The following report was filed by Bob West, Ph.D., in the Louisiana lawsuit entitled Tarver v. Wyeth.
United States District Court, W.D. Louisiana.
TARVER et al,
v.
WYETH INC et al.
No. 04CV02036.
August 20, 2006.
Summary of Opinions
Robins/Wyeth and other manufacturers of metoclopramide failed to adequately warn
physicians and ultimately patients, of the risks of extrapyramidal symptoms,
specifically tardive dyskinesia with long term (greater than 12 weeks) use of
Reglan/metoclopramide. Furthermore, when a patient takes Reglan/metoclopramide
beyond the recommended period and subsequently develops tardive dyskinesia, then
all of the Reglan/Metoclopramide ingested beyond the recommended period likely
contributed to the development of the tardive dyskinesia.
History
I am a pharmacologist and toxicologist with over 35 years experience in the drug
and medical device product field. I am a former president of the Drug Information
Association, a world-wide forum to exchange information on drug development among
industry, the FDA and other concerned groups about drug efficacy, safety,
manufacturing controls, pharmacovigilance and regulatory requirements. I have
worked directly and as a consultant in scientific and regulatory affairs for drug
manufacturers, and have knowledge and expertise of the requirements of FDA
regulations and statutes concerning drug labeling and reporting to the FDA. My
training and experience are more fully set forth in the copy of my Curriculum
Vitae which is attached hereto. A list of all publications 1 have authored or
co-authored as well as a list of all cases I have testified in are attached to my
Curriculum Vitae.
Compensation
My compensation for this study is a $275 per hour; compensation for testimony is
at $325 per hour.
Reglan (metoclopramide) is a dopaminergic antagonist and neuroleptic drug
developed as an antiemetic agent. It is also a prokinetic agent which is
administered in cases of gastric hypomotility such as seen in diabetic neuropathy
and gastroesophageal reflux (GERD). Reglan was marketed outside of the United
States, in France as Primperan in 1964, and in England as Maxilon, as well as
other areas of Europe and Canada. It was approved for marketing in the United
States in 1979 and 1980 for diabetic gastroparesis and in 1982 for intravenous use
as an antiemetic in cancer chemotherapy.
In 1984, Robins obtained approval to market Reglan (metoclopramide) as a short
term therapy for GERD, four to twelve weeks of administration. The labeling under
dosage and administration contains a statement, therapy longer than 12 weeks has
not been evaluated and cannot be recommended. The same statement remains on the
Reglan label until today, while Robins/Wyeth continues to market the product. A
telephone survey, conducted by Robins in 1985, found that 38% of Reglan users took
the drug for between one and two years and another 46% of Reglan users took the
drug for three to six months.
By the time Robins filed an IND with the FDA in 1973, several studies showed that
metoclopramide adversely affected the CNS. Dr. Tibor Bodi of Merck found 3 of 60
subjects developed dystonic phenomenon as did one of the dogs on chronic
administration as reported by Peck. In addition to this information Robins was
also aware of reports in the world medical literature suggesting that long term
metoclopramide therapy presented a significant risk of producing tardive
dyskinesia. As early as 1968, metoclopramide treatment, like treatment with
neuroleptics, caused extrapyramidal symptoms.
The annual report for 1975 of the National Drug Advisory Board in Eire notes that
during the seven year period, 1968 to 1975, there were twenty-eight reports of
side effects with metoclopramide. Most of these cases were dystonia and 30%
occurred in children under the age of 17 years. Other reports in the 1970s noted
the appearance of extrapyramidal symptoms following the use of metoclopramide
(Primperan, Makolon). The Australian Drug Evaluation Committee received
twenty-five reports of adverse reactions to metoclopramide, eighteen concerned the
extrapyramidal symptom. More than half of the patients were under the age of 20.
During the 1980s and prior to the U.S. approval of Reglan for GERD, there were
multiple literature reports on extrapyramidal symptoms, tardive dyskinesia and
Parkinsonian like symptoms involving almost 100 patients. However, the Reglan
Reporter only cites 30 cases since 1964.
