Dr. Michael Halpern, an expert witness retained by First DataBank, disputes that Reglan can cause tardive dyskinesia. This report was prepared in 2005, well before the Reglan Black Box Warning came out. The Black Box warning confirms that Reglan does in fact cause tardive dyskinesia if taken for long periods of time. Still, it is interesting to review an expert witness report in a Reglan lawsuit:
Thus, using the class of evidence rated most highly by the Oxford University Centre for Evidence Based Medicine, systematic reviews of clinical trials, rates for depression, Parkinsonism, tardive dyskinesia, and suicidality among patients receiving Reglan are similar to or lower than the rates of these symptoms spontaneously occurring in the elderly population. It can therefore be concluded that there is no evidence that Reglan causes these symptoms in general. Dr. Breggin's conclusion of general causation (that is, that Reglan causes depression, Parkinsonism, tardive dyskinesia, and suicidality) is not supported by the scientific evidence.
The expert who prepared this report works for a company called Exponent, which is generally well-regarded.
United States District Court, N.D. Alabama,
Southern Division.
Betty J. BROWN,
v.
FIRST DATABANK, INC., ET AL.
No. 2:04-cv-00999.
February 1, 2005.
J. Allen Sydnor, Jr., Esquire
Huie, Fernambucq & Stewart, LLP
Three Protective Center
2801 Highway 280 South, Suite 200
Birmingham, AL 35223-2484
Prepared by
Exponent
1800 Diagonal Rd., Suite 300
Alexandria, VA 22031
I. INTRODUCTION
At the request of Counsel for First DataBank, I undertook a review of the report
titled The Case of Robert Brown by Peter R. Breggin, M.D, an expert retained by
the plaintiff in the case Betty J. Brown, etc. v. First DataBank, Inc. My review
included a detailed evaluation of the information and conclusions presented by Dr.
Breggin as well as review of other case materials. To evaluate the scientific
validity of Dr. Breggin's conclusions, I reviewed additional published literature
related to the use of Reglan (metocolpramide) and performed my own analyses using
data from both published and unpublished sources.
II. BACKGROUND OF EXPERT
My summary CV is attached in Appendix A.
[ am a health sciences researcher employed as a Principal Scientist with Exponent,
Inc., based in Alexandria, VA. I have held this position since Sept. 2001. I
received my graduate training at The University of Michigan in the Medical
Scientist Training Program, a joint M,D./Ph,D. training program funded by the U.S.
National Institutes of Health. In addition to completing the M.D. degree, I
completed a Ph.D. in the Graduate Program in Cellular and Molecular Biology. I
also completed a Masters of Public Health (M.P.H.) degree in Epidemiology at The
University of Michigan School of Public Health.
Following my graduate training, I joined the faculty of The University of Michigan
School of Public Health. I subsequently left The University of Michigan and have
been employed as a researcher and consultant in the Washington D.C. area since
1993. I have over 70 peer- reviewed publications in epidemiology, health sciences,
and health outcomes research, as well as multiple book chapters, abstracts, and
presentations in these fields. I also hold the position of Adjunct Professor at
Georgetown University and am on the editorial boards of five journals. In
addition, I am the co-moderator of the Public Policy Institute presented by the
American College of Preventive Medicine, Feb. 16 2005, on "Integrity and Science".
III. MATERIALS REVIEWED
1. Case Materials
Report titled The Case of Robert Brown by Peter R. Breggin, M.D.
Plaintiff's Rule 26 Disclosure for the case of Betty J. Brown, etc. v. First
DataBank, Inc
2. Background Documents
FDA-approved product label for RegIan ( metoclopramide)
FDA Summary Basis of Approval and Medical Officer's Review of the New Drug
Application (NDA) for Reglan ( metoclopramide)
Medwatch and other adverse experiences reported to the FDA regarding Reglan (
metoclopramide)
Published clinical trials for Reglan ( metoclopramide), listed in Appendix B
Ppublished literature and web pages, listed as footnotes in this document
Mortality data for males aged 70 to 74 from the 1990 through 2001 Multiple Cause
of Death files from the National Center for Health Statistics, U.S. Centers for
Disease Control and Prevention
Sales data for Reglan ( metoclopramide) reported by AH Robins/Wyeth to the FDA for
1987 through 1996
Medicaid sales data for Reglan ( metoclopramide) for 1991 through 2004
IV. OVERVIEW AND SUMMARY OF OPINION
Epidemiology, as defined by the Dictionary of Epidemiology, is, "The study of the
distribution and determinants of health-related states or events in specific
populations, and the application of this study to control of health problems."
