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Expert Report from Reglan Lawsuit Discusses FDA Regulations, and Side Effects of Reglan

Posted in Reglan / Metoclopramide

One of the claims made in most Reglan or Metoclopramide lawsuits is that the manufacturer of the drug failed to adequately warn the plaintiff of the risks of using the drug.  (One of the risks of using Reglan  or Metoclopramide is developing a movement disorder; Tardive Dyskinesia is a known side-effect of Reglan use.)

The Reglan lawyers who represent the manufacturers of the drugs often argue that even if the warning label left something out, all that matters is that the manufacturer complied with the FDA regulations.  This is a very hotly contested issue that will probably be before the Supreme Court by 2011.

That said, here’s the report of one expert who believes that Teva appropriately labeled its generic Reglan product.

A. Metoclopramide, as a prescription drug marketed under an FDA-approved New Drug Application (NDA) has undergone rigorous scientific testing and evaluation for its efficacy and safety for use in the treatment of an assortment of digestive disorders. Further, It can only qualify as a pharmaceutical for therapeutic use if it has been appropriately labeled and properly manufactured, as required by the FDA regulations for approval of new drug products.

Pharmaceutical prescription drugs that are approved for marketing in the U.S. have been the subject of a rigorous program of scientific testing and evaluation that is required by the regulations of the U.S. Food & Drug Administration under the Food, Drug and Cosmetic Act.

This program includes in vitro testing, toxicology studies in multiple animal species and three phases of clinical testing that typically involve carefully controlled studies in thousands of patients to demonstrate that a pharmaceutical is safe and effective for human use. These steps are described in regulations that outline the different tests that are required to establish the efficacy and safety of a drug product (21 C.F.R. §312.21).

By way of background for the opinions offered, below is a brief summary of my training and qualifications and documents reviewed:
I. Training and Experience.

After graduation from Baylor College of Medicine, I trained and obtained boards in Internal Medicine and also obtained a PhD. in Pharmacology at the University of California, San Francisco. In addition to earlier clinical and academic practice in Internal Medicine, I began working with the FDA beginning in 1973. I began my interaction with the FDA in 1973 as a member of one of the OTC Advisory Committees that reviewed safety, efficacy and labeling of OTC ingredients until 1978. From August 1978 to November 1983, I served as the Director, Division of Drug (and Biological, beginning in 1982) Experience in the Bureau of Drugs (now the Center for Drug Research and Evaluation). From then until June 1985, I served as part-time Special Assistant to the Director of the Office of Biometrics & Epidemiology in the Bureau.

During my tenure as Director of the Division of Drug & Biological Experience at the FDA, I was responsible for administering the FDA's Drug Postmarketing Surveillance program, which included the spontaneous reports processing, monitoring of drug use, and administering an intra- and extra-mural pharmacoepidemiology program. These activities were for the purpose of gathering data to determine if the marketed drugs continued to be safe as labeled. Accordingly, a major task was to recommend changes in product labeling and work with the reviewing Divisions to effect labeling updates.

More recently, reflecting a long standing career interest in drug and biologic adverse effects, I formed and head a research company, The Degge Group, Ltd. This company specializes in epidemiologic studies and regulatory evaluation of drug and biologic safety and advises manufacturers on the appropriate management of the safety issues of their products, including regulatory actions and product labeling. I also head an organization, the Pharmaceutical Education and Research Institute (PERI) that educates personnel in the pharmaceutical and other medical products industry on the appropriate development, regulatory management, marketing and postmarketing surveillance of medical products. Further details on my background and qualifications are provided in my curriculum vitae which can be found in Attachment A.
II. Documents Reviewed.

In preparation for this report, I am listing materials reviewed in Attachment B to this report.
III. Compensation

My hourly rate to serve as an expert witness in this matter for consultation and related services is $500 per hour ($500 per hour for testimony at deposition or in court).
IV. Expert Testimony in Previous Four Years

Below is a list of all my deposition testimony during the previous four years.
TABLE

My opinions relating to this case are as follows:
V. The FDA's Regulatory Role

A. Metoclopramide, as a prescription drug marketed under an FDA-approved New Drug Application (NDA) has undergone rigorous scientific testing and evaluation for its efficacy and safety for use in the treatment of an assortment of digestive disorders. Further, It can only qualify as a pharmaceutical for therapeutic use if it has been appropriately labeled and properly manufactured, as required by the FDA regulations for approval of new drug products.

Pharmaceutical prescription drugs that are approved for marketing in the U.S. have been the subject of a rigorous program of scientific testing and evaluation that is required by the regulations of the U.S. Food & Drug Administration under the Food, Drug and Cosmetic Act.

This program includes in vitro testing, toxicology studies in multiple animal species and three phases of clinical testing that typically involve carefully controlled studies in thousands of patients to demonstrate that a pharmaceutical is safe and effective for human use. These steps are described in regulations that outline the different tests that are required to establish the efficacy and safety of a drug product (21 C.F.R. §312.21).

Specifically, the tasks that a pharmaceutical sponsor must complete prior to submission of a New Drug Application (NDA) for review include the following:

1. Extensive testing of the drug in multiple species of animals to determine acute and long-term toxicological effects, including the LD50 (the dose at which 50% of animals succumb after exposure), and specific tests for carcinogenicity and effects on reproduction.

2. Testing of the drug in in vitro cell-based systems for mutagenicity and carcinogenicity.

3. Submission of an Investigational New Drug (IND) Application to the FDA prior to clinical testing in humans. This IND includes results of the in vitro tests, and much of the animal toxicology testing as well as the protocols for the initial clinical studies and must be approved prior to initiation of these clinical studies.

4. Performance of several types of clinical studies including:

a. Phase I dose-finding studies to determine the optimal dose for subsequent clinical studies

b. Phase I pharmacokinetic studies to determine the absorption, distribution, metabolism and excretion of the drug in humans.

c. Phase II studies in individuals with the indication to initially assess the effects of the drug and to evaluate the methods for assessment of efficacy and safety that will be used in larger clinical trials. These studies may be conducted in -̈100 individuals, and may include various designs that further evaluate pharmacokinetics and pharmacodynamics of the drug.

d. Phase III clinical trials in larger numbers of patients (typically 2000-3000) to determine the efficacy and safety of the drug for treatment of the proposed indication. The regulations require that in most cases at least two of these trials, usually designated as “pivotal” trials, must be double-blinded, randomized controlled clinical trials. In very rare cases, a single trial will suffice, but two or more are customary. Where possible, unless clear ethical restrictions apply, the controlled trials include a group only exposed to placebo, as well another control group exposed to a comparison drug. Multiple other Phase III trials are customarily conducted to evaluate the safety and efficacy of the drug in special populations (e.g., elderly).