Obviously, during this period, Robins was not completely forthcoming with the FDA.
Meetings were held with the FDA Advisory committees, and when asked about the
incidences of these EPS, not all the latest information was provided. Robins
agreed to provide post marketing surveillance as one of its conditions of approval
for the gastroparesis indication. The evidence for this is rather scant.
Additional historic review of the metoclopramide IND reveals irregularities that
make the safety data base ultimately submitted to the FDA for the NDA quite
suspect. According to Dr. Sondervost, Director of Clinical Research at Robins, in
his letter of resignation to E. C. Robins, President (December 15, 1978), he
states that when he took over, he was quite perturbed with the ineffectual
surveillance of the medical program. He found a stack of 250 completely unreviewed
patient data records for another project which thus did not comply with lack of
statutory monitoring requirements. Serious adverse reactions, including patients
that had died, had not been reported by the regulatory staff to the FDA.
He also discusses the status of the oral metoclopramide NDA program and cites
figures of 1500 - 1800 patients who were treated under the IND without
accountability or patient review. Thousands of tablets were sent out with no
accountability. On the basis of the foregoing, one has to question the veracity of
the data base provided to the FDA in the IV/oral metoclopramide submissions. The
authenticity of a significant part of the safety data base is questionable at
best. Obviously, Robins is in violation of both the FDA IND and NDA regulations.
The clinical data base for the original NDA approval for metoclopramide consisted
of two placebo controlled studies representing a meager population of
approximately 100 patients. There were no studies of long duration, e.g. more than
twelve weeks and now twenty years after the original NDA approval for GERD, still
none have been performed.
Marketing
The Robins market plans for 1982 through 1988 reflect a strategy of promoting
Reglan to treat many commonly treated complaints of the upper GI tract and "to
significantly displace Tagamet and Gaviscon as a first choice prescription therapy
for GERD." They recognized the Reglan patent was about to expire and an
enhancement of the GERD indication could expand market share and allow Robins to
maintain their franchise for Reglan. In the period prior to 1985, this was a
subrosa promotion of an unapproved use and for an extended period of time over and
above the twelve week label indication.
The 1986 market plan for Reglan discusses a patient study which found that of
current users, 46% have taken Reglan for a period of 3 to 6 months, while another
38.1% have been on Reglan for 1-2 years (Plotkin). Thus, to state in the labeling
therapy longer than twelve weeks has not been evaluated and cannot be recommended
begs the issue.
During this period, Robins/Wyeth while "educating physicians," Robins continued to
receive letters inquiring about tardive dyskinesia. They were not completely
forthcoming with the medical community about the continuing reports in the medical
literature. Three days after the August 15, 1984 approval letter for Reglan as a
short term therapy for the GERD indication, Orme published an article in the
British medical literature indicating that metoclopramide should not be used by
the elderly for prolonged periods of time.
21 CFR 202.1(e)(5) requires that an advertisement not present false or misleading
information with respect to side effects, contraindications or effectiveness.
202.1(e)(6)(xi) prohibits a drug manufacturer from using literature, quotations or
references for purposes of "recommending or suggesting conditions of drug use that
are not approved or permitted in the drug package labeling."
Robins violated FDA regulations by its subrosa promotion of an unapproved use of
Reglan. It also permitted its marketing information to control the information it
was providing to the FDA in a timely fashion and only provided incomplete
information on its label. These are violations of FDA regulations, as well as
grossly unsafe, and unethical practices by Robins.
Adverse Event Reporting Requirements
21 CFR 314.80 controls post-marketing reporting to the FDA of adverse drug
reactions.
Subsection (C)(1)(i) requires 15 day "alert reports" for each drug experience that
is both "serious and unexpected" regardless of source within 15 working days of
initial receipt of the information. (Form 1639 report)
Subsection (c)(1)(ii) requires that the drug company review (at least annually)
the frequency of adverse drug experiences that are both serious and expected
(already listed in the label), regardless of source and report any significant
increase in frequency within 15 days of determining an increase in frequency.
