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Encyclopedia of Biopharmaceutical Statistics

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Adverse Event Reporting

Cynthia Pennise a; Cheng-Tao Chang a a Baxter Healthcare Corporation, New Providence, New Jersey, U.S.A. Online Publication Date: 23 April 2003

To cite this Section Pennise, Cynthia and Chang, Cheng-Tao(2003)'Adverse Event Reporting',Encyclopedia of Biopharmaceutical

Statistics,1:1,22 27

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Adverse Event Reporting

Cynthia Pennise Cheng-Tao Chang
Baxter Healthcare Corporation, New Providence, New Jersey, U.S.A.

INTRODUCTION In order for a chemical intended for use as a medicinal product to be sold for use in humans, research must be carried out to prove that the benefits of the drug outweigh the risks associated with the drug. Clinical studies of planned tests of the drug in people are performed following the protocols with predetermined statistical analyses planned for the safety and efficacy of the drug. These studies are conducted in a known number of patients. The results of these studies can be statistically analyzed to show that the results can be reproduced, and that the drug is useful to treat the condition and is safe in the intended population. Adverse events terminology is coded in order to group similar events and to categorize them into similar medical concepts within broad concepts for data retrieval. It is only by knowing the number of patients treated and by analyzing the adverse events reported that the safety profile of a drug can be drawn. By analyzing adverse events that occur within the test drug treatment and comparing it to a placebo-control or a known historical control, one can definitely show what side effects a drug causes. Once a drug is marketed, the number of patients who are exposed is unknown, as is the indication that the drug was used to treat and the dose used by each patient. Unless further clinical trials are conducted for a different indication or subset of patients, information gathered from the postmarketing safety reporting cannot be utilized to request a regulatory authority to change the labeling. When a new drug is marketed, the treated population is not restricted by protocol, and there is an exponential increase in the number of patients exposed (which can only be estimated from sales volumes). New adverse events are reported that were not seen in the trials conducted by the pharmaceutical company. Postmarketing safety reporting of adverse event information is performed voluntarily. No statistical analyses can be performed on postmarketing data because of the number of patients treated being unknown as well as the true number of occurrences of each adverse event. New adverse events can be added in the safety section of the package labeling from postmarketed use; however, no incidence for these new adverse events can be listed. This
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is why great care is taken in the design of clinical protocols so that appropriate claims for the efficacy and safety of a drug can be documented.

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BACKGROUND OF THE DRUG APPROVAL PROCESS The drug approval process is a long one, incorporating up to 15 yr of research from the drugs inception at the chemists bench to marketing. This process includes formulation testing, several stages of preclinical testing, and clinical testing that generally involves Phases I through III clinical trials prior to marketing. If the drug survives preclinical testing, Phase I studies are conducted in small populations, usually in 20 25 normal volunteers, to determine initial human safety. No formal statistical safety analysis is usually performed on these small studies because of the fact that the number of patients, or n, is small. If there appears to be no clinical safety issues after reviewing the results of the blood and urine analyses, preliminary efficacy studies are performed and are called Phase II trials. These trials study the drug in the intended patient population with the target disease to be treated. The trials are small, usually 50 100 patients, and are usually single-blind studies, generally with no control arm. Although safety is looked at from a clinical perspective, it is usually not analyzed statistically. The main focus of these studies is to see if the drug appears to show some efficacy to justify additional clinical research. If efficacy appears to show a positive trend, Phase III trials utilizing a placebo-control, a historical control, or a comparative control are conducted. Depending on the disease and the intended duration of human treatment (acute versus chronic use), these trials may range from 100 200 patients treated for several days to several months, or up to several hundreds of patients to 1000 or more patients treated up to several years. Two separate controlled clinical trials are usually required for regulatory approval in order to ensure that the results can be statistically reproduced. Recently, the Food and Drug Administration (FDA) has allowed some drugs intended for critical use to be evaluated for approval utilizing a single, controlled trial. Although there are many aspects
Encyclopedia of Biopharmaceutical Statistics DOI: 10.1081/E-EBS 120007380 Copyright D 2003 by Marcel Dekker, Inc. All rights reserved.