[FN1] The Dictionary of Epidemiology also defines Causality as, "The relating of
causes to the effects they product. Most of epidemiology concerns causality, and
several types of causes can be distinguished."[FN2]
FN1. Last JM, ed., A Dictionary of Epidemiology. Oxford University Press,
New York, Fourth Edition, 2001, p. 62
FN2. Ibid, p. 26.
One focus of epidemiology is the evaluation of putative associations between
medications and symptoms following exposure (i.e., use of the medications). In
scientific terms, an association refers to a statistical connection, not
necessarily a causal connection, between the exposure and the symptoms.
Epidemiologists use generally accepted scientific and statistical methods to
determine whether the medication is associated with specific symptoms in a
specific group of people and whether any reported association is likely to be
causal.
In section XIV of his report titled The Case of Robert Brown (page 19-20), Dr.
Breggin makes three conclusions:
A. Reglan can cause depression, suicidality, Parkinsonism, and tardive dyskinesia.
B. Reglan caused Mr. Brown's diagnosed Parkinsonism, depression, and suicidality,
and may have caused his tardive dyskinesia.
C. First DataBank's patient education monograph should have included a number of
additional warnings regarding Reglan,
Conclusion A refers to general causation of Reglan and the specified symptoms,
Conclusion B to specific causation of Reglan and the symptoms experienced by Mr.
Brown, and Conclusion C to warnings of symptoms presumably caused by Reglan. To
determine whether conclusions such as those in the report by Dr. Breggin are
scientifically valid, a number of criteria are used. These criteria include: (1)
has the theory or method used been tested; (2) has the method been subjected to
peer review or publication; (3) is the error rate quantifiable, known, and
reasonable; and (4) does the method enjoy general acceptance in the field.
Based upon my knowledge and experience as an epidemiologist and scientist, and
based upon my review of the materials listed above, for the reasons set out in
this report, it is my opinion that Dr. Breggin's conclusions are not supported by
the scientific evidence.
I reserve the right to supplement or amend my opinions upon receipt and review of
additional scientific literature and documents, including deposition transcripts
of expert witnesses and documents produced for those depositions.
V. REVIEW OF CONCLUSION A
1. Dr. Breggin presents inadequate evidence to demonstrate general causation
The information provided by Dr. Breggin on symptoms associated with use of Reglan
is limited to a number of case reports and case series. As defined by the Oxford
University Centre for Evidence Based Medicine[FN3], a case series,
FN3. http://www.cebm.net/glossary.asp
... is a report on a series of patients with an outcome of interest. No control
group is involved.
A further definition by the Duke University Medical Center, as part of their
Introduction to. Evidence Base Medicine Tutorial[FN4], indicates,
FN4. ">http://
www.hsl.unc.edu/Services/Tutorials/EBM/Supplements/QuestionSupplement.htm
a. Case Series: A descriptive, observational study of a series of cases, typically
describing the manifestations, clinical course, and prognosis of a condition. A
case series provides weak empirical evidence because of the lack of comparability
unless the findings are dramatically different from expectations. Case series are
best used as a source of hypotheses for investigation by stronger study designs,
leading some to suggest that the case series should be regarded as clinicians
talking to researchers. Unfortunately, the case series is the most common study
type in the clinical literature.
b. Case Report: Anecdotal evidence. A description of a single case, typically
describing the manifestations, clinical course, and prognosis of that case. Due to
the wide range of natural biologic variability in these aspects, a single case
report provides little empirical evidence to the clinician.
As clearly stated by Carey and Boden[FN5], "Case series cannot be used to draw
inferences regarding treatment effect." The Oxford University Centre for Evidence
Based Medicine also ranks case series as among the lowest level of evidence for
determining the validity of clinical information; only "expert opinion without
explicit critical appraisal" is ranked lower[FN6].
FN5. Carey TS, Boden SD. A critical guide to case series reports. Spine 2003
Aug l;28(15):163l-4.
FN6. http://www.cebm.net/IevelsjDf_evidence.asp
By presenting data only from case series and case reports, Dr. Breggin does
fulfill the scientific standard for demonstrating general causation. The
scientific standard requires determination of rates for the specified symptoms in
both the population exposed to Reglan and an overall comparison population. Case
series and case reports do not permit determination of rates, as they do not
provide information on the total number of individuals exposed (i.e., the number
who received Reglan). Dr. Breggin's methods with respect to this conclusion do not
enjoy general acceptance in clinical or epidemiological research, and his
conclusion is therefore unsubstantiated.
