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Witness Testimony
Dr. Cathryn M. Clary M.D.
Publication and Disclosure Issues in Anti-Depressant Pediatric Clinical Trials Summary of the Major Points of the Written Testimony of Pfizer Inc. Depression among children and teenagers is a serious medical condition with significant public health implications.
Pfizer has conducted a clinical program with Zoloft in the pediatric population.
Pfizer has disclosed the results of the Zoloft pediatric studies.
A Introduction This written testimony is submitted in support of the oral testimony to be provided by Cathryn M. Clary, M.D., Vice President, U.S. Medical, Neuroscience and Customer and Market Development, Pfizer Inc, before the United States House of Representatives, Committee on Energy and Commerce, Subcommittee on Oversight and Investigations, Hearing on Publication and Disclosure Issues in Antidepressant Pediatric Clinical Trials on September 9, 2004. This document summarizes the completed clinical trials that Pfizer has conducted in the pediatric population with Pfizer's selective serotonin reuptake inhibitor (SSRI) medicine, Zoloft® (sertraline HCl), with particular emphasis on Pfizer's public disclosure of these studies in publications and presentations at scientific meetings, medical information letters, and the addition of information to the Zoloft label (package insert)1 . A.1 The History of Zoloft Approvals in the United States The clinical development program for Zoloft began in the early 1980s, and Pfizer received its first approval for Zoloft from the U.S. Food and Drug Administration (FDA) in 1991 for the treatment of Major Depressive Disorder (MDD) in the adult population. Since 1991, Pfizer has received five additional approvals for Zoloft for the treatment of other mood and anxiety disorders, which are chronic and often debilitating psychiatric illnesses. For each of the approved indications in adults-Major Depressive Disorder (MDD), Obsessive-Compulsive Disorder (OCD), Panic Disorder, Posttraumatic Stress Disorder (PTSD), Premenstrual Dysphoric Disorder (PMDD), and Social Anxiety Disorder (SAD)-Pfizer submitted to the FDA two or more double-blind studies in patients with the indicated illness that demonstrated that Zoloft was more effective than placebo. Because Zoloft had been approved for adult OCD, only a single positive placebo-controlled trial was required by and submitted to FDA for the pediatric OCD labeling. OCD is the only approved use for Zoloft in the pediatric population. The following diagram illustrates the chronology of adult approvals for Zoloft, as well as the addition of pediatric information to the Zoloft label. ZOLOFT REGULATORY OVERVIEW DIAGRAM A.2 Prevalence, Symptoms and Impact of Major Depressive Disorder in the Pediatric Population Major depressive disorder is a significant public health issue for American children and teenagers. The annual prevalence of depression is estimated to be 2-3% in children aged 8-12 years and 4-8% in those aged 11 ½ to 18 years2, as compared with a rate of 6.6% in adults aged 18 and older3. It is estimated that one in five adolescents has had an episode of MDD by the age of 182. Studies have demonstrated that each successive generation since 1940 is at higher risk for MDD and that the disorder is being experienced earlier in life than it had been previously2. The Diagnostic and Statistical Manual of Mental Disorders version IV with revisions (DSM)4 is used to diagnose depression. As the Manual states, "Major Depressive Disorder may begin at any age." The diagnostic criteria for a Major Depressive Episode are five or more of the following symptoms during the same two-week period: - Depressed or irritable mood - Lack of interest or pleasure in activities - Sleep disturbance - Appetite/weight changes - Concentration and attention difficulties - Fatigue or loss of energy - Psychomotor agitation or retardation - Cognitive changes: worthlessness, excessive guilt, hopelessness - Recurrent thoughts of death, suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide The criteria used to diagnose children and adolescents are similar to those used to diagnose adults, with the exceptions that DSM notes that children and adolescents may exhibit an irritable mood, rather than a depressed mood, and that a child's failure to make expected weight gains should be considered. In all age groups, suicidal thinking or behavior is one of the diagnostic criteria. Depression in children is a devastating disease. Children and teenagers who suffer from MDD frequently experience thoughts of guilt, shame, and self-criticism that may leave them feeling worthless, helpless, and hopeless. As described in the Surgeon General's Report on Mental Health5: "Depressed children are sad, they lose interest in activities that used to please them, and they criticize themselves and feel that others criticize them. They feel unloved, pessimistic, or even hopeless about the future; they think that life is not worth living, and thoughts of suicide may be present. . . .. Associated anxiety symptoms, such as fears of separation or reluctance to meet people, and somatic symptoms, such as general aches and pains, stomachaches, and headaches, are more common in depressed children and adolescents than in adults with depression." Children with MDD frequently experience functional impairment such as a drop in school performance, family tension/problems, and conflicts with friends. They are also at risk for other psychiatric disorders, substance abuse, anxiety disorders, and disruptive behavior disorders2. In addition, follow-up studies have found