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regarding the evaluation of clinical trials, the focus of this entry is on the adverse event reporting for the safety data analysis using the Medical Dictionary for Regulatory Activities (MedDRA) coding system.

CODING DICTIONARIES The Need to Code In order to prepare an analysis of safety data and provide any meaningful results of the safety that was seen in the trial, the safety terms, as they were reported, must be combined into similar terminology, or coded, to allow the true occurrence of similar events to be analyzed. For example, if the reported terminology for adverse events from a study includes stomach ache, stomachache, stomach pain, and pain in stomach, if analyzed as reported, there is one occurrence of each of the four terms. However, when a coding dictionary is utilized, all of the terms would be coded (depending on the dictionary used), for example, to abdominal pain, upper with four occurrences of this one adverse event. Combining terminology via coding dictionaries allows the safety results to be analyzed statistically and more truly reflect what is occurring in the patient population being treated with the drug product. Common Dictionaries Utilized There are many adverse event coding dictionaries that have been created over the years throughout the world. Some of the common ones include MedDRA,[1] Costart,[2] Whoart,[3] and ICD-9.[4] Many pharmaceutical companies have also created their own versions of adverse event coding dictionaries, an example of which is HARTS.[5] One major problem with the existence of multiple coding dictionaries is that in addition to each pharmaceutical company choosing a dictionary to use, the regulatory authorities around the world are also using different dictionaries. This leads to many problems in companies who have to use multiple dictionaries for foreign versus domestic regulatory submissions and in regulatory authorities who have to recode the data into their dictionary of choice. This problem was the one that added to the need for the creation of the International Conference for Harmonization (ICH).[6] The goal of this group, which represents the regulatory bodies and research-based industry in the European Union, Japan, and U.S.A., was to find a way to harmonize all the types of regulatory submissions for global acceptance and approval. One of the resulting guidances that arose from the formation of this group was the need for a common coding dictionary to be utilized around the world by

countries in these regions. The resulting dictionary was called MedDRA. This dictionary was designed to provide a standardized coding dictionary to be utilized by industry and regulators around the world. The dictionary was made up of terminology already contained in many of the existing dictionaries, although its structure allowed greater specificity for the coding of terminology. Medical Dictionary for Regulatory Activities Instead of being divided into the common body systems used by previous dictionaries, MedDRA categorizes terminology into 26 System Organ Classes (SOCs). The division of terminology into these SOCs allows for the coding of medical history as well as adverse events arising from the use of both drugs and biological products. The dictionary is not currently used to code Medical Device Incidents or to code medications. The dictionary is hierarchical in that it provides vertical linking of terminology. The five-level hierarchy of the dictionary with the number of terms included in each level for version 4.1 is shown in Fig. 1. The LLT is the place where the reported term is located. Both the British and American English spellings are used at the LLT level. Each LLT is linked to only one PT. Preferred terms represent a single medical concept and can consist of several LLTs. The dictionary utilizes the British spelling of words at the PT level and higher. Terminology utilized in statistical tables is usually represented by the verbatim term as reported and the coded term, in this case, at the PT level. The dictionary allows for multiaxial coding, which means that certain terms at the PT level that can logically be coded to more than one SOC can be represented under more than one SOC. However, within each SOC, each PT is represented by only one HLT and one HLGT. Each PT has a primary pathway that must be used for the initial

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Fig. 1

MedDRA hierarchy.