5. Documentation on all aspects of the proposed manufacturing of the drug must comply with good manufacturing practices (GMPs).

6. Development of a proposed product label that conforms to the format and requirements for drug product labeling (21 C.F.R. §201.57) and corresponds to the data submitted in the NDA, which includes the details and data from all of the above steps as well as required summaries of both the efficacy (the Integrated Summary of Efficacy, ISE) and safety (the Integrated Summary of Safety, ISS).

All of this data is submitted for detailed review by the FDA prior to approval. These reviews demonstrate the detailed examination of all aspects of metoclopramide's safety and efficacy.

Even after approval of the NDA, ongoing dialogues between the FDA and the sponsor are the rule. Once an NDA is approved, the drug is required to be followed in specific post-marketing surveillance required by regulation (21 C.F.R. §314.81) to assure its continued safety under conditions of marketing and use by much broader and diverse populations as discussed in detail below. The activities in the post-marketing period frequently also require that the FDA re-review the NDA data, as does any submission by the sponsor that applies for additional indications for the product. Thus, the data within the NDA is subject to detailed initial as well as ongoing review by the agency.

B. The product label for metoclopramide provides extensive and appropriate information on proper dosage, administration, duration and use. It also contains appropriate precautions, warnings and a description of adverse events that might be seen with proper treatment. Drafting of that labeling is the product of a dialogue between the sponsor and the FDA, with the FDA having the final approval authority.

The product labeling reflects the current state of knowledge of the pharmaceutical's safety and efficacy and is a key component of an NDA. The product label of a new drug, as required by regulation (21 C.F.R. §201.57), constitutes a concise summary of all of the significant information developed on the drug relating to its chemical structure and properties; pharmacology; pharmacokinetics; the clinical indication basis for its use; the proper doses and dose regimens; and the contraindications, warnings, precautions and known adverse effects associated with the drug.

The regulations require both the NDA sponsor and the FDA to mutually assure the ongoing safety of approved pharmaceuticals once they enter the market. Both post-marketing surveillance for any new effects as well as clinical trials for new indications provide relevant new information that is incorporated into updated product labeling to assure that prescribers are informed of the appropriate dosage, administration, use and effects of the product.

Specifically, once a product reaches the market, the sponsor must collect, analyze and report all adverse events reported in association with the drug, whether or not the adverse events are thought to be related to the product, to the FDA (21 C.F.R. §314.81). Those events that are serious and not described in the label must be reported within 15 calendar days of the time that the sponsor was notified of the event.

Spontaneous reports of adverse events and other information about adverse effects from clinical or epidemiological studies are evaluated by both the sponsor and the FDA and certain findings may prompt either party to propose that the product label be updated to reflect these findings. Typically, new adverse events may be described in the adverse reactions section of the label; on occasion, information may be added to the Warnings or Precautions, sometimes in bold or capital letters or in a black box. Any change in the product label constitutes a supplement to the NDA that must be reviewed and approved by the FDA. Such was the case for the change in the 1986 metoclopramide label, when the extensive description of tardive dyskinesia was added. That warning will be discussed in detail below.

The regulatory standard for addition of an event to the product label Warning section currently provides:

“The labeling must be revised to include a warning about a clinically significant hazard as soon as there is reasonable evidence of a causal association with a drug; a causal relationship need not have been definitely established. (21 CFR.57(c)).[FN1]

    FN1. Formerly, during the relevant time period for this case, the applicable language read: “The labeling shall be revised to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug; a causal relationship need not have been proved.” (21 C.F.R. §201.57(e). This language was revised with the promulgation on January 24, 2006 of FDA's new labeling regulations which became effective June 30, 2006 (71 FR 3922-3997 at p. 3970).

There are no precise criteria for assessing whether there is “reasonable evidence of serious hazard with a drug”. Rather, this is a matter of judgment that, in general, is determined by the sponsor and the FDA. The mere fact that suspected adverse events have been reported to occur at or near the time of drug use does not mean that there is reasonable evidence of an association. Further, reports of suspected events associated with other drugs of the same class do not mean there is reasonable evidence of an association for all drugs of that class, per se.

A proposal to add information to the label in either the Warning or other sections of the label is a judgment made by the sponsor and/or the FDA that this added information will assure the prescriber has current relevant information on the profile of effects that may be associated with the product. This judgment is very specific to the drug, the nature and seriousness of the event reported the frequency of reports relative to estimated population exposure and the probability that the event is a direct result of exposure to the drug.

The sponsor and the FDA communicate frequently when they consider labeling changes. They study the meaning, relevance and potential impact of any label change on proper understanding, prescribing and use of the drug by the physician who must weigh benefits of the drugs against possible risks for the individual patient when prescribing the drug. This interaction results in a label that provides prescribing information for decision-making without inundating the clinician with too much information.

Some adverse events that are reported to be associated with a drug or drug class may represent a particularly challenging question for the FDA and the sponsor, and may be brought to an FDA Advisory Committee for deliberation on a broader scale. The FDA utilizes external Advisory Committees to advise it on selected decisions relating to the efficacy, safety and labeling of products. These committees are composed of individuals with diverse expertise (e.g., clinical, pharmacologic, statistical) who are asked to review specific questions by the FDA. On some occasions, they are asked to review materials and hear testimony by various parties relating to a general topic that may relate to multiple products or a drug class. Such an advisory committee met in 2004 to assess the NDA of a drug combination including metoclopramide. This meeting, and the FDA's role and conclusions will be discussed below.

Finally, other features of the processes that may play a role in determining the product label include the following:

1. Despite the fact that a sponsor may unilaterally add selected changes to the label as specified in the regulations known as a “changes being effected” or “CBE” labeling change (21 C.F.R. §314.70), by far the most common occurrence is that deliberations on such additions typically stem from a dialogue between the sponsor and the FDA. In any case, any change in a label constitutes a supplement to the NDA that must be reviewed and approved by the FDA. Accordingly, it must be consistent with the regulations and not be misleading.

2. Although products with similar pharmacological effects share some of the same adverse effects, the actual information on product labels varies from product to product. These differences exist primarily because the FDA must consider each individual drug product independently with respect to its safety, efficacy and product labeling. Thus, individual consideration is necessary because even small changes in a pharmacologic product's chemical structure or indication population can make considerable differences in the profile of adverse effects.

C. The Sponsor satisfied the regulatory requirements for development and labeling of metoclopramide.

I have previously reviewed the entire NDA for metoclopramide. In addition, I have examined the sponsor's Annual Reports, adverse reaction reports submitted to the company and the FDA, metoclopramide product labeling and correspondence between the Sponsor and the FDA. From my review, it is my opinion that these documents demonstrate that the Sponsor met the requirements outlined above. Plaintiff's expert's report has extensive comments alleging the contrary are incorrect and ignore the regulatory history of and the FDA's role in reviewing the Reglan NDA.