Section 314.81 requires that the drug company in its annual report include a
summary of "significant new information from the previous year that might effect
the safety, effectiveness or labeling of the drug product." The report is also
required to contain a brief description of actions that the applicant has taken or
intends to take as a result of this new information. For example, submit a
labeling supplement, add a warning to the labeling or initiate a new study.
Robins/Wyeth, and other manufacturers of metoclopramide, continued to receive ADRs
and literature reports throughout the 1980s and 1990s bearing upon the
extrapyramidal symptoms and tardive dyskinesia associated with metoclopramide
administration. In addition, the literature reinforced the thesis that
metoclopramide use was long term often in GERD for many years. (Stewart, et al.,
Ganzini, et al., Sewell, et al., Sweet, et al., Miller, et al. and Llau, et al.)
The information obtained via the Med Watch Reports and the ADR tabulations also
reflected the long term use of metoclopramide, e.g., 1-6 years. A visual
inspection of the U.S. sales for 1993-1996 suggests that while sales were
declining, the incidence of ADRs and extrapyramidal symptoms were increasing.
A review of the information provided to the FDA in the annual reports reveals that
Wyeth often provided abstracts of the literature to the Agency without any attempt
to present the complete papers and an analysis of their content. This is
particularly important as a number of these papers, some foreign, pertain to the
incidence of side effects or extrapyramidal symptoms associated with long term
metoclopramide use.
Despite the availability of the Ganzini and Sewell papers, since 1993 and 1994,
there is no evidence that Wyeth made any attempt to critically evaluate these
papers and perform a meta analysis to determine the significance of the data as it
effects the interpretation of ADRs and possible influence on labeling.
Wyeth made no effort to upgrade its data base based on the full interpretation of
the data and the literature thus violating this section of the regulation (Section
314.81).
Labeling
Reglan was approved for U.S. marketing August 15, 1984 as a short term treatment
for GERD without a tardive dyskinesia warning. In March 1985, the FDA notified
Robins that it was requiring a warning regarding tardive dyskinesia to be added to
the Reglan label. FDA approved the language of the tardive dyskinesia labeling for
Reglan on October 21, 1985. Robins also prepared a "Dear Doctor" letter dated
November 1985 which was supposed to call attention to the revised package insert.
The "Dear Doctor" letter and warning failed to draw attention to the potentially
irreversible tardive dyskinesia risk of long term metoclopramide therapy and that
prolonged use should be avoided.
For the GERD indication, Reglan is to be administered for four to twelve weeks,
but is does not specifically discourage use beyond four to twelve weeks. By
itself, the statement is buried in the rest of the text and does not sufficiently
highlight the impact or meaning of the statement. The indication and warning to
avoid long term use should have been placed in a single distinctive black hox at
the top of the label. Responsible manufacturers use this technique to highlight
important warnings for physicians.
During this period, Robins/Wyeth and later, other manufacturers, were continuing
to market Reglan for GERD with little regard to limiting its duration of use
despite their knowledge from multiple sources that it was being used chronically
(Plotkin, Stewart). Furthermore, literature continued to appear associating
metoclopramide with tardive dyskinesia and extrapyramidal side effects. Ganzini,
et al. found that the excess risk of developing tardive dyskinesia in patients on
long term use of metoclopramide was approximately 13%. They estimated this was
approximately 100 times greater than previously believed based on the information
in the Reglan package insert.
CFR 201.7(iii) states if there are specific conditions that should be met before
the drug is used on a long term basis, the labeling should identify the conditions
and specific indications for each use. Section 201.57(v)(3) Warnings. The labeling
shall be revised to include a warning as soon as there is a reasonable evidence of
an association of a serious hazard with the drug, a causal relationship need not
have been proved. Special problems, e.g., death or serious injury may be placed in
a prominently displaced box. Boxed warning.