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Adverse Event Reporting

Fig. 2
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Multiaxial pathway for one PT to two different SOCs.

analysis by companies. Secondary analyses can be performed utilizing these secondary pathways. An example of the multiaxial pathway for a term is shown in Fig. 2. The SOCs are not mutually exclusive. The MedDRA dictionary also contains Special Search Categories (SSC) that contain clinical concepts that cross SOCs. These SSCs allow linkage of PTs that are not necessarily equivalent or related in the hierarchy of MedDRA. These SSCs generally group PTs that are relevant to a medical issue, usually a disease or a syndrome. Preferred terms can exist in multiple SSCs. Examples of SSCs are listed in Fig. 3.

Dictionary Versions The MedDRA dictionary is constantly updated for coding. Updates are needed because of the companies submitting requests for additions of terminology to the company managing the dictionary. Requests for changes in mapping of terms, as well as updates for dictionary consistency, also result in the need to update the dictionary. The current MedDRA Maintenance and Support Services Organization is TRW, Inc. The original MedDRA dictionary was updated four times per year; current updates are made twice per year. Major updates are indicated by an increase in the first number of the version (e.g., 4.0), with minor updates of a version indicated by an increase of the decimal (e.g., 4.1). Various pharmaceutical companies do coding of the clinical studies in many ways. One method is to initiate coding of a study in the current version of MedDRA that is being utilized at the company and to remain with the same version throughout the study. At the end of the study, the entire study can be recoded in the current version of MedDRA. An alternative way to code a clinical study is to continually update the versions as they are published. Whichever method of coding is utilized, it is important to document the version of MedDRA utilized for the coding of each study.

STATISTICAL ANALYSES FOR ADVERSE EVENT DATA Individual Study Report Each individual study must be statistically analyzed to show its contribution toward the approval of a drug for

Fig. 3 Special Search Categories.

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Table 1 Typical side-by-side presentation of safety data Incidence of adverse events: number (%) System organ class Cardiac disorders Hepatobiliary disorders Vascular Disorders All MedDRA PT Asystole Myocardial infarction Hepatitis NOS Jaundice Hypertension Hypotension All Treatment A (n = 25) 1 0 5 10 1 2 13 (4%) (0%) (20%) (40%) (4%) (8%) (52%) Treatment B (n = 25) 5 2 2 0 6 12 20 (20%) (8%) (8%) (0%) (24%) (48%) (80%) Total (n = 50) 6 2 7 10 7 14 33 (12%) (4%) (14%) (20%) (14%) (28%) (66%)

both efficacy and safety.[7] Depending on the size and the objectives of the study, safety data may be analyzed with descriptive statistics (frequency, percentage, mean, and standard deviation) for most cases, or with rigorous statistical methods that provide p-values for comparison between different treatment groups. Note that safety data usually consist of clinical laboratory data, ECG, physical examination, and adverse events reporting. Adverse event data are one of the most, if not the most, important piece of safety data that are closely watched and reviewed by regulatory agencies. When safety data are analyzed, it is a common practice to include all patients who received at least one dose of the study drug(s) so that the investigation of the safety profile may be executed to the greatest possible extent. As far as adverse events are concerned, in a basic summary statistics, they are presented in tables showing the incidence of each adverse event in the comparative treatment groups. Incidence is represented by showing the number of occurrences of each adverse event with the percentage of patients who experienced the adverse event. When a patient experiences a particular adverse event on more than one occasion, the patient is only counted once for that adverse event. The same is true if a patient experiences a particular adverse event that recurs and that varies in intensity (mild, moderate, or severe). The patient is counted once for that adverse event, the occurrence with the greatest severity. Different adverse events are counted separately for the same patient. In addition to the presentation of occurrence of adverse events by treatment group, an overall cumulative tabulation of each adverse event that occurred in all treatment groups is presented. Another critical piece of the summary is the count and the percent of patients in each treatment group who experienced any adverse events. This provides a simple and condensed overall safety picture of the study drug in relation to the control/ comparator drug. Presentation of the adverse events in the summary table can be performed through sorting by SOC,