that 20% to 40% of teenagers with MDD will go on to develop bipolar I disorder (a disorder which is characterized by episodes of depression alternating with another clinical state called mania) within a period of 5 years after the onset of depression6. Exacerbating the distressing nature of MDD is the risk of suicidal behavior that often accompanies the disease, particularly in the young, who are ill equipped to manage the illness. Suicide is the third leading cause of death among young people aged 10 19 years and the incidence of suicide attempts peaks during the mid-adolescent years7. An ongoing surveillance of health-risk behaviors in young people reported in 2003 that among high school students nationwide in the preceding year, 28.6% had felt so sad and hopeless that they stopped doing some of their usual activities; 16.9% had seriously considered, and 16.5% had made a plan to attempt, suicide; and 8.5% had actually attempted suicide, 2.9% to the extent that they needed medical attention8 . The evidence is strong that over 90% of children and adolescents who commit suicide have a mental disorder9. As then-Surgeon General David Satcher noted in his Report on Mental Health in 1999, "Children, and particularly adolescents, who suffer from depression are at much greater risk of committing suicide than are children without depression"9. Approximately half of all teenagers with MDD attempt suicide at some time during their lives, and among children with MDD there is a 4- to 5-fold higher lifetime risk of suicide attempt, compared with healthy children without depression10 11 12. At the beginning of a study in outpatient youths with MDD, 66% of patients acknowledged a history of suicidal ideation, and 9% had already made at least one suicide attempt. The rate of suicide attempts in this study reached 24% by age 1713. Because mood disorders such as depression substantially increase the risk of suicide, suicidal behavior is a matter of serious concern for clinicians who deal with the mental health problems of children and adolescents. Given this background, it can be difficult to disentangle the causal factors for a suicide attempt when a child is being treated for MDD, regardless of the type of treatment. Studies in children and teenagers have shown that a typical episode of MDD lasts 2 9 months, although episodes may last much longer. Even after remission, which is defined as the complete absence of symptoms, i.e., recovery from the episode of depression, there is a high probability that the disease will return: up to 40% within 2 years and 70% by 5 years9. These rates are similar to the rates of recurrence that have been reported for adults14. A.3 Treatment Options for Major Depressive Disorder in the Pediatric Population The options for the treatment of MDD in children and adolescents have historically been limited. Prior to the advent of the SSRIs, tricyclic antidepressants (TCAs) were the most commonly used medications for MDD treatment. Although TCAs were associated with some improvement in small open studies in children, more rigorous controlled studies failed to demonstrate that TCAs were more effective than placebo. TCAs also pose certain safety risks in children, specifically, cardiac arrhythmias and a potential lethality in overdose2. The high degree of acceptance of SSRIs for the treatment of adult MDD, together with their low incidence of side effects, easy once-a-day administration, and safety when taken in overdose made it natural that physicians, faced with the need to treat patients suffering from MDD, would prescribe these in younger patients, even though most of these products had not been approved by FDA in that population. Fluoxetine (Prozac®), approved in January 2003, is the only SSRI that has been approved by FDA for the treatment of pediatric MDD. Psychotherapy, also used in the treatment of MDD, may take the form of individual, group, or family therapy; cognitive behavioral therapy; or interpersonal-, problem-solving-, or play therapy. There are, however, few controlled studies with psychotherapy. In small studies, cognitive-behavioral therapy has been shown to have some benefit in treating depression, but this treatment by itself does not appear to be as effective for episodes of depression with more severe symptoms2. The American Academy of Child and Adolescent Psychiatry currently recommends psychotherapy, SSRI treatment, or both combined, for first-line acute treatment of MDD in children and adolescents2. A recently published study16 of adolescents with major depression showed that of the treatments studied, the combination of fluoxetine and cognitive behavioral therapy was the most effective treatment, and that therapy alone was not more effective than placebo, while fluoxetine alone was also effective, though less so than combination treatment. Despite reports that antidepressants are being widely prescribed for America's youth, prescription data show that only 4% of antidepressant prescriptions are for the treatment of individuals younger than 18 years old17. It is interesting to note that concurrently with the introduction and usage of SSRIs, which is associated with higher diagnosis and treatment rates of depression, there has been a reduction in suicide rates among both the adult and pediatric populations. Epidemiological studies in both adults18 and adolescents19 addressed rates of suicide since the introduction of SSRIs. Each of these studies demonstrated that as the rate of SSRI usage increased, the rate of completed suicides decreased. The adolescent study, which entailed the assessment of a large managed-care database over