New Molecular Entity Postmarketing Safety Evaluation Pilot Program Final Report

  1. Executive Summary
  2. Introduction
  3. Background
  4. ODE I and OSE Collaborative Effort
  5. Results of the Pilot Program
  6. Recommended Changes to Evaluation Process after Pilot Program Completed
  7. Resources
  8. Conclusions 

1. Executive Summary

The New Molecular Entity Postmarketing Safety Evaluation Pilot Program was a collaborative drug safety surveillance project primarily conducted by two offices within FDA’s Center for Drug Evaluation and Research (CDER), the Office of Drug Evaluation I (ODE I) and Office of Surveillance and Epidemiology (OSE). These two offices worked together to develop and assess the value of a new systematic procedure for reviewing the safety profiles of new molecular entities.1 This report provides the background and results of these evaluations and is submitted by the Steering Committee that provided oversight to this pilot program. An interim report, describing the pilot program and results of its first two evaluations, was posted on CDER’s website in March 2008.

The pilot program was initiated in the fall of 2006, before the Institute of Medicine2 recommended that FDA evaluate new data on new molecular entities no later than 5 years after approval, and before the Food and Drug Administration Amendments Act (FDAAA) required FDA to perform summary analyses of adverse drug reaction reports received for recently approved drugs (both described in more detail below).

The pilot program required extensive collaboration between ODE I and OSE. The new surveillance procedure identified some previously unrecognized safety issues for the five NMEs evaluated and provided more information about some previously known safety issues for these drugs. Discussions between ODE I and OSE facilitated communication and consensus building regarding the safety signals that merited further investigation, the types of follow-up needed, and the projected timelines for completing follow-up tasks.

The pilot program also provided an estimate of the personnel resources involved in such NME evaluations. Although the general consensus among the pilot participants was that these evaluations were useful, the evaluations required substantial effort and personnel resources from both ODE I and OSE to retrieve, collate, and interpret a significant amount of data and to develop strategies for follow-up.

2. Introduction

In the New Molecular Entity Postmarketing Safety Evaluation Pilot Program (henceforth referred to as the “pilot program”), ODE I and OSE developed a new procedure to evaluate systematically and collaboratively the postmarketing safety profiles of selected NMEs. The Office of Clinical Pharmacology (OCP) and the Safety Policy and Communications Staff (SPCS) also provided valuable input in developing the new procedure.

The pilot program effort was in addition to CDER’s existing postmarketing evaluation process. CDER staff already routinely review postmarketing safety data of drug and therapeutic biologic products as part of their core functions. Data routinely reviewed include but are not limited to:

  • reports of serious and unexpected adverse drug experiences that must be submitted to FDA within 15 days;
  • periodic safety reports that are submitted to FDA by applicants;
  • reports of serious problems sent to FDA directly by healthcare professionals and consumers;
  • medical literature;
  • data from clinical trials; and
  • data from other drugs within the same pharmacologic class

The purpose of the pilot program was to determine the value of an additional effort: the periodic, systematic, and collaborative evaluation of the safety of marketed drugs. Five NMEs from ODE I were selected for evaluation, based on the following three criteria:

(a) Length of time on market. NMEs that had been marketed for varying lengths of time were selected to determine when, following approval, there would be sufficient information to conduct a useful safety evaluation.

(b) Number of postmarketing reports in the Adverse Event Reporting System (AERS). NMEs with varying numbers of reported adverse events in AERS were selected to obtain information as to whether there should be a “threshold” number of reports in AERS before conducting an evaluation.3

(c) Indication. A variety of NMEs was selected to assess the usefulness of the evaluation across a range of indications (e.g., psychiatric, neurologic, cardiac).

3. Background

In the spring of 2006, CDER began planning a new process for evaluating the postmarketing safety of NMEs. In the fall of 2006, formal meetings between CDER’s Office of Surveillance and Epidemiology and Office of Drug Evaluation I were held to develop the process. In early 2007, these two offices officially initiated the NME pilot program.