Plaintiff's expert also devoted many pages of his report to his allegation that the sponsors of metoclopramide knew or should have known of the risks associated with metoclopramide and warned doctors earlier and/or required additional education for gastroenterologists to enable them to identify tardive dyskinesia earlier in its onset. I strongly disagree. By approving metoclopramide, the FDA found it safe and effective. Any suggestion that it should not have been approved is erroneous. Furthermore, metoclopramide has been in use since 1964 when it was approved for use in France. Since that time, it has been studied widely; indeed a recent PubMed search of metoclopramide resulted in 5614 studies since 1964.[FN2] With widespread use of a drug comes clinical familiarity with its safety (including adverse event profile) and efficacy.

    FN2. PubMed search conducted October 9, 2008.

As described above, the regulatory process for any NDA is one of ongoing dialogue between the Sponsor and the FDA as new information is accrued and new marketing initiatives are submitted as supplements. It is the give-and-take process by which the FDA regulates activities in the postmarketing period.

D. The FDA was well aware of the risk of tardive dyskinesia and its association with long term use of metoclopramide, and remains aware of that risk today

In his statement, plaintiff's expert expressed concern that the FDA was not adequately informed about tardive dyskinesia. This allegation is completely unfounded. It would be difficult to be more transparent than to include the clear, complete and precise language that appears in the label's Warnings section:

“Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with metoclopramide. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients are likely to develop the syndrome. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase with the duration of treatment and the total cumulative dose.

Less commonly, the syndrome can develop after relatively brief treatment periods at low doses; in these cases, symptoms appear more likely to be reversible. There is no known treatment for established cases of tardive dyskinesia although the syndrome may remit, partially or completely, within several weeks-to-months after metoclopramide is withdrawn. Metoclopramide itself, however, may suppress (or partially suppress) the signs of tardive dyskinesia, thereby masking the underlying disease process. The effect of this symptomatic suppression upon the long-term course of the syndrome is unknown. Therefore, the use of metoclopramide for the symptomatic control of tardive dyskinesia is not recommended.”

The label also includes the following provision in the Adverse Reaction section:

“In general, the incidence of adverse reactions correlates with the dose and duration of metoclopramide administration. The following reactions have been reported although in most instances, data do not permit an estimate of frequency.

Tardive dyskinesia most frequently is characterized by involuntary movements of the tongue, face, mouth, or jaw and sometimes by involuntary movements of the trunk and/or extremities; movements may be choreoathetotic in appearance (see WARNINGS).”

This exact warning language has appeared in all metoclopramide labeling since 1986. The language clearly states that tardive dyskinesia is a possible side effect of use. Furthermore, it states that tardive dyskinesia may be:

• irreversible,

• more frequent in the elderly, especially elderly females;

• may increase with long term use; and

• the drug itself may mask the symptoms of tardive dyskinesia.

I know of no discussion in the literature that indicates that this warning language is inadequate. The inadequacies suggested by plaintiff's expert are not supported by the literature, evidence or the regulatory history.

In addition to the ongoing regulatory review, there is ample evidence that the FDA was aware at all times of the association between metoclopramide and tardive dyskinesia. Specific examples follow:

1. Personal experience

I can personally attest that the FDA was aware of reports of tardive dyskinesia both in the literature (Lavy et al, 1978) as well as spontaneous reports which were reviewed by the Division of Drug Experience that I headed at the FDA at the time. The Sponsor has disclosed and discussed tardive dyskinesia and relevant literature with the FDA throughout the years. Following both discussions with the Sponsor, as well as a separate FDA Advisory Committee meeting on defining the entity of tardive dyskinesia related to antipsychotic drugs, the FDA also requested the Sponsor add a statement to the Warnings section of the metoclopramide label describing tardive dyskinesia. In response, the Sponsor and the FDA agreed upon the tardive dyskinesia language which was published in the 1986 PDR.

2. Review of Cisapride

The FDA had an ongoing review of pro-kinetic treatments during and after weighing the benefit-risk of Propulsid(R) (cisapride). The FDA specifically considered the effects of metoclopramide, because it is one of the common alternatives to cisapride, which was removed from the market in 2000. Based upon my first-hand knowledge of the regulations and practices of the FDA, I can state that the FDA does consider the alternative therapies and their effects when determining whether to remove a product from the market (21 CFR 314.150, et seq.). The FDA would have, therefore, included consideration of metoclopramide. The FDA would have paid close attention to its product label, which clearly states its potential for association with neurological effects including tardive dyskinesia and the need for short-term use. Interestingly, cisapride was also used off-label for treatment of diabetic gastroparesis.

3. Increased frequency reports in the 1990s

Robins/Wyeth and the FDA received some reports of tardive dyskinesia associated with metoclopramide since the early 1980's, and these in part formed the basis for the labeling change in 1986.

They also received reports of other more common movement disorder including dystonia and other extrapyramidal disorders. More recently, in the mid-1990's, an increased frequency report of extrapyramidal symptoms, specifically relating to acute dystonia, was submitted by the Sponsor and thereby met with the regulatory requirement in effect at the time to provide a special report of this finding. Increased frequency reports were defined in the regulations to refer to a significantly increased number of reports relative to a selected denominator (such as total units or prescriptions) in a given time period. Until they were discontinued in July 1997, such reports were categorized as new and serious by the FDA reviewers; thus, this event would have stimulated further evaluation of this effect. Yet the FDA did not find any reason to change the product labeling.

4. Spontaneous reports

The FDA received all spontaneous reports of tardive dyskinesia sent to the Sponsor as well as literature reports collected by the sponsor. These communications included reference to relevant medical literature including articles by Drs. Sewell and Ganzini. The reports and literature were provided to the FDA in Annual and Periodic Reports, as well as in ongoing and frequent correspondence between the Sponsor and the FDA relating to various matters, including supplements (e.g., the Geriatric Supplement in 2000).

5. Metoclopramide was used as an example of the FDA Adverse Event Reporting System

In March of 2002, Dr. Douglas Shaffer, an FDA medical officer at CDER spoke on the issue of metoclopramide-associated tardive dyskinesia the Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics in Atlanta, Georgia. The title from the abstract of his paper was, “Metoclopramide and tardive dyskinesia: A review of the FDA Adverse Event Reporting System.” The abstract concluded, “TD is a rare, serious, and potentially irreversible adverse effect of metoclopramide use. Risk factors linked to TD observed in this case series were increasing duration of use, increasing age, female gender and concomitant drug & disease states. These risk factors relative to the benefit of intended & duration of use should be considered in metoclopramide prescribing.”[FN3] Subsequently, Dr. Shaffer published an analysis of risks of TD and metoclopramide use after the withdrawal of cisapride.[FN4] This article referenced the Ganzini and Sewell articles relied upon by plaintiffs experts. This article will be discussed below along with other medical literature.