the last decade, showed that as the use of antidepressants has increased, there has been an overall decrease in the suicide rate. These data can also be expressed as a risk reduction for adolescent suicide of 0.23/100,000 population per year with only a 1% increase in antidepressant usage19. B Pfizer's Zoloft Pediatric Program B.1 Introduction Clinical trials may be conducted as 'open-label' studies, in which there is no comparison group and patients and investigators know that all the patients are receiving the drug under study, or as 'double-blind' studies, in which patients are randomly assigned to receive study drug or placebo (an inert sugar pill made to look exactly like the study drug), with the treatment assignment unknown to everyone until the study is completed. The presence of a placebo comparison group and the anonymity of the treatment assignment, to both patients and investigators, lend an additional level of rigor to the data from these studies. Mental illnesses pose a unique challenge to researchers as they try to document the severity of the symptoms and the degree of change in these symptoms over time. In contrast to infections or physiological illness, mental illnesses, such as depression, do not have a simple laboratory test or physician finding that can accurately measure and quantify the changes in the illness. Instead, researchers must rely on responses to specific questions and on observations. The organization of this information into standard rating scales that are validated as meaningful and sensitive to treatment effects over time is the standard in the field of psychopharmacology research. Because the responses to such questions are inherently subjective (based on the patient's own feelings, thoughts, and willingness and ability to describe those feelings and thoughts accurately), psychiatric rating scales may show more differences between subjects and different investigators than tests used to measure other illnesses. In addition, patients with disorders such as depression can often get better due to their hopefulness about treatment, their faith in the doctor or research institution, or just the passage of time. When this occurs in patients who are randomized to placebo in a clinical trial, then the improvement is called a "placebo response." The distinction between a placebo response and a real treatment effect presents an additional challenge in clinical research. B.2 Studies Conducted by Pfizer Pfizer began a pediatric program for Zoloft in 1991 with studies in obsessive-compulsive disorder (OCD). Since then, Pfizer has completed nine studies and has two studies still in progress in the pediatric population (ages 6-18 years), demonstrating its commitment to understanding the safety, efficacy and tolerability profile of Zoloft in this population. Table 1 lists all 11 studies conducted or being conducted by Pfizer in the pediatric population. Six of these studies are open-label and five of these studies are double-blind. Table 1. Summary of Pediatric Studies Conducted with Zoloft (See attachment) MDD: Major Depressive Disorder; OCD: Obsessive-Compulsive Disorder; PTSD:
Posttraumatic Stress Disorder The early studies, 90CK21-0525 and its extension, 91CK21-0550, were open-label studies conducted to collect preliminary safety and tolerability data and to understand whether Zoloft dosing in young people was similar to adults. Study 90CE21-0498 and its extension, 91CE21-0536, were the basis of Zoloft's approval for treatment of children and adolescents with OCD. Pfizer also conducted two early pediatric depression studies. Study R-0246 was an open-label study in 53 adolescents with MDD conducted to fulfill Pfizer's post-approval commitment to FDA following the 1991 approval of Zoloft for MDD in adults. Study STL-CDN-94-002 was a small (27-patient) open-label study conducted by Pfizer Canada to evaluate the safety and tolerability of Zoloft in the treatment of adolescents. The placebo-controlled studies, A0501001 and A0501017, form the core of Pfizer's program to understand the effectiveness of Zoloft in the treatment of pediatric depression and are described in further detail in the following section. Their open-label extension, Study A0501015, gathered additional information about long-term treatment. Because of the current interest in clinical studies of SSRIs in pediatric patients with MDD, this document will describe in some detail Pfizer's studies of Zoloft in this population. However, in the following Section C, we discuss the dissemination of the clinical trial results of all of the studies in the Zoloft pediatric program. B.3 Design and Conduct of the Zoloft Pediatric Depression Program In April 1999, the FDA issued a Written Request20 for Pfizer to conduct pediatric depression studies with Zoloft. The FDA required that Pfizer conduct two trials, each enrolling equal numbers of children and adolescents, and using the Children's Depression Rating Scale-Revised to measure efficacy. Pfizer was required to submit the data from these studies within three years of FDA's Written Request, and did so. B.3.1 Study Design Issues To comply with the requirements of the Written Request, Pfizer conducted two identical, double-blind, flexible-dose, multicenter studies of Zoloft in children and adolescents with MDD. Study A0501001 was conducted from December 1999 to May 2001, and Study A0501017 was conducted from February 2000 to March 2001. Patients were required to have a current episode of MDD. As is typical in such depression studies, patients who had previously attempted suicide or who posed a serious suicidal or homicidal risk were