils (Boston Scientific, Natick, Mass) proved to be fairly straightforward in terms of passing through the regulatory process at the US Food and Drug Administration (FDA). Platinum coils were already approved by the FDA for treatment of cerebral aneurysms. PGLA polymer has been implanted in millions of humans as Vicryl (Ethicon, Cincinnati, Ohio) suture and is, therefore, well known to have an excellent safety profile in humans. With the help of this historical information, Boston Scientific managed to gain approval for Matrix coils by claiming that this device was “substantially equivalent” to another FDA-approved device (ie, platinum coils). Ironically, however, the marketing of these coils is based on the coils being substantially inequivalent to platinum coils. Whoever said that “you can’t have it both ways” clearly did not work for the medical device industry.

“Regulatory inactivity” has continued to have excessive influence on the development of biologically active coils. The Cerecyte coil (Micrus, Sunnyvale, Calif), the Nexus coil (MicroTherapeutics, Irvine, Calif), and the HydroCoil (MicroVention, Aliso Viejo, Calif) were all approved by the FDA on the basis of claims that they are “substantially equivalent” to platinum coils. Cerecyte and Nexus coils are “me-too” products that both deliver PGLA polymer. I am quite certain that they were produced and sold not because the manufacturers thought that they were the best way to reduce aneurysm recurrences. Rather, they were produced and sold because the manufacturers thought physicians would buy them just as they bought Matrix coils—and, of course, because the regulatory process was trivial. This is not “evidence-based” medicine. This is “fad-based” medicine. Other device modifications such as collagen 1,2 and cells on coils 6 might improve the recurrence rate of cerebral aneurysms. The regulatory pathway, however, would be rather difficult for such devices containing biologically derived materials, thus making medical device manufacturers much less interested in pursuing these treatment strategies. Why would a medical device manufacturer want to take a risk on devices that have expensive regulatory pathways when it can readily market the “biologic activity” of coils that have “regulatory inactivity”?

If you are not confused and concerned by inconsistencies in medical device regulation, you are probably not paying attention. Recently, drug-eluting stents have revolutionized the management of coronary artery disease. They, as were the coils containing PGLA, were designed to elicit a different response than bare metal. Because of regulatory inconsistencies, however, the introduction of drug-eluting stents had a very different course than the introduction of biologically active coils. Drug-eluting stents were required to get premarket approval (PMA) from the FDA. PMA of medical devices, in most cases, involves collection of data in prospective, randomized, controlled trials. Are coils that deliver PGLA not drug-eluting coils and therefore worthy of the same level of regulation as drug-eluting stents? These coils deliver a foreign material (ie, PGLA), which then dissolves over several weeks, with the clear intent of that material eliciting a biologic response from the surrounding tissue. Perhaps PGLA attached to coils was not looked at as a drug because of its historical use as a mechanical device (eg, Vicryl suture) rather than as a drug. In my opinion, however, the coils incorporating PGLA should be considered drug-eluting coils.

Few medical devices are truly revolutionary. Rather, most devices offer an incremental improvement in therapy. We need to realize that we rarely succeed with the first iteration of an invention. As a schoolboy, I learned that Thomas Edison’s laboratory tested thousands of filaments in the process of inventing the light bulb. With that in mind, doesn’t it seem absurd that we would expect the very first iterations of biologically active coils would dramatically reduce cerebral aneurysm recurrences?

It is time for the field of interventional neuroradiology to mature scientifically. Part of that maturation should be the development of a healthy skepticism toward new devices. The only reliable way to prove that an incremental improvement has truly been made is to conduct prospective, randomized, controlled trials that compare a theoretically improved device to the current standard of treatment. Thus far, biologically active coils have only been studied with single-center case series and postmarket registries. These registries are generally initiated, funded, and controlled by the device manufacturers. The device manufacturers have the right to “spin” the data from their own registry and also the right to entirely avoid the peer-reviewed literature process if they wish.14 Thus, postmarket registry data are potentially very biased. Also, because a postmarket registry lacks a control group other than historical controls from the literature, data interpretation is very limited. Indeed, unless a registry demonstrates an overwhelmingly positive or negative safety or efficacy result, it is impossible to conclude that the device evaluated is truly significantly different from other devices.

One hopes that the completion of the International Subarachnoid Aneurysm Trial (ISAT)8 marks a major turning point by proving that prospective, randomized, controlled trials of treatment strategies for cerebral aneurysms are quite feasible and tremendously valuable. Indeed, such trials are the primary means by which we can advance the field. ISAT established that endovascular therapy of ruptured cerebral aneurysms was associated with a 7.4% absolute reduction in morbidity and mortality relative to surgical clipping.8 This demonstration of risk reduction has resulted in a major shift toward the use of endovascular therapy for cerebral aneurysms. It is very encouraging that prospective, randomized, controlled trials to compare safety and efficacy of platinum coils to biologically active coils are underway. The HydroCoil Endovascular Aneurysm Occlusion and Packing Study (HELPS) and the Ceracyte Coil Trial are prospective, randomized, controlled trials evaluating the safety and efficacy of biologically active coils relative to platinum coils. These are extremely important because they represent an essential maturation of the field of endovascular aneurysm therapy.

Medical device manufacturers are in the business of making money. They make money by selling medical devices. They interface primarily with physicians in making those sales. Physicians have proved to be pretty easy “marks” for marketing and sales personnel from the medical device industry. Under the influence of the medical device industry, physicians have been spent millions of health care dollars for unproven devices. If we buy these devices with little or no proof of superior safety and/or efficacy, we are a major part of the problem. We are then not leading the development of devices through science, but rather following the development of devices through marketing. The only clear winner here is the medical device industry, which measures its success primarily in terms of financial profits and stock price. As physicians adhering to the Hippocratic Oath, our success is measured in terms of clinical outcomes. We have a responsibility to our patients to conduct clinically relevant, scientific research that proves or disproves the clinical efficacy and safety of the devices that we permanently implant into those patients.

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