or by the frequency (or percent) of each SOC in decreasing order of the active treatment group. The latter presentation shows a clear trend of the occurrences of the SOCs for the test drug. Within each SOC in the summary table is the listing of the PTs that are primarily coded to that specific SOC, in alphabetical order or by decreasing order of occurrence and percent. When a large-scale multicenter trial is involved, in addition to a pooled summary of all the study centers, it may be relevant to summarize the adverse events by each individual study site. An example of a typical side-by-side presentation of the safety data is shown in Table 1. According to the ICH guidelines, the presentation of individual patient events by drug, adverse event, severity, and relationship to treatment can be presented in Table 2. It may be pertinent to statistically compare some SOCs that showed the highest occurrences of adverse events between and among treatment groups for a large-scale clinical trial where these SOCs are of clinical relevance for the drug product. Because there are 26 SOCs, and some SOCs may have zero count of occurrences, it would not provide any clinically meaningful information to compare every SOC. The following statistical methods are commonly used to compare adverse events within each SOC between treatment groups: 1. Chi-square test for a 2 2 summary table: this is employed in cases of comparing two treatment groups, and the number of patients with adverse events (AE) and no AE for each treatment group should be equal to or exceed 5 (preferably over 10). 2. Fisher-exact test for a 2 2 summary table: this is employed in cases of comparing two treatment groups regardless of the magnitude of the number of patients with and without AE. 3. Mantel Haenszel test for 2 2 q summary tables: this is employed in cases of comparing two treatment groups while at the same time controlling another

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Adverse Event Reporting

Table 2 Incidence of adverse events (primary organ class and preferred term) by severity and relationshipa Treatment group: AAAA Severity = mild Severity = moderate Severity = severe Overall

Primary system Preferred Not Not Not Not organ class term Related related Total Related related Total Related related Total Related related Total Gastrointestinal disorders Nausea 5 N11b N12 N13 N14 N15 4 N11 N16 N17 N18 8 N11 N12 N13 N14 N15 N16 N17 N18 1 N19 2 N20 N21 3 N19 N20 N21 0 1 N20 1 N20 6 N11 N12 N13 N14 N15 N19 6 N11 N16 N17 N18 N20 N21 11 N11 N12 N13 N14 N15 N19 N16 N17 N18 N20 N21 6 N22 N23 N24 N26 N25 N27

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Vomiting NOS

3 N22 N23 N24

2 N23 N25

4 N22 N23 N24 N25

2 N24 N26

3 N24 N26 N27

3 N24 N26 N27

4 N22 N23 N24 N26

5 N23 N24 N25 N26 N27

Related includes adverse events that are possibly, probably, and highly probably related to the study drug. Not related includes adverse events that are not related or remotely related to the study drug. a Patients are counted only once in each cell. b Nxx represents patient ID number.

explanatory variable (such as study sites in a multicenter study, ages grouped by at least two classes, gender, and severity of underlying disease) as the stratum, where q refers to the number of levels for the stratum. This test is statistically valid when the combined row counts are sufficiently large (for example, greater than 30). 4. Extended Mantel Haenszel test for 2 r q summary tables: this is employed in cases of comparing more than two treatment groups (r > 2) while at the same time controlling another explanatory variable as the stratum as in Case 3 above. The case when q = 1 may represent a single-center clinical trial with more than two treatment groups. A realistic and conservative guideline for the modeling validity is to choose one or more cutpoints for the column for each stratum, say j ( j  1). Add the 1st through jth columns together and ( j + 1)th through the last columns. Then the sample size is adequate if all the cells in each new reduced 2 2 table of the q tables are 5 or more. Note

that the cutpoints across all strata are not necessary to be the same.[8] If there is more than one treatment period in a study per protocol, the adverse events that occurred during each period should be presented separately. Also, depending on the patient population and the disease being studied, subset analyses of adverse event data can be performed. These can be performed by specific demographics, or SSC, for example. The incidence of adverse events is evaluated for clinical significance in addition to the statistical analysis that was performed. A high incidence of a particular adverse event can often be explained by the concurrent disease state of the patients being treated. Other times there are known side effects of a particular drug class. One of the primary reasons that new drugs are developed is to be able to market a drug that is effective in treating the condition and is either the first of its kind or is better than the products already available. One of the ways this

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superiority can be documented is by using a comparative drug as a positive control in a study and being able to show a better safety profile, or that the innovator is faster in onset or lasts longer in duration.

should be written to include detailed statistical approach to this secondary analysis.