3.1. Institute of Medicine Report. Although CDER began planning a new process for evaluating the postmarketing safety of NMEs in the spring of 2006, the NME Pilot Program addresses a recommendation in the Institute of Medicine report, “The Future of Drug Safety: Promoting and Protecting the Health of the Public,” published several months later in September 2006. Recommendation 5.4 in this report states:
“The committee recommends that FDA evaluate all new data on new molecular entities no later than 5 years after approval….”

3.2. FDAAA Section 915. The NME pilot program is also pertinent to a provision of the Food and Drug Administration Amendments Act (FDAAA) enacted in September 2007. Section 915 of FDAAA, Postmarketing Drug Safety Information for Patients and Providers, created section 505(r) of the Food Drug and Cosmetic Act that includes a requirement for FDA to prepare summary safety analyses of adverse drug reaction reports for recently approved drugs (505(r)(2)(D)). Such analyses must be prepared by 18 months after approval of a drug or after its use by 10,000 individuals—whichever is later—and must identify any new risks not previously identified, potential new risks, or known risks reported in unusual number.

4. ODE I and OSE Collaborative Effort

ODE I and OSE personnel worked both independently and collaboratively to develop a systematic procedure for evaluating postmarketing data for the five NMEs selected for the pilot program. Approximately 50 reviewers from these offices, as well as the Office of Clinical Pharmacology (OCP) and the Safety Policy and Communications Staff (SPCS), and others provided input into the development of this new pilot procedure. The agreed upon procedure consisted of a comprehensive review of postmarketing safety data for each NME, including:

  • summary review of FDA’s Adverse Event Reporting System (AERS) data;
  • data mining analysis of AERS data;
  • review of applicant-submitted periodic safety reports;
  • literature review;
  • medication error analysis;
  • analysis of product use;
  • risk management review; and
  • review of postmarketing clinical trial and epidemiologic study findings

Following this approach, each NME was evaluated jointly by ODE I and OSE. Preliminary findings were then discussed by primary reviewers and senior staff from ODE I, OSE, OCP, and SPCS at separate meetings on each product. After discussion of these early findings, the group developed a consensus regarding the safety signals that merited further investigation; the type of follow-up required (e.g., OSE safety review, request to sponsor for further information); and the projected timelines for completion. An interim report, describing the pilot program and results of its first two evaluations, was posted on CDER’s website in March 2008.

5. Results of the Pilot Program

Findings for the five NMEs piloted are summarized in Sections 5.1 through 5.5 below. Additional information is available on FDA’s Postmarketing Safety Evaluation of New Molecular Entities: Final Report website.  

5.1 Cymbalta® (duloxetine hydrochloride). Cymbalta® Delayed-Release Capsules, by Eli Lilly and Company, is a serotonin and norepinephrine reuptake inhibitor (SNRI) for oral administration initially approved in August 2004 to treat major depressive disorder. Subsequently, FDA approved Cymbalta® for the treatment of diabetic peripheral neuropathic pain (September 2004); generalized anxiety disorder (February 2007); and fibromyalgia (June 2008).

Between August 2004 and December 2006, more than 3 million patients in the United States received a prescription for Cymbalta®. Use was seen in all adult age ranges: approximately 8% in patients 17-30 years of age; 15% in patients 31-40 years of age; 27% in patients 41-50 years of age; 26% in patients 51-60; 12% in patients 61-70 years of age and 10% in patients 71 years of age and older.4   Pediatric patients (ages 0-16 years) accounted for less than 1% of total dispensed prescriptions.5

The NME pilot evaluation for Cymbalta® during January 2007 through March 2007 identified a number of adverse events requiring further evaluation and more detailed review. These events included reports of bleeding, blindness, drug interactions, falls/loss of consciousness, hyponatremia, urinary hesitancy/retention, liver toxicity, and medication errors.