2. Dr. Breggin employs inadequate methods to demonstrate general causation
As noted above, the Oxford University Centre for Evidence Based Medicine ranks
case series as among the lowest level of evidence for determining the validity of
clinical information. Information from comparative studies such as randomized
controlled trials is ranked higher, and the highest ranking is accorded to
systematic review of randomized clinical trials[FN7]. We conducted such a
systematic review. Published English-language clinical trials of
orally-administered Reglan ( metoclopramide) for gastrointestinal diseases were
identified from the National Library of Medicine's MEDLINE/PubMed database[FN8] .
Studies of patients with diabetes were excluded, as these patients have other risk
factors for depression and neurologic symptoms. Data on adverse events were
abstracted from all identified publications. If a study presented results for the
same population for two different treatment periods, the longer period was
selected in order to obtain results with the maximum duration of therapy with
Reglan. A list of all studies included is presented in Appendix B at the end of
this document.
FN7. ibid
FN8. http://gateway.nlm.nih.gov/gw/Cmd?GMBasicSearch&loc=lhc
Results from this systematic review are presented in Table 1, summarizing findings
from published Reglan clinical trials on rates of depression, Parkinsonism,
tardive dyskinesia, and suicidality (respectively). Summary rates are presented at
the end of the table. Among the 768 patients treated with Reglan in published
clinical trials, the rate of depression was 0.65%, and the rates of dyskinesia,
Parkinsonism, and suicidality were 0.00%. A number of the studies presented in
Table 1 were of very short duration (e.g., one day). To provide a more
conservative estimate of the rates of adverse events reported in clinical trials
of Reglan, we also performed this analysis including only those studies with a
duration of therapy of at least two weeks. Results are presented in Table 2, and
are similar to those from Table 1. Among the 566 patients in published Reglan
clinical trials with durations of at least two weeks, the rate of depression was
0.88%; the rates of Parkinsonism, tardive dyskinesia, and suicidality remained at
0.00%. It should be noted that all except one (Paull & Grant, 1974) of these
studies involved daily doses of Reglan of at least 30 mg; a majority of these
studies (12) involved daily doses of 40 mg or more. Thus, these rates were largely
from studies of patients who received substantially higher doses of Reglan than
did Mr. Brown.
Table 3 presents the summary rates from Table 2 in comparison to population rates
for depression, Parkinsonism, dyskinesia, and suicide. Sources for the population
rates are also presented in Table 3. As indicated in Table 3, the rates of
depression from the Reglan clinical trials are similar to or substantially lower
than the depression incidence rates among elderly populations from published
studies. Further, the population rates for Parkinsonism and dyskinesia are clearly
higher than the zero rates calculated from the Reglan trials. The two published
studies listed in this table that provide rates for dyskinesia are specific to
"normal elderly" patients who develop spontaneous dyskinesia, and exclude
neuroleptic-associated dyskinesia. As stated by Khot and Wyatt,[FN9]" ... After
age 40 the prevalence of spontaneous dyskinesia is sufficiently high to conclude
that many patients with diagnoses of tardive dyskinesia have abnormal movements
attributable to causes other than neuroleptics." Finally, using data from the U.S.
National Center for Health Statistics[FN10], we calculated the annual rate of
mortality due to suicide among males age 70-74. Between 1990 and 2001, the average
rate was 0.3%.
FN9. Khot V, Wyatt RJ. Not all that moves is tardive dyskinesia. Am
JPsychiartty 1991; 148:661-6.
FN10. http://www.cdc.gov/nchs/products/elec_prods/subject/mortmcd.htm
Thus, using the class of evidence rated most highly by the Oxford University
Centre for Evidence Based Medicine, systematic reviews of clinical trials, rates
for depression, Parkinsonism, tardive dyskinesia, and suicidality among patients
receiving Reglan are similar to or lower than the rates of these symptoms
spontaneously occurring in the elderly population. It can therefore be concluded
that there is no evidence that Reglan causes these symptoms in general. Dr.
Breggin's conclusion of general causation (that is, that Reglan causes depression,
Parkinsonism, tardive dyskinesia, and suicidality) is not supported by the
scientific evidence.