    FN3. Shaffer, D. Clin PharmTher. 2002; 71:MPI-78, P24.

    FN4. D. Shaffer, M. Butterfield, C. Pamer, and A. C. Mackey. Tardive dyskinesia risks and metoclopramide use before and after U.S. market withdrawal of cisapride. J Am Pharm Assoc (Wash.DC.) 44(6) (Nov-Dec):661-665, 2004.

6. Metoclopromide and tardive dyskinesia have recently been reexamined because it is an ingredient in other products

As a part of the review of MT 100, a combination drug consisting of metoclopramide and naproxen for treatment of severe migraine headaches, the FDA re-examined metoclopramide and tardive dyskinesia. The FDA convened an Advisory Committee which also examined tardive dyskinesia. On Thursday, August 4, 2004, the Peripheral and Central Nervous System Drugs Advisory Committee voted 9 to 0 with 3 abstentions not to recommend the drug for approval because they determined that it is not an effective treatment. However in that examination, the Advisory Committee also indicated that since they had decided that there was no benefit to migraine sufferers from the combination drug, the risk of tardive dyskinesia was therefore too high. As evidence of my point that the FDA was and is well aware of tardive dyskinesia and metoclopramide, two FDA staff members presented at the Advisory Committee meeting.

Eric Bastings, M.D., Clinical Team Leader for CDER's Division of Neurology Products, spoke on the FDA's Risk/Benefit Considerations. He stated:

“TD is a well known side effect of metoclopramide Exact incidence of metoclopramide-induced TD remains unclear.”

Mary Ross Southworth, Pharm.D., Safety Evaluator Division of Drug Risk Evaluation, spoke on the Post-marketing Review of Movement Disorders and Neuroleptic Malignant Syndrome Associated with Metoclopramide. Thus, Dr. Southworth discussed metoclopramide-induced tardive dyskinesia in greater detail. She presented a slide of the Total Number of Prescriptions Dispensed (in thousands) in Retail Pharmacies Nationwide for Metoclopramide Products, IMS Health, NPA Plus™, 1995-2004. Prescriptions totaled 63,164,000, and the FDA received reports of 67 cases, or 1 case per 1 million prescriptions.

Kevin Prohaska, D.O., was the primary FDA medical reviewer for MT 100. He recommended against approval for the drug primarily because the combination drug was not efficacious in relieving migraine symptoms, and thus the risks of the drug were not acceptable. Dr. Prohaska specifically stated that: “extrapyramidal symptoms, mainly acute dystonic reactions, occur in approximately 0.2% of patients receiving oral metoclopramide at doses between 30 to 40 mg per day and 2% of patients receiving intravenous metoclopramide. Symptoms include involuntary movement of limbs, facial grimacing, torticollis, oculogyric crises, rhythmic protrusion of tongue, bulbar type speech, trismus, opisthotonus and rarely, stridor and dyspnea possibly due to laryngospasm. Motor restlessness (akathisia) may consist of feeling of anxiety, agitation, jitteriness, and insomnia as well as an inability to sit still, pacing and foot tapping.”[FN5] Dr. Prohaska continued on to describe two clinical trial participants who suffered acute dystonic reactions to MT 100. Further, the review does briefly address the issue of tardive dyskinesias at the conclusion of his safety review of extrapyramidal effects but does not make any additional recommendations. In fact, Dr. Prohaska recommended that, should it be approved, “[t]he labeling for MT 100 should include language similar to that described in the Reglan label for this concern.[FN6]

    FN5. Clinical Review NDA 21-645, Pozen, Inc. Myzan, MT 100) April 13, 2004, Page 119.

    FN6. Id.

These specific activities argue against plaintiff's experts' contentions that the FDA was unaware of or not fully informed of tardive dyskinesias. Thus, it is quite clear that the FDA is well aware that tardive dyskinesia is a known risk factor in the use of metoclopramide, and that the FDA believes that the label adequately warns of the risks for tardive dyskinesia as well as all other extrapyramidal symptoms, and that any new label for products including metoclopramide should include similar language. Plaintiff's suggestion that the label is inadequate is contrary to this evidence.

E. Metoclopramide is not, and has never been approved for long term use. Such use therefore, is considered “off-label” and is not regulated by the FDA, nor controlled by the manufacturer. Rather, such use is a decision made by the licensed physician based on their clinical knowledge and the symptoms of the patient.

Metoclopramide is indicated for use for up to 12 weeks. Longer use is considered “off label.” A medication is considered used “off-label” when it is used:

• In treatment for an indication that is not included in the labeling:

• In treatment of an approved indication, but in a population for which it is not approved (i.e., children, pregnant women);

• At a higher dose than that indicated in the labeling;

• For a longer duration than stated in the labeling;

• In patients for which the drug is contraindicated due to other health factors.

Use of a drug off-label is common practice. It is a decision between the doctor and the patient, based on the symptoms and available alternative therapies. While use of medications such as metoclopramide off-label is not uncommon, it is not possible for the FDA or the sponsor to prevent it. Off-label use does not necessarily mean that the labeling is inadequate.

The FDA has publicly stated that 13 percent of patients appeared to have used metoclopramide for more than 90 days; approximately 7% have used it for more than 180 days.[FN7] Such off-label use is much less when compared with other drugs. Further, off-label use may be necessary in some cases. The labeling clearly and properly states that the risk of tardive dyskinesia increases with duration of treatment and total cumulative dose.

    FN7. Peripheral and Central Nervous System Drugs Advisory Committee Meeting, to discuss NDA 21-645, MT 100 (naproxen sodium and metoclopramide hydrochloride) Tablets, Pozen, Inc., for the proposed indication of acute treatment of migraine headache with or without aura; Thursday, August 4, 2004. Transcript at page 119.

F. Metoclopramide and its indications

During the time when the plaintiff took metoclopramide, the drug was indicated for short term use for:

• Symptomatic gastroesophageal reflux (GERD)

• Diabetic gastroparesis (Diabetic Gastric Stasis)

• Prevention of nausea and vomiting associated with emetogenic cancer chemotherapy

• Prevention of postoperative nausea and vomiting

• Small bowel intubation

• Radiological examination

1. Gastroesophageal reflux (GERD)

Gastroesophageal reflux (GERD) is a condition caused by changes in the sphincter muscles that form the barrier between the esophagus and the stomach, keeping food and acid in the stomach and preventing regurgitation. Symptoms of GERD include heartburn, esophagatitis, difficulty swallowing, chronic chest pain, hoarseness, vocal changes, chronic ear ache, burning chest pains, nausea and sinusitis. GERD can lead to far more serious illness, including Barrett's esophagus, as well as cancer, spasms and ulcers of the esophagus. Difficult cases of GERD may have failed to respond to conventional therapies and metoclopramide can successfully treat unresponsive GERD.