The cases of blindness were subsequently determined to be related to underlying disease or other causes, rather than to drug use. The potential for loss of consciousness appeared to be appropriately reflected in current labeling. The potential risk of liver toxicity associated with Cymbalta® use had been previously identified in clinical trials and prior analyses of postmarketing information, and is reflected in current labeling. Analysis of additional reports of liver injury is ongoing and labeling will be modified as needed. FDA is currently reviewing cases of drug interactions associated with Cymbalta® use. For the remaining adverse events identified in this NME evaluation, it was concluded that labeling or packaging should be modified. Based on these recommendations, the following changes have been made to the Cymbalta® labeling or to the product container label:

(a) Bleeding. Information on the risk of bleeding has been added to the Warnings/Precautions and Patient Information sections and language has been added on concomitant use of Cymbalta® with warfarin and other drugs that affect hemostasis. The revised labeling states that concurrent use of an NSAID, aspirin, warfarin, or any other drug that affects hemostasis may potentiate the risk of bleeding. In addition, the labeling states that patients receiving warfarin therapy should be carefully monitored when Cymbalta® is initiated or discontinued.

(b) Hyponatremia and falls. Although hyponatremia (low serum sodium levels) was described in the Cymbalta® labeling at the time of the NME evaluation, FDA concluded that labeling would be more informative if it better described the symptoms of hyponatremia. Changes have been made to the hyponatremia and overdosage sections of labeling to describe clinical manifestations of hyponatremia, including headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls, as well as hallucination, syncope, seizure, coma, respiratory arrest, and death in more severe and/or acute cases.

(c) Urinary Hesitancy/Retention. The existing product labeling had described the possibility of urinary hesitation with Cymbalta®. The labeling has been updated in the Warnings/Precautions Section to inform healthcare providers of the potential for serious outcomes (catheterization and/or hospitalization).

(d) Medication Errors. Cases of medication errors were reviewed and classified as: wrong strength, administration errors associated with opening the capsules, and wrong drug. For each of these error types, reviewers identified contributing factors associated with the container label, carton, and insert labeling. Changes have been made to the product container labels and labeling in an effort to prevent future medication errors, including warning against opening the capsules, which can affect the enteric coating.

5.2 Ranexa® (ranolazine). Ranexa® Extended-Release Tablets by CV Therapeutics, Inc., is an antianginal drug approved in January 2006. From January 2006 through March 2007, approximately 39,000 patients received a prescription for Ranexa®. Most use was in patients over 70 years of age (47%), with about 26% and 20% of use in patients aged 61-70 years and 51-60 years, respectively.6

As part of the NME pilot program evaluation for Ranexa®, from March 2007 through May 2007, cases of death and torsade de pointes were reviewed. Few deaths were reported, and details surrounding them were not provided in most cases. No pattern in the deaths suggested a causal role of Ranexa®. Cases of torsade de pointes were determined to have been related to underlying disease or other causes, rather than to Ranexa®. The NME pilot program evaluation of Ranexa® thus did not result in changes to the label or other FDA regulatory action.

5.3 Apokyn® (apomorphine hydrochloride). Apokyn® injection, by Ipsen, is a non-ergoline dopamine agonist approved in April 2004 indicated for the acute, intermittent treatment of hypomobility, “off” episodes (“end-of-dose wearing off” and unpredictable “on/off” episodes) associated with advanced Parkinson’s disease.

Between July 2004 and July 2007, 2,764 patients in the United States received a prescription for Apokyn®. Approximately 80% of use was in patients over 60 years of age. Patients below 30 years of age accounted for less than 1% of total dispensed prescriptions.7

The NME pilot program evaluation for Apokyn® from May 2007 through September 2007 identified three types of adverse events requiring further evaluation and more detailed review:

(a) Psychotic-like behavior. Although the labeling for Apokyn® already mentioned “hallucinations” (one specific manifestation of psychotic-like behavior) in the “Warnings” section, cases of psychiatric adverse events reflecting other manifestations of psychotic-like behavior associated with Apokyn® were identified and reviewed. These adverse events included acute psychosis, paranoia, confusional state/confusion, psychotic disorder, aggressive behavior, agitation, and hallucinations. Apokyn®-induced exacerbation of psychotic-like behavior in patients with a major psychotic disorder is also a possible concern. FDA continues to follow-up on this issue.

