Update on the Illegal Promotion of Gabapentin (NEURONTIN)

In the May 2002 issue of Worst Pills, Best Pills News, we wrote about gabapentin (NEURONTIN), a drug approved by the Food and Drug Administration (FDA) for treating seizures, a somewhat limited potential market, that was illegally transformed into a “blockbuster” drug with sales approaching $1.5 billion in 2001. The metamorphosis was accomplished by fabricating a number of uses for the drug that are not FDA approved. These included bipolar disorder, attention deficient disorder, and migraine. The use of a drug that is not approved by the FDA is referred to as an “off-label” use.

The May article was based on New York Times reporting and documents from the U. S. District Court for the District of Massachusetts. This court recently released new documents that for the first time gave the public an inside picture of the lengths to which a pharmaceutical company will go to sell a drug even when there is no evidence that it is safe or effective for the uses being promoted.

This article is based on allegations made in recently released court documents.

Gabapentin was originally produced by Parke-Davis, which was acquired by Pfizer, Inc, of New York in 2000. The only FDA approved use for gabapentin at that time was as an add-on treatment for epilepsy. This is a very limited market with little upward potential for sales. The new court documents allege that Parke-Davis knew that pain management, psychiatric disorders, anxiety and depression were immense markets which, if tapped, could yield enormous profits from sales of gabapentin.

The Decision to Promote Gabapentin for Unapproved Uses

Documents revealed that after an extensive economic analysis, senior officials at Parke-Davis determined that it was not sufficiently profitable for Parke-Davis to obtain FDA approval for gabapentin’s alternative uses mentioned above by doing the types of studies necessary for approval. Instead, company officials developed a strategy that would allow Parke-Davis to avoid the costs of proving gabapentin’s safety and effectiveness for these other uses, while allowing the company to enter the lucrative off-label markets.

Taking advantage of a loophole in the FDA’s off-label marketing rules, Parke-Davis decided to employ a “publication strategy” that would allow it to promote gabapentin by the massive distribution of publications supposedly written by independent researchers who purportedly described the scientific evaluation of gabapentin. Another advantage of this strategy, from the company’s perspective, was that it could be done immediately. There was no need to wait for the results of scientifically conducted clinical trials to determine if gabapentin was actually effective in the treatment of these conditions and submit them to the FDA for approval.

Payment to Doctors to Increase Gabapentin Prescriptions

The company’s “publication strategy” required doctors to perform the work normally performed by the company’s sales force in order to promote gabapentin. This necessitated that Parke-Davis make tens of thousands of payments to the doctors who would act as a surrogate sales force as well as to the practicing physicians who would receive the message. In other words, adoption of the “publication strategy” required the company to pay physicians to either recommend the prescription of gabapentin or to order gabapentin, in violation of the federal anti-kickback regulations, according to the newly released court documents.

A description of the various programs Parke-Davis used to make these payments to physicians follows.

Consultants’ Meetings
A common trick used by Parke-Davis to funnel illegal payments to doctors to encourage them to prescribe gabapentin off-label was through “consultants’” meetings. Under this front, Parke-Davis invited doctors to dinners or conferences and paid them to hear presentations about off-label uses of the drug. Under the guise that these doctors were acting as consultants, Parke-Davis sometimes, but not always, had the doctors sign bogus consulting agreements. At these meetings, the company would give these doctors lengthy presentations relating to gabapentin, particularly regarding off-label usage. Presentations would be made by Parke-Davis employees or physician speakers hired by the company for the purpose of promoting gabapentin, and questions relating to the use of gabapentin would be solicited and answered. At some conferences, the sponsoring organization or Parke-Davis intentionally posed questions to the speakers about off-label use to insure that the doctors were exposed to such information.

Parke-Davis would routinely analyze whether the consultants’ meetings were successful in getting doctors to change their prescription writing practices. At some meetings, the so-called consultants were asked directly if they would write more gabapentin prescriptions as a result of the meeting. This question would have been irrelevant if the actual purpose of the meeting was to receive the consultants’ advice. Parke-Davis also routinely tracked consultants’ gabapentin prescription writing practices after these meetings. Parke-Davis actually analyzed whether the doctors they had paid had in fact written more gabapentin prescriptions after the meeting, using market data purchased from third parties.

Medical Education Seminars
The court documents revealed another platform used by the company to pay kickbacks to doctors to hear off-label promotion of gabapentin. These were programs billed as Continuing Medical Education (CME) seminars. These conferences and seminars were set up to appear to qualify for an exception to the FDA’s off-label marketing restrictions which permits doctors to learn about off-label uses of drugs at independent seminars. Such seminars, however, must be truly independent of the drug companies. The companies may make “unrestricted grants” for the purpose of a seminar, but may not be involved in formulating the content of the presentations, picking the speakers or selecting who attends the seminars. Parke-Davis retained third party companies to present seminars while in fact retaining control of virtually every aspect of these events. The seminar companies obtained Parke-Davis’ approval for all content presented at the seminars. Parke-Davis also paid all expenses, including all the seminar companies’ fees.