excluded from the studies. In both studies an equal number of children and adolescents received Zoloft and placebo. The Children's Depression Rating Scale-Revised (CDRS-R) was agreed upon with FDA as the primary outcome measure in the study, i.e., the way to measure depressive symptoms. At the time Pfizer began these studies, the CDRS-R was emerging in the psychiatric field as the gold-standard depression rating scale for the pediatric population, although it had only been validated in children, not adolescents. It had also not previously been used in any multicenter study. With this scale, both the children and their parents are asked to rate the severity of the depressive symptoms being experienced by the child. The clinical investigator then combines the patient and the parent scores to derive a composite score for the patient. A higher score represents more severe symptoms; a decrease in score indicates improvement. It is a somewhat difficult scale to utilize, and there can be variability in ratings from investigator to investigator. To ensure greater consistency in the use of the CDRS-R, all investigators performing the CDRS-R evaluations were required to participate in a training session at the startup of the study, and to demonstrate proficiency in using this scale. An important element in the design of any clinical trial is the estimation of the number of patients to be included. Statisticians determine this number by looking at the data from previous similar trials to obtain information regarding the extent to which differences between treatment groups represent a true effect of treatment or might be due to random variability between patients. The larger the number of patients, the greater the confidence that an effect observed in a study accurately reflects the true effect. However, in a homogeneous group it can be expected that a smaller sample will be representative, whereas, if the whole group is diverse and has greater variability, a larger sample is required in order to see an effect, if one is there. Pfizer determined the number of patients needed for its two pediatric MDD studies by examining data from a small (96 patients) single center study of fluoxetine (Prozac®) in children and adolescents with MDD, the only published placebo-controlled study of an SSRI utilizing the CDRS-R at the time21. Based on these data, Pfizer estimated that 160 subjects would be required to provide reasonable confidence that an observed effect would represent a true situation. At the time Pfizer was designing its two multicenter studies, there had been no published multicenter trial that had used the CDRS-R to demonstrate efficacy, and hence no data to provide information regarding any additional variability, between subjects and between sites, that might be expected in a larger, multicenter trial. To address the concern that the random variability in such a study might be greater than in a small well-controlled single-site study, the two studies were designed to be identical in order to allow a combined analysis. Indeed, before the studies were completed, and before the blind was broken (before investigators or Pfizer researchers knew what treatment anyone was taking) Pfizer decided to pool the two studies, in order to have sufficient power to show a difference, if one existed. B.3.2 Results Efficacy Table 2 shows the results from the two MDD studies for the primary measurement of efficacy (reduction in CDRS-R score from the start of the study). In each study, the improvement in the Zoloft group was greater than in the placebo group, but the difference was not statistically significant (statistical significance in these studies required a p-value less than 0.05), except for a greater proportion of responders on Zoloft in Study A0501017. However, when the two studies were pooled, thus providing an adequate sample size to test if there were true differences, the treatment effect of Zoloft compared to placebo, although modest in size, was shown to be statistically significant. Table 2. Efficacy Outcome for Primary Endpoint in Zoloft Pediatric MDD Studies (See attachment) * Responders were individuals who had a 40% decrease in the adjusted CDRS-R
total score from baseline to endpoint. Although the difference between Zoloft and placebo was not statistically significant in the two individual studies, this does not mean that Zoloft did not bring about an improvement in depressive symptoms. In fact, on average, CDRS-R scores were almost halved, and approximately two thirds of the patients responded to treatment with Zoloft, a rate similar to that seen in adults. However, the patients receiving placebo also showed a substantial improvement from baseline. This is known as the 'placebo effect,' and its occurrence is not unusual in clinical studies of depression. In these studies the placebo effect was so high that in the individual, uncombined studies there was not a statistically significant difference between the effect seen with Zoloft and that seen with placebo. Research suggests that two psychological variables significantly increase the placebo effect: high suggestibility, and high expectancy22 23 24 . Children are known to be more suggestible than adults, and the younger the children, the more suggestible they tend to be. Children also show higher expectancy effects, i.e., a treatment effect produced from the belief or expectation that the doctor and the treatment will help them, compared to adults, especially when treated in the novel setting of a treatment research office, often in an academic center. In addition, the time that their parents or caregivers take in bringing