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| ![](media/image    | **Department of Veterans Affairs**              |
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| 756944444444445in" | #### Veterans Health Administration             |
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| 56944444444445in"} | **Pharmacy Benefits Management Service**        |
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|                    | **810 Vermont Avenue, NW**                      |
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|                    | **Washington, DC 20420**                        |
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Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

Re: *"Guidance for Industry: Good Reprint Practices for the Distribution
of Medical Journal Articles and Medical or Scientific Reference
Publications on Unapproved New Uses of Approved Drugs and Approved or
Cleared Medical Devices \[Docket No. FDA-2008-D-0053\]."*

The Department of Veterans Affairs Pharmacy Benefits Management Services
office is providing the following comments to draft guidance referenced
above. Based on our belief that relaxing the requirements for
disseminating reprints for unapproved uses of products regulated by the
United States Food and Drug Administration (FDA) is likely to provide
little benefit to the public and health care professionals, but does
have the potential to negatively impact drug safety, **we urge the FDA
to withdraw the current guidance** **and return to the previous policy**
known as Section 401 of the Food and Drug Administration Modernization
Act (FDAMA(21 U.S.C. § 369aaa, § 551, Federal Food, Drug, and Cosmetics
Act (FD&C Act))) which governed how information on unapproved uses could
be disseminated.

The FDAMA provided more restrictions on the distribution of journal
articles and medical and scientific references for off-label uses than
the draft guidance, established incentives for manufacturers to submit
supplemental applications for unapproved uses, and provided oversight of
the unapproved use information distribution process. We believe the
draft guidance is flawed, will not result in improved drug safety, and
favors business interests over public safety.

**[Generally, we are concerned with the draft guidance for the following
reasons:]{.underline}**

-   It will not improve drug safety and could very well result in a
    decline in drug safety. We are troubled that the FDA is considering
    a reversal of the previous FDAMA policy that restricted the
    distribution of medical and scientific journal articles, required
    pre-submission of materials to the FDA, required biannual lists of
    titles of articles and reference publications related to the drug's
    new use that were used for distribution, and required a manufacturer
    to maintain records that identify the recipients of said distributed
    information.

-   It may be perceived as vague and could leave room for variation of
    interpretation. It is not clear who is allowed to distribute
    reprints on unapproved use. Previously, only members of the Medical
    Science departments of manufacturers could distribute this
    information when it was requested. The current draft document allows
    members of marketing and sales departments to distribute the
    information. In effect, this could set the stage for significant
    conflict of interest.

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-   If drug manufacturers can more easily promote unapproved uses for
    their drugs, it significantly decreases their motivation to seek new
    supplemental indications by doing appropriate, well done clinical
    trials. Second-rate "studies" published in journals with
    questionable peer review processes will be used to convince
    physicians to use drugs for an ever-increasing number of unapproved
    uses where safety and efficacy have not clearly been established and
    the studies do not meet the FDA's regulatory rigor for evidence.

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-   Several reports have surfaced lately of pharmaceutical manufacturers
    engaging in "ghost authorship" of articles published in peer
    reviewed journals, when the author(s) have had little involvement in
    writing the articles (see additional information below). Allowing
    dissemination of reprints for unapproved uses could spawn a cottage
    industry of little known, hastily established "peer-reviewed"
    publications whose sole purpose is to extend the marketing and
    advertising of pharmaceuticals.

**[Examples of negative outcomes resulting from promotion of unapproved
uses:]{.underline}**

-   The FDA is urging caution in the use of Botulinum toxin, due to
    deaths and serious side effects linked to [unapproved
    uses]{.underline} of this drug.

-   Fines were levied when ralozifene was promoted for the [unapproved
    use]{.underline} of prevention and reduction in the risk for breast
    cancer through the use of medical reprints highlighting key results
    with raloxifene, while hiding the disclosure statement that
    effectiveness had not been established.

-   Gabapentin was aggressively marketed to treat a variety of diseases
    for which it was [not approved.]{.underline} Since the manufacturer
    decided not to pursue FDA approval for any of the new uses, a
    multi-million dollar penalty imposed on the manufacturer came after
    the damage was done and patients were exposed to potential
    unforeseen adverse events.