CONCLUSION Integrated Summary of Safety When filing an New Drug Application (NDA), in addition to reporting a summary of each individual study where the safety and the efficacy are analyzed for that particular study, a combined safety analysis, the Integrated Summary of Safety (ISS), must be written.[9] The safety data from each controlled clinical trial are combined into a single data set and are analyzed to see if the safety results from the individual studies are changed when the data from all studies are analyzed together. In addition to comparing the treatment groups to one another as a whole, if there is sufficient power, subset analyses can be performed. These subset analyses depend on the patient population treated. Data can be separated and analyzed by age, sex, race, or disease state, for example. The results of these subset analyses can provide valuable information that will eventually be included in the indications, dosing, precautions, or adverse event sections of the package insert or the Core Data Sheet. Depending on the results of the subset analysis, some adverse events may be separately described to list their incidence, for example, in pediatric or geriatric populations compared with the overall incidence for that adverse event in the total population that was treated. Safety analyses of the different disease states have provided safety results that show that the drug cannot be administered to certain patient populations (e.g., renalimpaired or hepatic-impaired patients). Within the ISS, it is sometimes useful to determine whether there is a trend when several dosing levels of the test drug are involved. The safety of a drug product is important for its approval for marketing. Careful planning of the clinical trials for study design is important. Analysis of adverse events can be performed as a basic necessity to show the safety of a drug product. In some cases, adverse event data can also be analyzed as a safety endpoint in order to provide data for labeling claims. This is one of the many reasons to be sure that your statisticians are well informed about the disease and the patients being treated when the protocol is written to ensure sufficient power for labeling claims.

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REFERENCES
1. MSSO, Medical Dictionary for Regulatory Activities Terminology, MedDRA Introductory Guide v4.1, MSSODI-6003-4.1.0; TRW Inc., 2001. Department of Health and Human Services. Costart: Coding Symbols for Thesaurus of Adverse Reaction Terms, Fifth Edition, 1995, USA Food and Drug Administration, PB95269023, FDA/CDER-95/24; U.S. Department of Commerce, National Technical Information Service: Springfield, VA, 1995. World Health Organization Collaborating Centre for International Drug Monitoring, WHO Adverse Reaction Terminology (WHOART), 1998, Uppsala, Sweden, http:// www.who.int/home-page/, (accessed in December 2001). ICD-9-CM: International Classification of Diseases, 9th Revision; Clinical Modification, PB2001-500083, U.S. Department of Commerce, National Technical Information Service: Springfield, VA, 2001. Hoeschst Adverse Reaction Terminology System (HARTS); 1992, Aventis Pharma. ICH: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use; http://www.ifpma.org/ich2.html, (accessed in December 2001). Food and Drug Administration Code of Federal Regulations, 21 CFR 314.50 (d) (5) (ii). Categorical Data Analysis Using The SAS System, 2nd Ed.; Stokes, M., Davis, C., Koch, G., Eds.; 2000, SAS Institute Inc. Food and Drug Administration Code of Federal Regulations, 21 CFR 314.50 (d) (5) (vi).

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Adverse Events as Secondary Endpoint In addition to proving that a drug is effective, for certain disease states, there are certain known side effects, or sequelae, that occur in the usual course of the treatment. If these sequelae are known in advance of protocol design, the study can be designed to show that the study drug is safer than other products available by resulting in a lower incidence of the known side effects. The protocol
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