them to the office and speaking with the clinical staff about their disorder can, in itself, be therapeutic. It is worth noting that when the combined data from the Studies A0501001 and A0501017 were analyzed separately for children (6-12 years) and adolescents (13-17 years), the children's group had a higher placebo response than the adolescent group. In fact, the adolescents treated with Zoloft had a statistically significant greater improvement in CDRS-R scores than placebo-treated adolescents25. In contrast, in the children's group, although the Zoloft-treated patients also had greater improvement than the placebo-treated patients, the higher placebo effect resulted in the difference not meeting statistical significance. Safety In the Zoloft pediatric depression program, as well as in the other pediatric studies, safety data, including time and severity of adverse events, vital signs, laboratory test values, electrocardiograms, and other events occurring during the trial were systematically collected and analyzed. This information was submitted to FDA as part of the clinical study reports and a summary of this information was also disclosed in the clinical trial publications. In addition, the safety of pharmaceutical drug products, such as Zoloft, is evaluated through an ongoing analysis of Pfizer's spontaneous adverse event report database. We have not included general safety data about Zoloft in this Testimony, although Pfizer is willing to provide such information to the Committee. Instead, because of current discussion and debate surrounding the issue, we are focusing our comments about Zoloft safety on the issue of suicide-related behaviors from the pediatric controlled trials. This issue will also be discussed at a joint meeting of the FDA Pediatric Advisory Committee and the Psychopharmacologic Drugs Advisory Committee scheduled to take place on September 13 and 14, 2004. Suicide-Related Behaviors in the Controlled Pediatric Studies There were no suicides in these studies, nor were there suicides in any of Pfizer's other pediatric trials with Zoloft. In addition, a comprehensive evaluation conducted by Pfizer of the Zoloft placebo-controlled trials shows that the risk of suicide-related behavior in children and adolescents treated with Zoloft in clinical trials of MDD is no greater than that with placebo. In the MDD program, in Study A0501001, one patient in the Zoloft-treated group was classified by the investigator as having made a suicide attempt. In Study A0501017, two patients in the Zoloft-treated group and two patients in the placebo-treated group made a suicide attempt. One patient in the placebo-treated group attempted suicide twice. Three cases of suicidal thinking (also called "ideation") were reported in MDD study A0501001, and one in the OCD program (90CE21-0498), none of which were deemed by the investigator to be related to the study drug. The following tables summarize the incidence of suicide attempts and suicide ideation in the placebo-controlled Zoloft pediatric trials. Table 3. Incidence of suicide attempts in placebo-controlled studies of Zoloft in children and adolescents (See attachment) * there were 3 attempts in 2 persons Table 4. Incidence of suicidal ideation in placebo-controlled studies of Zoloft in children and adolescents (See attachment) Table 5. Incidence of suicide attempts and suicidal ideation in placebo-controlled studies of Zoloft in children and adolescents (See attachment) In the tables above, it is clear that the number of events is very small, and because none of these numbers are statistically significant, no conclusion can be drawn that treatment with Zoloft in these studies is associated with an increased risk of suicidal behaviors. These data, which are congruent with the classification of the Zoloft cases conducted by the Columbia University researchers, as requested by FDA, will be discussed in more detail at the upcoming FDA Advisory Committee meeting on September 13 and 14. C Pfizer's Disclosure of the Zoloft Pediatric Studies As a research-based pharmaceutical company, Pfizer recognizes that the availability of meaningful clinical trial results is critical to the communication of important new information for the medical profession, patients and the public. Pfizer is committed to the timely communication of meaningful results of Pfizer sponsored hypothesis-testing clinical trials (essentially all Phase 3 and 4 trials), regardless of outcome, for Pfizer's marketed prescription medicines. In short, Pfizer is dedicated to making public the results of all clinical trials that have the potential to improve patient care. Pfizer's practices conform to the PhRMA Principles on the Conduct of Clinical Studies and Communication of Clinical Trial Results and are also codified in Pfizer's Policy on Public Disclosure of Clinical Trial Results which is available on Pfizer's website26 (http://www.pfizer.com/are/about_public/mn_about_ethical_trials.html). Pfizer continues to examine ways to improve accessibility to meaningful clinical trial information. To that end, Pfizer is actively participating in and supports a recent PhRMA initiative to develop a centralized database to provide access to clinical trial results on studies that fall within the scope of the PhRMA Principles. Pfizer believes that the development of a single database containing summaries of studies sponsored by all participating PhRMA member companies will facilitate healthcare providers' accessibility to clinical trial results and positively impact patient care. Important safety and efficacy information generated from clinical trials can be