(b) Hemolytic anemia. Cases of hemolytic anemia were identified, but all these cases were of foreign origin and lacked clarifying details, such as laboratory findings and information regarding the route of administration. Apokyn® is approved in other countries for administration via continuous subcutaneous infusion and subcutaneous injection, but in the U.S., Apokyn® is approved for subcutaneous administration only. FDA determined that no specific regulatory action was needed at this time. FDA will continue to monitor cases of hemolytic anemia.

(c) Disseminated intravascular coagulation. One case coded as disseminated intravascular coagulation, reported by the United Kingdom, was identified. Upon further review of this case, it was determined that the report reflected a laboratory error.

5.4 Abilify® (aripiprazole). Abilify® by Otsuka is an atypical (second generation) antipsychotic agent. Abilify® is available as tablets, orally disintegrating tablets, oral solution, and intramuscular injection.

Oral formulations of Abilify® are indicated for:

  • Treatment of Schizophrenia in adults (approved November 2002) and adolescents aged 13 to 17 years (approved October 2007)
  • Treatment of manic or mixed episodes associated with Bipolar I Disorder as monotherapy or adjunctive to lithium or valproate in adults (approved May 2008) and pediatric patients aged 10 to 17 years (approved February 2008)
  • Adjunctive treatment of Major Depressive Disorder in adults (approved November 2007)

The injectable form of Abilify® is indicated for treatment of adults with agitation associated with schizophrenia or bipolar I disorder, manic or mixed episodes (September 2006).

Between November 2002 and October 2007, more than 2 million patients in the United States received a prescription for Abilify®.8  Use was seen in all adult age ranges, approximately 18% in patients 17-30 years of age; 14% in patients 31-40 years of age; 20% in patients 41-50 years of age; 14% in patients 51-60; 5% in patients 61-70 years of age and about 4% in patients 71 years of age and older. Pediatric patients (ages 0-16 years) accounted for approximately 23% of total dispensed prescriptions.9

As a result of the NME pilot program evaluation for Abilify® from January 2008 through March 2008, the potential safety concerns requiring further review included:

(a) Hepatotoxicity. Cases describing serious hepatic disorders associated with Abilify® use were identified and reviewed. These cases included reports of hepatic failure and fulminant hepatitis; these cases were, however, confounded by a combination of underlying hepatic disorders and/or concomitant medications labeled for an association with hepatotoxicity. Therefore, FDA did not recommend any labeling changes regarding the potential for hepatotoxicity associated with Abilify®. The labeling for Abilify® had already mentioned hepatitis, jaundice, and hepatic enzyme elevation.

(b) Torsade de pointes. Cases describing Torsade de pointes were identified, but these cases were confounded by the use of concomitant medications, including one case reporting use of an antiarrhythmic agent known to be associated with QT prolongation and Torsade de pointes. 

(c) Extrapyramidal symptoms. As part of the Abilify® NME evaluation, the medical literature was reviewed. A meta-analysis published by Scherk et al10 in 2007 suggested that aripiprazole’s overall incidence rate of extrapyramidal symptoms was similar to other second generation antipsychotic drugs. FDA determined that these findings were consistent with information currently provided in the label and that no labeling changes were needed.

(d) Antipsychotic switch syndrome. FDA sent a letter to the applicant asking for more information regarding exacerbation of psychosis when clinically stable patients were switched to Abilify® from another antipsychotic medication. The FDA has reviewed the applicant’s analyses and concluded that the analyses do not indicate clear evidence of exacerbation of psychosis after switching to Abilify® or a switch syndrome associated with changing treatment to Abilify®. Therefore, FDA has not recommended any labeling changes and no further action is planned at this time.

(e) Simultaneous CYP2D6 and CYP3A4 inhibition during Abilify® therapy. Current Abilify® labeling recommends a 50% reduction in aripiprazole dose when aripiprazole is coadministered with either a CYP2D6 or a CYP3A4 inhibitor, but no dosing guidance is provided for simultaneous CYP2D6 and CYP3A4 inhibition—for example coadministration with ketoconazole and fluoxetine (or ketoconazole in a patient who is a CYP2D6 poor metabolizer). FDA sent a letter to the applicant asking for more information regarding this issue and is in the process of reviewing the applicant’s response. FDA continues to monitor the issue.