**[Examples of manipulation of the scientific literature:]{.underline}**

There is substantial evidence that the pharmaceutical industry has
inappropriately influenced the scientific literature through selective
publication and ghost authorship. In fact, such practices have led to a
number of corrective actions including the creation of a clinical trials
database by the Department of Health and Human Services (HHS), fraud and
abuse prosecution by State and Federal government, and the
implementation in several states of mandatory disclosure of compensation
to health care providers by pharmaceutical manufacturers. The draft
guidance allowing pharmaceutical manufacturer distribution of unapproved
use information ignores the possibility that such distribution may be
part of a larger strategy to inappropriately shape the scientific
literature to favor certain products and product uses. The draft
guidance is also inconsistent with positive steps being taken to prevent
such manipulation of the literature on which health care providers and
payers depend to make clinical and reimbursement decisions. Two recent
examples of such practices are:

> [Promotion of gabapentin (Neurontin)]{.underline}
>
> A study of internal industry documents on the promotion of the drug
> gabapentin (Neurontin) indicates that "Parke-Davis employed a
> 'publication strategy,' the goal of which was to use research not as a
> means to gain FDA approval for new indications but 'to disseminate the
> information as widely as possible through the world's medical
> literature', generating excitement in the market and stimulating
> off-label prescribing despite the lack of FDA approval. This strategy
> focused primarily on expanding gabapentin use in neuropathic pain and
> bipolar disorders, for which detailed decision analyses projected the
> greatest revenue potential.... \[And,\] as stated in a marketing
> assessment, 'The results of the recommended exploratory trials in
> neuropathic pain, *if positive*, will be publicized in medical
> congresses and published" (italics added). Similarly, in discussing 2
> nearly identical trials that yielded conflicting results on gabapentin
> as seizure monotherapy, the "core marketing team" concluded that "the
> results of \[the negative trial\] will not be published.'" (Steinman
> et al, p. 288)
>
> This analysis also found that in addition to publishing its own
> clinical trials, "Parke-Davis expanded the literature on gabapentin by
> contracting with medical education companies to develop review papers,
> original articles, and letters to the editor about gabapentin for
> \$13,375 to \$18,000 per article, including a \$1000 honorarium for
> the physician or pharmacist author." (Steinman et al, p. 288)
>
> [Promotion of dexfenfluramine (Redux)]{.underline}
>
> The pharmaceutical company Wyeth used a ghostwriting scheme in
> promoting its drug Redux (dexfenfluramine). Using Excerpta Medica Inc,
> a medical communications firm, Wyeth contracted for a series of
> articles on obesity treatment to be published in prominent medical
> journals. Excerpta Medica wrote the articles under close control by
> Wyeth and then paid university researchers to edit them and assume
> authorship of the published pieces. One of the paid "authors" wrote a
> letter to Excerpta Medica congratulating them on the thoroughness and
> clarity of their article. \"Perhaps I can get you to write all my
> papers for me!\" he wrote. He did have one reservation about the piece
> he was signing: \"My only general comment is that this piece may make
> dexfenfluramine sound better than it really is.\" (Cited in Mundy,
> 2001, p. 164), Dexfenfluramine was approved by the FDA April 29, 1996
> and was withdrawn from the market 19 months later because of the risks
> of valvular heart disease.

For all of these reasons, we strongly recommend that the FDA: 1) rescind
its draft guidance and replaced it with guidance that highly restricts
the distribution and promotion of drugs for unapproved uses; 2) provide
strong oversight on all pharmaceutical company employees' interactions
with health care professionals regarding unapproved uses; and 3) solicit
input on the draft guidance from individual members of the FDA Safety
Oversight Board. We do not believe the draft guidance is in the best
interests of the American public, we believe it is inconsistent with the
FDA's mission to protect the public health, and we do not believe it
will help the American public and health care professionals get the
accurate, evidence-based information they need.

[References]{.underline}

Mundy A. Dispensing with the truth: the victims, the drug companies, and
the dramatic story behind the battle over Fen-Phen New York : St.
Martin\'s Press, 2001.

Steinman MA, et al. "The Promotion of Gabapentin: An Analysis of
Internal Industry Documents.\" *Annals of Internal Medicine* 2006;
145(4):284-93.

For additional information, please contact Michael Valentino at the
Pharmacy Benefits Management Services at 202-461-7306.

![](media/image2.png){width="2.3743055555555554in"
height="0.7833333333333333in"}

Michael Valentino, R.Ph, MHSA

Chief Consultant, Pharmacy Benefits Management Services

Department of Veterans Affairs