publicized and disseminated in a number of ways: Through abstracts, posters and presentations at scientific meetings, Most frequently, clinical data from studies are presented first as abstracts and posters at scientific meetings. This is useful since it is relatively rapid, provides opportunity for questions and discussion and, because scientific meetings may be attended by many thousands of individuals, has the potential to reach a large audience. The more rigorous system of publication in a peer-reviewed journal may take longer due to the time involved in peer review and journal publication dates, but benefits from the thoughtful scrutiny of subject-matter experts. These peer reviewers are appointed by the journal and, working independently and anonymously, may suggest additions or deletions, as well as challenge analyses and suggest new ones, as pre-requisites for publication. C.1 Pfizer's Publication of Zoloft Pediatric Data at Scientific Meetings and in Peer-Reviewed Journals Information obtained from the Zoloft pediatric program has been made public in numerous ways. Seven of the nine completed studies have been published in respected journals, and one has been submitted for publication to the Journal of Child and Adolescent Psychopharmacology, where it has recently undergone peer review. Some of the Zoloft pediatric trials have provided data for multiple publications. For example, large placebo-controlled studies like A0501001 and A0501017 with extensions (like A0501015, in which some patients were followed for up to 34 weeks) are rich in data and have provided the opportunity to understand the results better through subset analyses. The data from Studies A0501001 and A0501017 have been used to revise and validate efficacy scales (CDRS-R and PQ-LES-Q) for use in adolescent populations and provided technical advances in this field of research27. Table 6 lists the nine completed studies and a selection of the posters and publications they have generated. In addition, a comprehensive review of Zoloft safety data, including the individual efficacy results of the two pediatric depression studies, was presented at a special invited session during the annual meeting of the American Academy of Child and Adolescent Psychopharmacology in October, 2003. Table 6. Zoloft Pediatric Studies: Selected Abstracts, Posters, and Publications (See attachment) JAMA: Journal of the American Medical Association The only study that Pfizer has not published, although the data from the study have been submitted to FDA, is open-label extension study 91CK21-0550. Because this was a small, open-label study-32 patients with depression, 10 patients with OCD, and one patient with OCD and depression-and its results were consistent with known data about Zoloft in this population, Pfizer did not seek to have it published. However, given the current interest in SSRI data in the pediatric population, Pfizer is preparing a manuscript of this study for submission and publication. Since this was also an extension study, all of these 43 patients had participated in the parent study (90CK21-0525) that was published by the Pfizer researchers who conducted the study28. C.2 Dissemination of Information by Medical Information Letters Medical Information letters are another means by which pharmaceutical companies provide important information about their products to interested healthcare practitioners and the public. These letters generally respond to unsolicited inquiries about a particular drug from health care professionals, patients or others. Healthcare professionals employed by the pharmaceutical company prepare these letters after an extensive review of the particular topic to be addressed. There are two letters in the Pfizer Medical Information database that are related to the Zoloft pediatric program. One letter reviews data related to the two Zoloft pediatric depression trials, as well as related published data. It should be noted that in this letter, Pfizer clearly states that Zoloft is not approved by the FDA for the treatment of MDD or dysthymic disorder in pediatric patients and that Pfizer does not recommend the use of Zoloft for these conditions. The second letter provides all available information on suicide-related adverse events in children and adolescents from Pfizer's pediatric program for Zoloft, as well as from independently conducted (non-Pfizer) studies. In this letter, Pfizer also provides a review of the case reports in the scientific literature as well as position statements concerning the topic of suicidal behavior in children and adolescents with major depression. C.3 Changes to Zoloft Labeling In today's demanding and complex healthcare system, doctors lack the time, and often the capacity, to review, analyze and evaluate the enormous quantity of clinical data that is generated for the enormous number of drug products that are on the U.S. market, as well as the many others that are in clinical development. Because of this, the FDA, by virtue of its statutory authority, conducts comprehensive reviews of the data related to each drug to make determinations about its overall Risk/Benefit profile and approvability. The FDA objectively evaluates the wealth of data that are gathered in the preclinical and clinical development programs of a new drug, as well as the ongoing clinical research that expands knowledge of approved medications. The output of its review is the product label, which, through its consistent presentation of data, allows doctors to objectively compare drugs in a therapeutic class and make the best decisions for their patients. The product label is arguably the