(f) Blood dyscrasias. Cases of bone marrow failure, hemolytic anemia, and pancytopenia were identified and reviewed. These cases either did not provide adequate clinical information or were confounded by a combination of underlying hematologic disorders and/or concomitant medications labeled for an association with bone marrow suppression, hematological toxicity, hemolytic anemia, and pancytopenia. The Abilify® labeling already mentioned leukopenia, neutropenia, and thrombocytopenia in the “adverse reactions” section. None of the cases reviewed provided compelling evidence to suggest a significant safety signal of hematologic abnormalities associated with Abilify®. Therefore, FDA did not recommend any labeling changes regarding this issue.

5.5 Azilect® (rasagiline). Azilect® (rasagiline) tablets, by Teva Neuroscience, Inc. is an irreversible, non-selective monoamine oxidase inhibitor (MAOI) initially approved in May 2006 for the treatment of idiopathic Parkinson’s disease.

Nearly 33,000 patients had received a prescription for Azilect® from a U.S. retail pharmacy from May 2006 through September 2007.11 Most use was among those aged 71 years and older (47%) and patients 61-70 years of age (29%). Pediatric patients, ages 0-16 years, accounted for less than 1% of total dispensed prescriptions.12

As a result of the NME pilot program evaluation for Azilect® from December 2007 through March 2008, a number of adverse events requiring further evaluation and more detailed review were identified. FDA formed an internal working group to review AERS cases of these events and also to determine whether rasagaline produced similar cases of these events in a new Phase 3, placebo-controlled clinical trial. 

These events included:

(a) Flu-like symptoms. In controlled trials, various symptoms (e.g., fever, headache, arthralgia, malaise, anorexia, rhinitis, conjunctivitis) associated with the flu, including the adverse event of flu syndrome, were more common in patients treated with rasagaline than in patients who received placebo. Several post-marketing cases included one or more of these adverse events. 

(b) Musculoskeletal symptoms. Patients who were treated with rasagaline had more musculoskeletal adverse events (e.g., arthralgia, arthritis, tenosynovitis, neck pain, myasthenia) than patients who received placebo in clinical trials. 

(c) Hypertension. Several cases of increased blood pressure or hypertension associated with Azilect® use were noted in the post-marketing review. In the placebo-controlled trials of adjunctive treatment, there was an increased incidence of moderately increased blood pressure compared to controls. Some analyses also showed an increased frequency of moderately increased blood pressure after eating associated with rasagaline treatment compared to placebo. 

(d) Melanoma. Clinical trial data showed that patients treated with Azilect® had a higher risk of developing melanoma than the general population. However, other epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (approximately two to six fold higher) of developing melanoma than the general population. Thus, it is not clear whether the increased risk of melanoma observed with Azilect® is due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease. To study this issue further, the applicant is planning to conduct a retrospective cohort study using data from various large healthcare databases. The FDA Working Group is providing the applicant with feedback on the applicant’s proposed study protocol. Initial data from this study are expected to be collected by 2010. 

(e) Drug Interactions. The Working Group noted that the Azilect® labeling may need to be updated to mention specifically the potential for the development of serotonin syndrome when Azilect® is co-administered with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). The Drug-Drug Interactions section of the Azilect® labeling had already mentioned “severe CNS toxicity associated with hyperpyrexia and death” and the Warnings section had mentioned “hyperthermia, rigidity, myoclonus, autonomic instability with rapid vital sign fluctuations, and mental status changes progressing to extreme agitation, delirium, and coma” as possible adverse reactions when monoamine oxidase inhibitors (such as Azilect®) are co-administered with SSRIs and SNRIs. Serotonin syndrome as a clinical entity, however, was not specifically described in the labeling. Moreover, when mentioning this potential interaction, the Azilect® labeling provided a list of the names of several SSRIs (by generic and trade names) but there was no specification of any SNRI for this potential interaction, despite the fact that an interaction resulting in serotonin syndrome has been observed with venlafaxine (Effexor®) treatment. FDA continues to follow up on this issue.