2. Gastroparesis is a serious medical condition and options for its treatment are very limited.

Gastroparesis is a condition where the ability of the stomach itself to contract and crush the contents of the stomach and thus facilitate its passage into the small intestine is diminished. Symptoms include early satiety, bloating, nausea, feeling of fullness while eating, heartburn and pain. Nausea, regurgitation and vomiting are common. Severe cases can result in significant weight loss, vitamin and mineral deficiencies, inability to metabolize medications and anorexia. Gastroparesis can be caused by diabetes, obesity, infections, endocrine disorders, connective tissue disorders such as scleroderma, neuromuscular diseases, idiopathic causes, cancer, radiation treatment, chemotherapy or upper Gl surgery which can damage the vagus nerve. In addition, some medications can cause gastroparesis. They include:

• Calcium channel blocking medications

• Clonidine

• Dopamine agonists

• Lithium

• Narcotic pain medications

• Nicotine

• Progesterone containing medications

• Tricyclic antidepressants

Treatment options for gastroparesis are extremely limited. They include:

• Cisapride, a therapy that was removed from the market in 2000 due to reports of serious cardiac arrhythmias. Interestingly, before its withdrawal from the market, cisapride was not indicated for, and thus used off-label for, diabetic gastroparesis;

• Domperidone, which is not available in the United States;

• Erythromycin, a commonly used antibiotic. It is associated with numerous drug interactions, may cause vomiting and other effects and there are concerns regarding development of antibiotic resistance; and

• Metoclopramide.

The FDA has evaluated and found that metoclopramide is effective in treating both gastroparesis and GERD. The studies submitted to and considered by the FDA established efficacy. Further, subsequent literature and studies continue to support the efficacy of metoclopramide for these indications.

G. Plaintiff's expert Is incorrect in his understanding of metoclopramide and its use

Plaintiff's expert produced a report in which he accuses Wyeth, its predecessor A.H. Robins, and its successor Schwarz Pharma of many flaws in its development, testing, marketing and labeling of metoclopramide. Indeed, his report is so broad as to cover allegations of wrongdoing that are not even the subject of this litigation. As those issues, including: akathisia, use in treatment of diabetic gastroparesis, use in elderly women, use in children, spontaneous dyskinesias and numerous others, are not germane in this instance, this report will not address them. However, I would like to reserve my right to rebut the allegations should the court deem them relevant. Instead, this report will focus on use of metoclopramide by the plaintiff for treatment of GERD, and on the issue of tardive dyskinesia.

1. Classification of metoclopramide

Plaintiff's expert has opined that because metoclopramide is a dopamine antagonist, that it should therefore be classified as a neuroleptic. He is incorrect. The category of dopamine antagonist drugs includes dozens of drugs, the many of which are not considered neuroleptics and the majority of which have no known association with tardive dyskinesia. Indeed, some dopamine antagonists are used to treat tardive dyskinesias. As explained below, while metoclopramide is a dopamine antagonist, it is not a neuroleptic.

a) Metoclopramide is not a neuroleptic drug

In 1985, the FDA promulgated a notice to manufacturers of neuroleptic drugs that mandated a warning of the risk of tardive dyskinesia from the use of neuroleptic drugs. At that time, I served in the Office of Biometrics of the FDA's Center for Drugs & Biologies. This class warning did not apply to metoclopramide, because, as demonstrated below, it is not a neuroleptic drug. While metoclopramide shares some pharmacological properties with neuroleptics, it is primarily an anti-emetic agent, a different category of drug used in entirely different indications. In fact, when Robins was asked to include tardive dyskinesia in its label, the correspondence specifically reveals that the FDA agreed it should not be referred to as a “neuroleptic.” Metoclopramide is used for the treatment of digestive disorders, not psychiatric ones.

There is no scientific evidence to show that the risk for tardive dyskinesia with metoclopramide is the same as for antipsychotic drugs. The following demonstrates further that metoclopramide is a very different chemical entity.

1. Definition

The USPDI lists metoclopramide in 4 categories: (1) dopaminergic blocking agent; (2) gastrointestinal emptying (delayed) adjunct; (3) peristaltic stimulant; and (4) antiemetic. Metoclopramide is not listed as a neuroleptic.

“Neuroleptics” is a name applied to a class of drugs made up of antipsychotics, both conventional and atypical, used in the treatment of schizophrenia and other severe mental illnesses. The list of neuroleptic drugs is made up of conventional antipsychotics: Haldol (haloperidol); Mellaril (thioridazine); Navane (thiothixene); Prolixin (fluphenazine); Stelazine (trifluoperazine); Thorazine (chlorpromazine); Trilafon (perphenazine); and newer, atypical antipsychotics: Abilify (aripiprazole); Clozaril (clozapine); Geodon (ziprasidone); Risperdal (Risperidone); Seroquel (quetiapine); and Zyprexa (olanzapine).

The term “neuroleptic” is synonymous with “antipsychotic”. Webster's New World Dictionary defines it as follows:

“Neuroleptic: A term that refers to the effects of antipsychotic drugs on a patient, especially on his or her cognition and behavior. Neuroleptic drugs may produce a state of apathy, lack of initiative and limited range of emotion. In psychotic patients, neuroleptic drugs cause a reduction in confusion and agitation and tend to normalize psychomotor activity.

The term comes from the Greek “lepsis” meaning a taking hold.”[FN8]

    FN8. http://www.medterms.com/script/main/art.asp?articlekev=10983

The Meriam Webster Online Medical dictionary has a more simple definition:

“neu-ro-lep-tic Pronunciation: ln(y)úr-a-'lep-tik Function: noun: antipsychotic”[FN9]

    FN9. http://www2.merriam-webster.com/cgi-bin/mwmednlm

Furthermore, the medical community generally refers to antipsychotic drugs as “neuroleptics”.

2. All dopamine antagonists do not share the same profile of adverse events — the pharmacological properties of metoclopramide v. other drugs

There is a long list of drugs that can be classified as dopamine antagonists. One subset of drugs are the neuroleptics, which are known to cause tardive dyskinesia. However, other dopamine antagonists have no known association with tardive dyskinesia. The pharmacology of these agents, their uses as well as adverse event profile are not uniform. In fact, the pharmacological properties of agents in the neuroleptic class of drugs can be quite different from each other and even more different than from a gastrointestinal active agent such as metoclopramide.