CFR 201.57(10) Geriatric Use (c). Evidence from clinical studies and other
reported clinical experience available to the sponsor indicates that use of the
drug in elderly patients is associated with differences in safety or effectiveness
or requires specific monitoring or dosage adjustment then appropriate information
should be added to Contraindications, Warnings - etc. or other sections of the
labeling.
CFR 201.57(9) (ii) Pediatric Use. This subsection of the labeling states that the
manufacturer shall cite any limitations in the pediatric use statement, if there
is a need for specific monitoring and hazards associated with use of the drug in
any subsets of the pediatric population. Furthermore, this should be cited in the
"Contraindications" and "Warnings," "Precautions" and "Dosage" and
"Administration" subsections.
Further, the Reglan/metoclopramide label is misbranded since it does not provide
adequate directions for use or adequate warnings about the appropriate maximum
duration and dose for the labeled indication. (21 USC, para. 352) In addition, the
label is false and misleading since it provides misinformation for the risk of all
EPS from Reglan/metoclopramide being stated to be 1:500 which has little
scientific foundation. In fact, studies published over the twenty year period
since the NDA approval demonstrate the risk of EPS is much higher. Despite this
information, Wyeth and the other manufacturers of Reglan/metoclopramide have
failed to purse appropriate follow-up and conduct their own studies, clinical or
epidemiological regarding the risk of EPS and, in particular, tardive dyskinesia
with long term administration of Reglan/metoclopramide.
CFR 201.57(d). Contraindications states that the contraindication section of the
label shall describe those situations in which the drug should not be used because
the risk of use clearly out ways any possible benefit. These situations include
"continued use of the drug in the face of an unacceptably hazardous adverse
reaction." If a manufacturer has knowledge that the risk of a drug producing a
serious side effect, such as tardive dyskinesia, is substantially increased after
a certain period of dosing, the manufacturers' duty is to state, use past that
time is contraindicated. Wyeth's metoclopramide product in Italy specifically
states in bold print, DO NOT USE FOR LONG TERM USE. Today, there are numerous H2
receptor antagonists and proton pump inhibitors available to treat GERD without
the risk of serious neurological side effects.
CFR 201.57(e). States that the warning section of a label shall describe serious
adverse reactions and potential safety hazards, limitations in use imposed by
them, and steps that should be taken if they occur. Thus, the warning section
should address the hazard of long term use, as well as the need for physicians to
periodically monitor patients on metoclopramide to look for the earliest signs of
EPS and discontinue use.
Section 314.70 deals with Supplements and other changes to an approved
application. Labeling, states that a change in labeling to add or strengthen a
contraindication, warnings, precautions or adverse reactions can be made without
filing a supplement. Both Wyeth and the other manufacturers of
Reglan/metoclopramide should have expanded the warnings to physicians under
314.70(2) with a labeling supplement to strengthen the warnings or precautions.
Robins/Wyeth, for a period of over ten years after obtaining Reglan marketing
approval for GERD, had multiple opportunities to update their labeling by
providing a black box warning, making a more positive statement about limiting
metoclopramide use in GERD, highlighting the higher incidence of extrapyramidal
side effects and adding additional statements about the proper geriatric use. The
only plausible explanation for this inaction is allowing market motives to control
proper medical information and consumer protection. A review of Jolene Linger's
Reglan/Metoclopramide prescriptions from March 1995 to August 2002 and matching
that to the corresponding National Drug Code ("NDC") shows that Mrs. Linger
received Reglan/Metoclopramide in excess of the PDR and package insert information
from the following manufacturers: Wyeth, Inc., ESI Lederle, Inc., Teva
Pharmaceuticals USA, United Research Laboratories, Inc., and Pliva, Inc.
I reserve the right to supplement or amend this report based upon additional
information provided to me as a part of this case or additional discovery taken by
the parties.