The company designed and approved the seminars, hand-picked the speakers, approved the seminar presentations, previewed (in most cases) the contents of the seminars prior to a presentation, selected the attendees based on their ability and willingness to prescribe high quantities of gabapentin, evaluated the presentations to make sure Parke-Davis’ “message” was appropriately delivered, black-listed presenters whose presentations were not sufficiently pro-gabapentin, and monitored the prescribing patterns of the physicians who attended.

Grants and Studies
Parke-Davis also made outright payments, in the form of grants, to reward demonstrated gabapentin advocates. Company sales managers identified key doctors who actively prescribed gabapentin or programs which were willing to host gabapentin speakers and encouraged such persons or programs to obtain “educational grants” from the company. Parke-Davis’ sales people informed leading gabapentin subscribers that significant advocacy for gabapentin would result in the payment of large grants. These studies did not involve significant work for the physicians. Often they required little more than collating and writing up office notes or records. Parke-Davis frequently hired technical writers to write the articles for which the “authors” had been given grants.

Payments to “Authors” of Ghost-Written Articles
Another method of paying off doctors for backing gabapentin was to pay honoraria for the use of their names on scientific articles intended for publication in various neurology and psychiatry journals, but actually ghost-written by technical writers hired by Parke-Davis, which retained control of all such articles. In 1996 Parke-Davis paid for at least 20 such articles, most of which dealt with off-label use of gabapentin, and were placed according to the company’s “publication strategy.” Naturally, Parke-Davis paid all expenses in connection with these articles.

Once Parke-Davis and the technical writers conceived the articles, the company and its outside firms attempted to find recognized gabapentin prescribers whose names could be used as the authors of these articles. In some cases, drafts of the articles were completed even before an “author” agreed to place his or her name on the article. This even occurred in connection with case histories that purported to describe the “author’s” personal treatment of actual patients. The “authors” were paid an honorarium of $1,000 to lend their names to these articles, and also were able to claim publication credit on their professional resumes.

Speakers’ Bureau
Parke-Davis also formed a Speakers’ Bureau, another tactic to make large and numerous payments to doctors who recommended gabapentin at teleconferences, dinner meetings, consultants meetings, educational seminars, and other events. These speakers repeatedly gave short presentations relating to gabapentin for which they were paid anywhere from $250 to $3,000. Some speakers received tens of thousands of dollars annually in exchange for recommending to fellow physicians that gabapentin be prescribed, particularly for off-label uses. Speakers who most zealously advocated gabapentin were hired most frequently for speaking events, regardless of the fact that many of these events were billed as independent medical education seminars where objective information was supposed to be delivered.

Circumstantial and some direct evidence over the years suggests that the behavior of Parke-Davis in the off-label promotion of gabapentin is not isolated, but rather an integral part of the pharmaceutical industry’s marketing practices. However, in the Health Research Group’s experience, the gabapentin episode is the most complete and well documented case of off-label promotion to ever come into public view. Because of the detail of fabrications, pay-offs, manipulation, and their effect on gabapentin sales some widely held myths have been shattered.

First, and perhaps the most important to the health and safety of patients, is the belief that doctors are not fooled or influenced by drug company promotional ploys such as gifts to attend medical meetings or expensive meals. The evidence presented in the court documents unambiguously shows that such schemes work. Congress recognized 40 years ago that a large proportion of physicians in everyday practice have neither the training nor the background to differentiate between a useful drug and a harmful one. This is why Congress created a process by which the FDA approves drugs based on validated science—to protect patients from worthless or dangerous drugs. But this says nothing about the apparently substantial number of doctors who accepted kickbacks or bribes to prescribe gabapentin for uses that had not been proven. The memorable words of the inspector in the movie Casablanca—”I am shocked—shocked!” come to mind.

Second, the sacrosanct position of peer reviewed medical literature as a vehicle for scientific exchange has been seriously damaged. The manipulation of information about gabapentin that Parke-Davis exercised would astonish George Orwell. In defense of the many physicians who try their best for patients by diligently keeping up with the medical literature, there is no way for a doctor, scientist, or medical journal editor to know if a study is a fabrication.

There are major differences between the way the FDA reviews clinical trials as part of the new drug approval process and the process used by a peer reviewed medical journal to accept a study for publication. The FDA bases its drug approval decisions on its own review of the actual data submitted by a manufacturer, not on published journal articles. The agency has a staff of highly trained statisticians who do their own analyses of the manufacturer’s data, thus ensuring that approval decisions are based on valid data. Also, the agency has authority to inspect clinical sites in order to keep investigators honest.

On the other hand, the editor of a peer reviewed medical journal must accept the veracity of a study submitted for publication. The editor will send the study to several peer reviewers for their recommendations, but these people have other things to do, and may spend only a few hours on their review. Peer reviewers also must accept the veracity of the underlying data presented in the study. The journal editor has neither the authority nor the resources to inspect clinical sites. This is a system that can be “gamed,” as documented in the court papers about Parke-Davis’ gabapentin publication strategy.

The message for patients is that if you have been prescribed a drug for an off-label use, the evidence supporting such a use may be good or it may be fabricated. The doctor prescribing the drug may have based the decision to use the drug on an expensive dinner, received a kickback or was bribed, or was simply fooled by a fabricated medical journal article.

What You Can Do

If you or a family member receive gabapentin for a use not listed in the FDA approved professional product labeling, discuss with your doctor the continued need for taking gabapentin.