The pharmacologic potential of an agent to induce EPS reactions is mediated by its binding capacity to dopamine D2 receptors in the mid-brain. Neuroleptics bind tightly to these receptors; metoclopramide binds weakly to them. The strength or weakness of this capacity is denoted by the dissociation constant Kd with units in nanomoles (nM). The lower the constant, the stronger the binding. Endogenous dopamine itself has a Kd between 2-7 nM. Neuroleptic agents with low Kd values bind tightly to D2 receptors and thus may elicit EPS (Kd <1 nM; e.g., trifluoperazine, chlorpromazine, thioridazine, haloperidol and fluphenazine). Metoclopramide has a high dissociation constant ≥ 10 nM, which means that the drug binds weakly to D2 receptors.[FN10]

    FN10. Tonini M, Cipollina L, Poluzzi E, Crema F, Corazza GR, DePonti F. Clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics. Aliment Pharmacol Ther 2004; 19:379-390. Accessed October 7, 2008.

Furthermore, the lipophilicity of these drugs is different. A substance is lipophilic if it is miscible (able to dissolve or mix without separating) much more easily in organic solvents than it can in water. Lipophilicity is a measure of a drug's ability to move across lipid membranes. If a drug is highly lipid soluble, higher proportions will move into the tissues (such as the lipohilic environment of the brain). Lipophilicity is related to absorption, bioavailability, lipophilic drug-receptor interactions, metabolism and toxicity.

Measures of lipophilicity indicate the relative attraction or repulsion of agents to organic solvents. To measure lipophilicity, chemists use the LogP: partition coefficient value or logarithmic ratio of the concentrations of a solute in a solvent. Typically the solvents are octanol and water. The octanol-water partition coefficient is a measure of the lipophilicity of a substance (conversely hydrophilicity).

The following table illustrates the lipophilicity of metoclopramide relative to neuroleptics, both conventional, those drugs long associated with tardive dyskinesia, and atypical, which have far less risk of tardive dyskinesia. For reference, ethanol's logP value is 0.017, or almost completely miscible in water.

Table. Partition coefficients of representative drugs[FN11]

    FN11. Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, et al. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006;34 (Database issue):D668-D672.

TABLE

3. Different users

Neuroleptic users cannot be compared to metoclopramide users. Metoclopramide is used by gastroenterologists and internists for selected gastrointestinal disorders; neuroleptics are used by psychiatrists for severe mental illnesses such as schizophrenia. Metoclopramide is not approved, not effective and is not used to treat such mental disorders. This difference is especially pertinent when reviewing the Sewell and Ganzini articles, as those studies took place in Veterans Health Administration (VHA) hospital settings, where many of the predominantly male veteran population suffer from various psychiatric disorders for which neuroleptic drugs are routinely prescribed for long term use.

Plaintiff's expert himself asserts that “the evidence supports that the vast majority (approaching 100%) of MCP is prescribed by non-psychiatrists.” His statement reiterates my previous point; metoclopramide is a drug used to treat gastric, not psychiatric conditions.

b) The labeling for metoclopramide was appropriate and adequately warned physicians of the risks of this drug

As demonstrated, by 1986, fourteen years before the first reported use of metoclopramide by the plaintiff, the label for metoclopramide included warnings of the different categories of movement disorders that may be associated with use of this product, including acute dystonias, extrapyramidal symptoms, akathisia and tardive dyskinesia. The label specifically described the risk for tardive dyskinesia in the Warnings section, both with respect to demographic risk factors and the fact that risk increased with dosage and duration of use.

I believe that plaintiff's expert's interpretation of the labeling is incorrect in its discussion of the risk for tardive dyskinesia. The 1 in 500 figure for EPS reactions he cites does not relate to tardive dyskinesia, but instead to acute dystonic reactions. This is repeated in the MT100 medical evaluation where these dystonic reactions and their frequency is discussed in detail ( vide supra). Further, plaintiff's expert's assertions about the regulatory history (including single dose application) are mistaken.

Based upon my research, I believe that the most likely source of the “approximately 1 in 500” statement is a 1967 article entitled “Étude Clinique de la Tolérance du Métoclopramide” (CLINICAL STUDY OF METOCLOPRAMIDE TOLERANCE) by M. Derbanne. In this article, which was cited in the Reglan NDA, the author examined “2,540 cases where metoclopramide has been prescribed” from hospitals in France, Germany, Belgium and Japan. Of the 2,540 subjects on metoclopramide, the study found 4 cases of extrapyramidal symptoms (0.16%).

There are several reasons why this article is likely the source of the original “approximately 1 in 500” statement. First, as I have previously stated, it is both the practice of the FDA and drug manufacturers to have a source for any numerical data in the NDA. Second, a manufacturer such as AH Robins could have appropriately rounded the Derbanne results (1 in 635) to “approximately 1 in 500”. One in 500 was a normal method of expressing frequency and it would be appropriate to be more conservative (i.e., round 1 in 635 down as opposed to up). Further, the label states that the frequency is “approximately 1 in 500,” and 1 in 635 is approximately 1 in 500. Third, AH Robbins cited and attached the Derbanne article to its NDA. Fourth, the Derbanne article reviewed data from a very large subject group for the time period in which the study was performed. Thus, it is the type of study upon which a manufacturer and the FDA would rely to put a frequency number in the label.

To provide further context for the “approximately 1 in 500” statement, I have also analyzed the data from the clinical studies performed for the original NDA for Reglan. Based upon my review of the clinical data the frequency of acute dystonic reactions, as well as other types of extrapyramidal manifestations in the clinical trials, is far less than 1 in 500. My analysis is contrary to that of plaintiff's expert and his recharacterization of the NDA is not correct and inappropriate. Thus, the “approximately 1 in 500” statement based on the Derbanne article is more conservative than the clinical data that was available to AH Robins at the time the statement was made.

Lastly, there is no indication in the medical literature that the labeling fails to warn of the risk of tardive dyskinesia with metoclopramide treatment. Further warnings about additional risk factors are not necessary.

c) Duration of use

Plaintiff's expert opines that the Sponsor failed to warn of the risks of non-compliance with the recommended treatment duration guidance. I disagree. The label indicates in both the Indications and Usage and the Dose and Administration sections that metoclopramide is recommended for short term use, and that therapy is not recommended for use for more than 12 weeks. Furthermore, as demonstrated previously, the Warnings section clearly addresses the risk of tardive dyskinesia among other possible adverse events with prolonged therapy.

d) Gastroparesis was an early indication for metoclopramide and all the risks associated with the drug's use in that population were assessed appropriately

Plaintiff's expert suggests that there is an increased risk of tardive dyskinesia in diabetic patients. He claims that sponsors failed in their duty to warn of that increased risk of tardive dyskinesia in diabetics. There is little data to support this allegation. Metoclopramide is indicated for use in patients with diabetic gastroparesis. It follows logically, then, that a significant portion of at risk patients will be diabetic, and thus any allegation of increased risk may simply be a result of confounding by indication.