The FDA Working Group is continuing to review cases of flu-like syndrome, musculoskeletal symptoms, and hypertension associated with Azilect® (see “a” through “c” above). 

6. Recommended Changes to Evaluation Process after Pilot Program Completed

After completion of all 5 NME evaluations in the pilot program, the Steering Committee sought feedback on the process from OSE and ODE I personnel. Only minor changes were suggested; the most significant recommendation was to document more thoroughly the literature reviewed by OSE epidemiologists.

7. Resources

ODE I and OSE personnel were asked to record the time they spent in their evaluation of each NME. Different teams evaluated different NMEs and the teams varied with regard to years of experience, work styles, and other factors. Moreover, the NMEs selected for evaluation varied greatly in terms of indication, the number of months since approval, the extent of use, and the number of adverse events reported and entered into the AERS database (Table 1).

Table 1: NME Pilot Product Details and Resources Used to Complete Pilot Evaluations
NMENumber of Months After ApprovalNumber of Patients Receiving PrescriptionCrude Number of AERS ReportsNumber of Hours Spent on NME EvaluationNumber of Safety Issues Identified for Follow-up
Cymbalta® (duloxetine)313,059,9376,4902158
Ranexa® (ranolazine)1739,074941610
Apokyn® (apomorphine)412,7642451113
Abilify® (aripiprazole)642,156,4006,1833696
Azilect® (rasagiline)2232,732491825

In all cases, however, even for drugs with modest use, evaluation required substantial resources, as shown in Table 1. The number of hours required to complete each evaluation ranged from 111 for Apokyn® to 369 for Abilify®. The greatest time was spent on Abilify® and Cymbalta®, the two drugs with by far the greatest extent of use and numbers of AERS reports.

The correlation between the number of hours spent to complete an NME evaluation and the number of AERS reports submitted was not as strong as might have been expected, perhaps suggesting a minimum number of hours for review even if not much information is found. Thus, as shown in Table 1, Azilect® had the fewest number of reports, but the evaluation still took 182 hours—not very different than Cymbalta®, requiring 215 hours, even though the latter had 130 times as many AERS reports.

The number of hours spent was also not closely linked to the number of patients who had received a prescription for the product. The evaluation of Apokyn®, with use by fewer than 3,000 patients, took 111 hours to complete, which is not markedly lower than the time spent on the evaluation of Cymbalta®, with use by over 3 million patients, which took 215 hours to complete.

The Ranexa® NME evaluation is noteworthy because the time at which this evaluation was conducted closely mirrors the requirement of Section 915 of FDAAA, which states that an analysis “must be prepared by 18 months after approval of a drug or after its use by 10,000 individuals, whichever is later.” The Ranexa® evaluation was conducted 17 months post-approval and with over 10,000 patients having received a prescription. Both the 18 month time period and the 10,000 patient requirement as contemplated by FDAAA were exceeded for 3 of the NMEs evaluated (Cymbalta®, Abilify®, and Azilect®). The remaining NME (Apokyn®), although evaluated after 18 months, still had fewer than 3,000 patients who received a prescription, well below the 10,000 patient requirement.

The kind of evaluation carried out in the pilot is clearly quite labor intensive. The considerable number of hours spent completing these evaluations might be explained in part by the “pilot” nature of the process. Because participants were learning a new process, some analyses may have taken longer than they would have if the process had been more familiar. Moreover, modifications of the process were implemented while some of the evaluations were ongoing, when it was discovered that enhancements were needed; these modifications also added time. Even when these points are factored into the assessment of the effort, however, it is clear that such evaluations will require a significant amount of time because of the need for a hands-on review of reported cases that cannot be conducted automatically. In addition, although the Steering Committee believes the large multi-organizational group discussions of the findings were a critical element to the success of the process, the time spent coordinating and holding these discussions, which involved many reviewers from various divisions and disciplines, was also considerable.