VI. REVIEW OF CONCLUSION B
1. Dr. Breggin has not demonstrated general causation
Conclusion B is made with respect to specific causation of Reglan and the symptoms
experienced by Mr. Brown. As noted in section II (above), Dr. Breggin has not
demonstrated general causation for Reglan and these symptoms. Since general
causation must be demonstrated prior to claiming specific causation, this
conclusion is unsubstantiated.
2. Dr. Breggin does not demonstrate specific causation
In part, specific causation relates to whether a putative case is similar to
previously-studied cases that provide evidence suggestive of general causation.
Dr. Breggin does not provide any information on whether Mr. Brown's case is
similar to or different from previously-studied cases involving similar symptoms.
To evaluate this, I analyzed patient characteristics from data submitted to the
FDA's Medwatch program from 1987 through 2004 on adverse events associated with
Reglan. Data were separately analyzed from patients reporting depression,
Parkinsonism, dyskinesia, and suicidality. Results from this analysis are
presented in Table 6. Both median and mean values are presented for this analysis,
since when a distribution is skewed and/or not normally distributed, median values
are more representative than are means.
While the proportions of female versus male patients reporting suicidality while
receiving Reglan in the Medwatch data are similar, the majority of reports of
depression, Parkinsonism, and dyskinesia are from female patients. The median (and
mean) ages for patients reporting each of these symptoms are younger than Mr.
Brown's age (71); for depression, dyskinesia, and suicidality, these patients are
more than two decades younger. Duration of therapy for Mr. Brown was approximately
9 months; this is longer than the median duration of therapy for each of the
symptoms from patients in the Medwatch data and substantially longer than the
median duration of therapy for patient reporting depression, Parkinsonism, or
suicidality. Finally, the median daily dose of Reglan for patients reporting these
symptoms in the Medwatch data was 30 to 40 milligrams, while Mr. Brown received 20
milligrams per day.
Thus, patients in the Medwatch data who reported depression, Parkinsonism,
dyskinesia, or suicidality while receiving Reglan did not have similar
characteristics to Mr. Brown. The Medwatch patients were largely female and
younger than Mr. Brown. Most importantly, they were receiving greater daily doses
of Reglan than was Mr. Brown, and experienced these symptoms substantially earlier
in their course of therapy. These differences, indicating that Mr. Brown was not
similar to previously-studied cases, argue against Reglan being the specific cause
of Mr. Brown's depression, Parkinsonism, dyskinesia, or suicidality, Therefore,
this conclusion by Dr. Breggin is unsubstantiated.
VII. REVIEW OF CONCLUSION C
1. Dr. Breggin has not demonstrated general causation
Dr. Breggin's third conclusion, regarding actions that First DataBank should have
followed, cannot be substantiated if there is no demonstrated general causation
for Reglan and the indicated symptoms (depression, Parkinsonism, dyskinesia, and
suicidality). As discussed in section II (above), Dr, Breggin failed to
demonstrate general causation. Further, based on a systematic review of clinical
trials of Reglan, rates of these symptoms among patients receiving Reglan are not
substantially higher than background rates in the U.S. Thus, this conclusion is
not supported by the scientific evidence.
2. Dr. Breggin has not demonstrated specific causation
Dr. Breggin's third conclusion also cannot be substantiated if there is no
demonstrated specific causation for Reglan and the symptoms (depression,
Parkinsonism, dyskinesia, and suicidality) experienced by Mr. Brown. As discussed
in section III (above), Dr. Breggin failed to demonstrate specific causation.
Further, an analysis of the characteristics of patients reporting these symptoms
while receiving Reglan in the FDA's Medwatch data indicated Mr. Brown was not
similar to patients who previously-reported such symptoms. Patients in the
Medwatch data were predominantly female, younger, received higher doses of Reglan,
and experienced symptoms after shorter periods of therapy. Thus, specific
causation is not established, and this conclusion has no basis.
VIII. EXPERT'S CONCLUSION
Applying established, generally accepted scientific methods, it is my opinion that
Dr. Breggin's conclusions stated in his report titled The Case of Robert Brown are
unsubstantiated.
IX. COMPENSATION
Exponent is compensated for my services at the rate of $365 per hour.
X. PRIOR DEPOSITION AND TRIAL TESTIMONY (1999-PRESENT)
None
Feb, 1, 2005
Michael T. Halpem, M.D., Ph.D., M.P.H.