The studies that have data relating to this question present conflicting results. For example, Miller and colleagues “found no support for [diabetes mellitus] or hypertension increasing the risk of [tardive dyskinesia] (Miller et al., 2005). In his review in 2000, Marsalek (Marsalek 2000) found an association, but he examined psychiatric patients being treated with antipsychotics rather than drugs for gastroparesis. Lata and Pigarelli examined chronic metoclopramide therapy for diabetic gastroparesis in their 2003 review article. They review the available data (in studies by Stewart, Sewell and Ganzini) relating to the question of greater risk in diabetics. They conclude that there is some data suggesting this, but it requires further study. However, as noted below, this research would be extremely difficult if not infeasible because of the ethical and logistical problems cited. Further, it is notable that a recent large study of tardive dyskinesia in schizophrenics specifically did not find any relationship of this disorder to diabetes (Caligiuri and Jeste, 2004).

Nevertheless, warnings of risk of tardive dyskinesia with use of metoclopramide has been in the labeling since 1986 — for all patients, including diabetics, the most likely population that would use metoclopramide for diabetic gastroparesis. It is my opinion that the warnings are appropriate for both diabetic and non-diabetic patients.

e) “Intended use”

To the extent plaintiffs experts asserts that Section 201.128 of the FDA regulations requires additional labeling, his argument is wrong. Section 201.128 of the regulations does not apply to metoclopramide. His interpretation is inconsistent with FDA practice and regulations, the legislative history of the Federal Food, Drug and Cosmetic Act, and my over 20 years personal experience in interpretation of FDA regulations related to labeling.

f) Plaintiff's expert charges that the Sponsor was not forthright in NDA process

As stated previously, I have examined the majority of documents relating to the metoclopramide NDA. Furthermore, I have examined ADE reports submitted on the drug. In my review, I found that the sponsors complied at all times with both the FDA regulations and with the standards of drug development and approval. I find plaintiff's expert's characterization that Robins and its successors were not forthright with the FDA during the NDA review process to be incorrect. Therefore, I can only conclude that they are unsupportable. Many of the instances of alleged misconduct are not correct or are irrelevant to the labeling issues.

An illustration of the sponsor's full disclosure of tardive dyskinesia was a letter to the editor published in the New England Journal of Medicine on August 21, 1986. At that time, AH Robin's Medical Director, Anne Woodnum Board responded to reports of tardive dyskinesia in patients taking metoclopramide. In her letter, Dr. Board discussed a case reported by Dr. Breitbart to Robins, published in the same issue. Dr. Breitbart's patient improved after discontinuation of metoclopramide until his symptoms were considered mild. The patient died thereafter from an unrelated cause. Dr. Board expanded her commentary and went on to discuss one similar case of tardive dyskinesia from injectable metoclopramide, which continued for two days and then subsided. She also disclosed 26 cases of tardive dyskinesia reported to Robins. Six of those cases had no follow up data as they were very new. Eleven saw their symptoms disappear after about 7 months and six had substantial improvement within about 14 months. One patient had remission of symptoms with discontinuation of metoclopramide, but the symptoms returned with use of another medication to treat severe GERD. Two other cases continued to have moderate difficulty at the time of writing. This letter and many other documents demonstrate Robins' clear and forthright disclosure, well beyond the response to Dr. Breitbart's original letter. Publication of this commentary in the widely read New England Journal of Medicine can hardly be viewed as an attempt by the sponsor to hide adverse events.

g) Analysis of metoclopramide's ADEs and the medical literature on metoclopramlde-associated tardive dyskinesia support the product labeling

ADEs, and the existing medical literature reporting the association of tardive dyskinesia with metoclopramide, do not provide the basis for more specific information than is already present in the product label (see Miller and Jankovic, (1989); small population studies by Stewart et al (1992); Sewell et al (1992); and Ganzini et al (1992)). The ADEs, case reports and medical literature provide no basis for estimate of frequency of this effect.

Special mention must be made of the Sewell and Ganzini articles, which provide little on the risk of tardive dyskinesia from metoclopramide and specifically do not determine the incidence of tardive dyskinesia. Although their cases show use longer than recommended by the label, this data cannot be used to estimate proportion of patients using metoclopramide beyond 12 weeks. In fact, these two studies themselves suggest that the VHA populations are already at risk based upon high baseline rates of tardive dyskinesia associated with use of neuroleptic drugs in this population. The prevalence rates cited in these special studies would not be the same in the broader population; thus it would not be informative to cite this information in the product label because neither study probes the issue of causation of tardive dyskinesia. Furthermore, plaintiff's expert's suggestion that nearly one fourth of patients exposed to metoclopramide will develop tardive dyskinesia is incorrect. The studies do not address the rate or frequency of developing tardive dyskinesia from taking metoclopramide.

Furthermore, these two studies were conducted in the very special VHA predominantly male population which is not representative of the general population. In fact, the National Research Council said the following regarding generalizability of VHA data:

“First, because virtually all studies have been limited to veterans who receive care in VHA, findings are not immediately generalizable. There is overwhelming evidence that veterans who use VHA have significantly fewer financial resources and less, if any, supplemental health insurance (Wolinsky et al., 1985; Randall et al., 1987); report meaningfully lower scores on health related quality-of-life measures (Kazis et al., 1997; Weinberger et al., 1996); and have significantly less experience with the traditional doctor-patient relationship (Inui et al., 1984). These data clearly indicate that veterans receiving care within VHA are more medically and socioeconomically vulnerable than either nonveterans or veterans who do not use VHA.”[FN12]

    FN12. Oddone, EZ, Petersen LA, and Weinberger M, Health-Care Use in the Veterans Health Administration: Racial Trends and the Spirit of Inquiry, Chapter in America Becoming Racial Trends and Their Consequences Volume II, Smelser, Wilson and Mitchell, Editors, Commission on Behavioral and Social Sciences and Education, National Research Council, National Academy Press, Washington DC, 2001.

Furthermore, the higher baseline risk in this population is quite possibly due to frequent use of antipsychotic medications, with their own risk of tardive dyskinesia. The high rates of spontaneous dyskinesias are contrary to published literature.

h) Plaintiff's experts' speculation on the percentage of patients taking metoclopramide long term is exaggerated.