most important vehicle for the dissemination of information about drug safety and efficacy. The nine completed Zoloft pediatric studies have all been submitted to the FDA. Together with the extensive written reports and complete analyses for each study, the FDA also receives all the efficacy and safety data collected in these trials, allowing its medical and statistical reviewers to conduct additional analyses and checks. In addition, the FDA routinely receives safety data in the form of Annual Reports. These mandated reports require a drug sponsor to summarize, for each drug in development or already on the market, the safety information from trials in progress or completed in the previous year, including tabular summaries of adverse events, information about patients who dropped out of a study for adverse events, and any new information that is learned relating to a drug's actions. These studies have led to a series of important changes in the Zoloft Package Insert (PI) and have consequently informed doctors about valuable information learned from those studies. In October 1997, on the basis of data from Studies 90CK21-0525 and 90CE21-0498, Zoloft was approved for the treatment of pediatric OCD. Text added to the label informed doctors about how the blood levels observed in children and adolescents compared with those in adults, described the conduct of the double-blind clinical trial, the magnitude of the improvement observed, noted adverse events that had been recorded, and gave specific dosing recommendations for children and adolescents. In October 2001, additional text was added to the label that described the one-year continuation study in pediatric OCD (Study 91CE21-0536) providing information on the long-term safety of Zoloft in pediatric use. Since the study supporting this label change was open label, no long-term efficacy information was added. In September 2003, the Zoloft label was again modified to add safety information gained from the pediatric MDD trials, Studies A0501001 and A0501017 and the long-term extension, Study A0501015. Specifically, the added text advised doctors that weight loss had been observed in the first ten weeks of treatment, although with longer treatment weight gain was again as expected. Regular monitoring of weight and growth in children treated with Zoloft was recommended. An indication for the use of Zoloft in pediatric MDD was denied since Pfizer had not fulfilled the requirement for two positive trials (individually the two studies were not each positive, and the pooled efficacy analysis, albeit positive, constituted just a single trial). The FDA chose not to describe the studies in the label, stating in their letter to Pfizer that: "Given the fact that negative trials are frequently seen, even for antidepressant drugs that we know are effective, we do not feel that it would be useful to describe these negative trials in labeling, since this may be misinterpreted as evidence that Zoloft does not work in this population. Rather, we feel that the existing language, suggesting simply that efficacy has not been established in this population, is still most appropriate"29. In August 2004, the Warnings section of the Zoloft label was amended to advise doctors that adult and pediatric patients with MDD could experience a worsening of their illness that might include thoughts of suicide. The Warning further advised that patients should be carefully monitored, especially when starting treatment with an antidepressant or changing dose levels. The label also advised that caregivers should be told to be watchful for changes in symptoms and notify healthcare providers if they notice a change in symptoms. In summary, there have been four additions to the Zoloft label relating to pediatric use: (1) the original pediatric use for OCD on 10/10/97 These four important label changes to the Zoloft label served to provide new information about Zoloft to healthcare professionals and in particular to those responsible for prescribing Zoloft. D Conclusions Pfizer has conducted a rigorous pediatric program for Zoloft, consisting of nine completed studies and two studies still in progress. In 1997, FDA approved Zoloft for the treatment of Obsessive-Compulsive Disorder in the pediatric population. Although Zoloft was not approved for the treatment of major depression in this population, Pfizer's studies yielded important information that was added to the Zoloft label. There were no patients who committed suicide in the Zoloft pediatric studies. The number of suicide-related events in the Zoloft pediatric studies is small, and, because none of these numbers are statistically significant, no conclusion can be drawn that treatment with Zoloft in these studies is associated with an increased risk of suicidal behaviors. Pfizer submitted all of the completed studies to the FDA, resulting in several important changes to the Zoloft label, providing doctors with important safety and efficacy information from those studies. Moreover, Pfizer sought a wider dissemination of the safety and efficacy results of its pediatric program through its publication of study results. The results of eight of Pfizer's pediatric studies have been shared with the medical and scientific community in the form of abstracts, posters, and presentations at scientific meetings as well as publication in respected peer-reviewed journals. Publications based on the databases generated in the Zoloft pediatric trials have not only served to disclose the findings from the studies, but have also contributed to the understanding and evaluation of devastating psychiatric illnesses in a vulnerable patient population. 