8. Conclusions

After completion of all five pilot program evaluations, the Steering Committee was able to draw some conclusions about the program. First, the process required extensive collaboration between CDER’s Office of New Drugs and Office of Surveillance and Epidemiology. The general opinion among the five evaluation teams was that this collaboration was extremely useful and productive. After the primary reviewers gathered the data for each NME, these reviewers and senior staff from ODE I, OSE, OCP, and SPCS discussed the preliminary findings at a large group meeting. Everyone was “at the table” at the same time reviewing the same data. These meetings facilitated communication and consensus building regarding the safety signals meriting further investigation, the type of follow-up required, and the projected timeline for completion of follow-up tasks.

Second, the Steering Committee found that the new pilot approach succeeded in identifying some new, previously unknown safety issues. Review of Cymbalta® and Abilify®, drugs with substantial duration and extent of use, led to identification of several aspects of existing labeling that would benefit from modification. Even for Apokyn® and Azilect®, however, drugs with more moderate extent of use, the evaluation was of value, identifying several safety issues that led to appropriate interventions.

As previously noted, of the five NMEs evaluated, the Ranexa® evaluation most closely mirrored the FDAAA Section 915 requirement in terms of the time following approval and number of patients receiving a prescription. While no specific safety issues requiring regulatory action were discovered as a result of this particular evaluation, the team that evaluated Ranexa® was reassured that no significant safety issue had gone undetected for this NME.

It should be appreciated that not discovering major new adverse effects or major labeling deficiencies does not represent a “failure” of the evaluation process, but rather suggests that the existing routine processes of monitoring of adverse events by FDA and drug applicants, and the resulting labeling revisions, were effective.

Third, the Steering Committee learned that these evaluations require considerable resources from both ODE I and OSE. The evaluations are labor intensive, requiring a number of reviewers to retrieve, collate, and interpret a significant amount of data. Although CDER expects that some data analytical processes will be automated in the near future, it is clear that such NME evaluations will still require a significant amount of time when complex safety issues are discovered requiring hands-on review of individual cases.

1 The term "new molecular entity" (NME) refers to drugs that include an active ingredient that has not previously been approved for marketing in the United States.

2 The Institute of Medicine (IOM) is a non-profit, non-governmental American organization that is part of the United States National Academy of Sciences

3 The Adverse Event Reporting System (AERS) is FDA’s database designed to support FDA's postmarketing safety surveillance program for all approved drug and therapeutic biologic products.  FDA uses AERS to monitor new adverse events and medication errors that might occur with these marketed products.  http://www.fda.gov/cder/aers/default.htm

4 SDI, LLC: Total Patient Tracker, Aug04-Dec06, extracted Feb07.

5 SDI, LLC: Vector One®: National, Aug04-Dec06, extracted Feb07, Mar07.

6 SDI LLC: Total Patient Tracker, extracted Apr07.

7 Data provided by the applicant to FDA.

8 SDI, LLC: Total patient Tracker, Nov02-Oct07, Extracted Feb08.  File:  TPT 2007-2336 Abilify Aggregate Age Range Patient Count.xls.

9 SDI, LLC: Vector One®: National, Nov 02-Oct07, Extracted Feb 2008.  File:  Vector One:  National 2007-2336 Abilify NME TRx by Age2.qry and Vector One:  National 2007-2336 Abilify NME TRx by Peds.qry

10 Scherk H, Pajonk FG, Leucht S. Second-generation antipsychotic agents in the treatment of acute mania: a systematic review and meta-analysis of randomized controlled trials. Arch Gen Psychiatry. 2007 Apr;64(4):442-55.

11 SDI, Total Patient Tracker, data extracted 11-29-07. Source Files:2007-1702 TPT 11-29-07 Azilect age may06-sept07 agg.xls and 2007-1702 TPT 11-29-07 Azilect gender may06-sept07 agg.xls

12 SDI, LLC: Vector One®: Prescription Services (VONA and VOMA). Data extracted 11-29-07 
Source file:2007-1702 VONA 11-29-07 Azilect NME TRx age gender.qry

Posted 10/15/2009

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