To the extent plaintiff's expert contends that metoclopramide is used long term by a significant percentage of patients, I disagree. Dr. Stewart's study (Stewart, et al., 1992), in which he claims that 32.4% of elderly patients use metoclopramide for longer than 12 weeks, does not mean that 1/3 of all metoclopramide users take metoclopramide long-term. Dr. Stewart's study examined only 34 patients, a number unlikely to provide significant data on any of the issues in question in this case. Dr. Stewart's tiny sample can hardly be seen as representative of the patients who took the 63 million metoclopramide prescriptions that were written between 1995 and 2004. The FDA, furthermore, disagrees with Dr. Stewart's figure. During his presentation to the Advisory Committee examining MT 100, FDA Clinical Team Leader Eric Bastings, presented a significantly lower rate for long term exposure to metoclopramide when he said that:

“13 percent of patients appeared to have received prescriptions for more than 90 days and 7 percent of patients for more than 180 days”.[FN13]

    FN13. Peripheral and Central Nervous System Drugs Advisory Committee Meeting, to discuss NDA 21-645, MT 100 (naproxen sodium and metoclopramide hydrochloride) Tablets, Pozen, Incforthe proposed indication of acute treatment of migraine headache with or without aura; Thursday, August 4, 2004. Transcript at page 119.

A study by the FDA (Kaplan, et al., 2007) examined prescription claims for metoclopramide from 2002 to 2004 in the Caremark Pharmacy database. It found that during that period 15% of metoclopramide patients were treated for more than 90 days.

In a small study of 434 TD patients evaluated at Baylor College of Medicine between 1981 and January 2006, Kenney et al. found that 30% of TD patients were treated for gastrointestinal indications, and

“that the most common medications associated with the onset of TD were haloperidol (n=191, 44%), Metoclopramide (n=171, 39.4%), amitriptyline/perphenazine (n-85, 19.6%), and thioridazine (n-72, 16.6%).

They state that from 2000 to 2006, metoclopramide-induced TD was more common than any other cause, accounting for 34.5% of all cases compared with 24.4% for haloperidol. This ratio may seem to indicate that the incidents of MCP-induced TD are increasing. If this study were representative of the overall population with TD, it might simply reflect the decreasing use of typical antipsychotics, haloperidol, amitriptyline/perphenazine and thioridazine, as well as the recent (at that time) removal of Cisapride from the market which resulted in an increased use of metoclopramide. Thus the results are skewed over this time period.

It is very important to emphasize that the Kenney paper is not a population study; it is a case series of patients seen at a particular Houston clinic. Therefore, the numerical estimates of proportions of cases do not necessarily reflect true frequencies of these events in the overall population, but rather the particular patterns of referral to the clinic. In order to determine true relative proportions, one would need a population-based study.

i) Why wasn't a study to determine rates of tardive dyskinesia done?

Plaintiff's expert also suggested that the Sponsor should have done a study on the effects of off-label use, especially the risk of tardive dyskinesia. I disagree for several reasons. First, ethical issues preclude a prospective clinical study that would extend beyond the recommended 12 weeks when the risk generally begins. It is my opinion that no reputable sponsor would design and no institutional review board would approve a study to tabulate the rate of occurrence of a potentially irreversible, serious event that might be associated with a drug. Second, a retrospective study in medical claims data or chart data would be very difficult because the manifestations are so varied and variably described in either claims or medical charts, if even recorded, that it would be very difficult to determine a reliable rate of events. Lastly, further studies on tardive dyskinesia are not warranted as the label already clearly warns of this risk and because it is rare, further quantification would be of questionable value to the prescribing physician. There was no signal or reason to do further study.

j) Plaintiff's expert's analysis is not appropriate for estimating the risk of tardive dyskinesia for metoclopramide.

I have examined plaintiff's expert opinions about the risk of tardive dyskinesia including prevalence and rate ratios in metoclopramide users. I must respectfully disagree with his method of analysis and therefore his conclusions. First, let me re-emphasize that I do not dispute any assertions that tardive dyskinesia prevalence is higher in metoclopramide users than in non-users.

Plaintiff's expert derived an incidence statistic from prevalence data taken from two cross-sectional studies. However, cross-sectional studies are unreliable when used to estimate the incidence of any outcome. These studies are a “snapshot” of a point in time that illustrates the prevalence of a disease (tardive dyskinesia) in a population. At best, the studies indicate that metoclopramide-exposed subjects have a higher prevalence of tardive dyskinesia than non-metoclopramide subjects. However, one cannot interpret a point prevalence as an incidence statistic without any measure of time.

Second, estimating an incidence rate from a point prevalence is highly dependent on the duration of disease. The longer the duration, the less reliable the prevalence. Using a point prevalence such as that in the Sewell and Ganzini studies, rather than a period prevalence further decreases the reliability of an incidence estimate. A point prevalence cannot estimate the loss of cases at any future time due to death or clinical improvement for example. This is especially relevant when assessing an adverse event produced by long exposure to a drug.

These two limitations preclude any interpretation of a prevalence statistic as an “incidence rate ratio”.

Earlier I discussed the pharmacological differences between neuroleptics and metoclopramide. In making their calculations, plaintiff's expert fails to factor that these are very different drugs. Nor does he examine the variabilities in dose, duration, absorption, distribution, elimination, and metabolism in the population.

Both the Sewell and Ganzini studies displayed unexpectedly high rates of tardive dyskinesia in the control group of 12% and 18% respectively. Similarly, plaintiffs expert includes conclusions reached in the Matson (2005) study. This study was conducted in a special population of mentally retarded patients, and the conclusions reached, like those reached by Sewell and Ganzini, are not applicable to the general public.

Only one study attempted to study the actual incidence of tardive dyskinesia associated with metoclopramide. That study, done by Wiholm in 1984, calculated total drug sales and prescription statistics to determine the incidence of metoclopramide induced tardive dyskinesia, and determined that there was an incidence of 11 cases in 11 million prescribed daily doses, 1 in 2760 patient years. Outpatient usage was one in 17,800 prescriptions, with an average treatment time of 42 days making it 1 in 2050 patient years. In fact, the Wiholm study showed that the risk of TD with metoclopramide is minimal.
VI. Summary and Conclusions

In summary, the Sponsor, Robins/Wyeth, has satisfied the FDA regulatory requirements for the metoclopramide NDA throughout its long lifetime on the market. Throughout this time, the Sponsor has had an ongoing dialogue with the FDA on various matters relating to the labeling consistent with usual practices in the pharmaceutical industry. The product labeling has been under the frequent scrutiny of and review by the FDA, in part due to other related activities on tardive dyskinesia and other gastrointestinal drugs, and thus reflects the FDA's ongoing and current approval of the labeling. Accordingly, it is my opinion that the labeling for metoclopramide has been thoroughly reviewed, considered, and is appropriate to reflect the current data and state of knowledge on this drug and its associated effects, notably, tardive dyskinesia.

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Judith K. Jones, M.D., Ph.D