1 - This document does not address studies conducted as Independent Research Grants by researchers outside of Pfizer and funded or otherwise supported by Pfizer or studies that were neither supported nor sponsored by Pfizer. 2 - American Academy of Child and Adolescent Psychiatry (1998), Practice Parameters for the Assessment and Treatment of Children and Adolescents with Depressive Disorders. J Amer Acad Child Adolesc Psychiatry 37 (10 suppl). 3 - Kessler RC et al. The epidemiology of Major Depressive Disorder; results from the National Comorbidity Survey Replication (NCS-R) JAMA 2003; 289: 1395-1305. 4 - Diagnostic and Statistical Manual of Mental Disorders version IV with revisions (DSM-IV TR) p353-354. 5 - Mental Health: A Report of the Surgeon General, published 1999, (David Satcher, Surgeon General). p150-152. 6 - Birmaher B; Ryan ND, Williamson DE, etal. Childhood and Adolescent Depression: A Review of the Past 10 Years. Part I, J Amer Acad Child Adolesc Psychiatry 1996 35(11):1427-1439. 7 - Centers for Disease Control and Prevention. Web-based Injury Statistics Query and Reporting System (WISQARS) [Online]. (2003). National Center for Injury Prevention and Control, Centers for Disease Control and Prevention (producer). Available from: URL: www.cdc.gov/ncipc/wisqars. 30 Aug 2004. 8 - Youth Risk Behavior Surveillance System - United States, 2003; Volume 53/SS-2. 9 - Mental Health: A Report of the Surgeon General, published 1999 (David Satcher, Surgeon General). p150-152. 10 - Rao U, Weissman MM, Martin JA and Hammond RW (1993) Childhood depression and risk of suicide: a preliminary report of a longitudinal study. J Am Acad Child Adolesc Psychiatry 32:21-27. 11 - Weissman MM, Wolk S, Goldstein RB et al (1999a). Depressed adolescents grown up. JAMA 281:1701-1713. 12 - Weissman MM, Wolk S, Wickramaratne P et al (1999b). Children with prepubertal-onset major depressive disorder and anxiety grown up. Arch Gen Psychiatry 56:794-801. 13 - Kovacs M, Goldston D, and Gatsonis C (1993). Suicidal behaviors and childhood-onset depressive disorders: A longitudinal investigation. J. Am. Acad. Child & Adol. Psychiatry 32(1):8-20. 14 - Birmaher B; Ryan ND, Williamson DE, et al. Childhood and Adolescent Depression: A Review of the Past 10 Years. Part I, J Amer Acad Child Adolesc Psychiatry 1996 35(11):1427-1439. 15 - http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01187.html [FDA Talk Paper announcing approval of Prozac for MDD]. 16 - Treatment for Adolescents with Depression Study (TADS) team (2004). Fluoxetine, Cognitive Behavioral Therapy, and their combination for adolescents with depression. JAMA 292:807-820. 17 - Scott-Levin MAT, May 2004. 18 - Hall WD, Mant A, Mitchell PB et al (2003). Association between antidepressant prescribing and suicide in Australia, 1991-2000: trend analysis. BMJ 326:1008-1012. 19 - Olfson M, Shaffer D, Marcus SC et al (2003). Relationship between antidepressant medication treatment and suicide in adolescents. Arch. Gen. Psychiatry 60:978-982. 20 - In 1997, Congress passed the Food and Drug Administration Modernization Act (FDAMA), intending in part to ensure that medicines that could benefit children were properly evaluated in the pediatric population. It allowed the FDA to issue Written Requests to manufacturers of these medicines to conduct the relevant trials within a specified time. Clinical trials in children are more difficult to conduct than trials in adult populations. To provide incentive for manufacturers to conduct such trials and to balance their cost, sponsors could be eligible for a 6-month patent extension upon submission of the complete package of required data to the FDA. 21 - Emslie GJ, Rush AJ, Weinberg WA et al (1997). A double-blind, randomized, placebo controlled trial of fluoxetine in children and adolescents with depression. Arch. Gen. Psychiatry 54:1031-1037. 22 - De Pascalis V, Chiaradia C, Carotenuto E. The contribution of suggestibility and expectation to placebo analgesia phenomenon in an experimental setting. Pain 2002;96:393-402. 23 - Leigh R, MacQueen G, Tougas G, Hargreave FE, Bienenstock J. Change in forced expiratory volume in 1 second after sham bronchoconstrictor in suggestible but not suggestion-resistant asthmatic subjects: a pilot study. Psychosom Med 2003;65:791-795. 24 - Vase L, Robinson ME, Verne GN, Price DD. The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients. An empirical investigation. Pain 2003;105:17-25. 25 - Donnelly C et al. A comparison of the response to sertraline in children and adolescents with major depressive disorder; NCDEU 2003 (poster) and Donnelly C et al. A comparison of the response to sertraline in children and adolescents with major depressive disorder (submitted to J Am Acad Child Adolesc Psychiatry). 26 - Publication of findings from Zoloft pediatric studies predates the formulation of the current disclosure policy, but is concordant with all the principles embraced in the policy. 27 - See Endicott J et al. Reliability and validity of the CDRS - Revised in children and adolescents treated with sertraline; NCDEU 2002 (poster) and Endicott J et al: The Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q): Reliability and Validity (submitted to J Am Acad Child Adolesc Psychiatry, April 2004). 28 - Alderman J et al. Sertraline treatment of children and adolescents with obsessive-compulsive disorder or depression: pharmacokinetics, tolerability, and efficacy. J Am Acad Child Adoles. Psychiatry 1998; 37 (4): 386-394. 29 - Correspondence from FDA to Pfizer, September 30, 2002.
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