Recommendations for Guidelines on Clinical Trials of Mucoactive Drugs in Chronic Bronchitis and Chronic Obstructive Pulmonary Disease

special report Recommendations for Guidelines on Clinical Trials of Mucoactive Drugs in Chronic Bronchitis and Chronic Obstructive Pulmonary Disease* Task Group on Mucoactive Drugs

(Chest 1994; 106:1532-37) ATS=American Thoracic Society; CB=chronic bronchitis; COB=chronic obstructive bronchitis; COPD=chronic obstructive pulmonary disease; GCP=good clinical practice; MRC=Medical Research Council; NCE=new chemical entities; QoL=quality of life

This paper reflects a scientific evaluation of the current state of the art on clinical trials of mucoactive drugs in chronic bronchitis (CB) and chronic obstructive pulmonary disease (COPD) as discussed by international experts. It has been structured in such a way as to constitute the basis for future guidelines. This document is mainly concerned with the evaluation of clinical efficacy during the conduct of phase III studies. Safety aspects have deliberately not been addressed, but it is assumed that all clinical trial protocols will include appropriate methods for monitoring safety issues and collection of adverse drug events. It must be acknowledged that clinical development and relevant protocols should be tailored in respect to the uniqueness of each compound. Furthermore, all investigational protocols must be conducted according to good clinical practice (GCP) . GENERAL PRINCIPLES

Background Information The complexity of airway diseases and the many confounding factors in the therapeutic outcome can explain the difficulty associated with demonstrating the effectiveness by objective criteria and lack of conclusive data. In CB and COPD , even the definition of "event" (required to assess the improvement) is more problematic than in other diseases. *From the Task Group on Mucoactive Drugs, Milan, Italy. A complete list of authors appears at the end of this article. Manuscript received February 8,1994; revision accepted Ma y 20. Reprint requests: Dr. Tabusso, Via San Pietro, All'Orto, 17, 20121, Milan , Italy.

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In recent years, in an attempt to avoid the use of subjective measurements related to global clinical scores of the patient's status, standardized scores, "objective" quantitative outcomes such as pulmonary function tests, mucociliary and tussive clearances, rheologic measurements and biochemical data, and evaluation of volumes of expectoration have been proposed.

Applicability of Position Paper This position paper applies to all mucoactive drugs (new chemical entities [NCEs] and established medicinal products or new combinations thereof) to be used in CB and COPD because these diseases are characterized by quali-quantitative alterations of mucus and by modification in the associated relationship between mucus, cilia, and periciliary fluid.

Definition of the Disease Definition of airway diseases is in accordance with American Thoracic Society (A TS) and Medical Research Council (MR C) criteria. 1•2 Chronic bronchitis is a syndrome including heterogeneous diseases, with multiple etiologies and can be defined as follows:

Chronic nonobstructive, so-called simple bronchitis is a condition characterized by chronic or recur-

rent cough and hypersecretion of mucus into the bronchial tree which occurs on most days for at least 3 months of the year, for at least 2 successive years. It is a condition , without signs of airway obstruction as measured by conventional pulmonary function tests. The excess of mucus secretion should not be caused or accompanied by specific diseases, such as bronchiectasis or tuberculosis, etc. Chronic obstructive pulmonary disease refers to pulmonary diseases characterized by dypsnea and irreversible or partially reversible airflow obstruction, often accompanied by impaired gas exchange. Chronic obstructive bronchitis (COB) refers to a

Clinical Trial Guidelines of Mucoactive Drugs in Chronic Bronchitis and COPD (Tabusso et aQ

form of CB with signs of airway obstruction. The diagnosis of the above pathologic conditions results from clinical history , physical examination, pulmonary function testing to detect lung overinflation, airflow obstruction and gas exchange impairment, physical signs, chest x-ray film , and ECG to detect cor pulmonale. Risk factors of major influence are represented by the demographic and socioeconomic conditions, by environment and individual behavior (cigarette smoking, air pollution, etc.), respiratory infections, and genetic characteristics (protease inhibitor deficiency) . Chronic bronchitis and COPD lead to an increased risk of morbidity and mortality, since they may result in acute exacerbations often associated with respiratory infections, to a decline in FEV 1 and chronic respiratory insufficiency , pulmonary hypertension, and eventually, cor pulmonale.

Definition of Mucoactive Drugs A mucoactive drug is an agent that possesses, as its primary action , the capability of modifying mucus production, secretion, its nature and composition, and / or interactions with the mucociliary epithelium . ANIMAL PHARMACODYNAMICS

Animal models are useful tools for pharmacodynamic investigations and assist the design of clinical studies. They should be chosen on consideration of the comparative anatomy of the respiratory tract , and the similarity in morphologic, biochemical, and physiologic determinants of the human and animal disease under investigation . Nevertheless, even if the physiologic end points may be similar, animals cannot provide the ideal model of human CB with and without obstruction and COPD, but each model presents its own advantages and disadvantages. The morphologic and physiologic changes of human COPD can be reproduced in animals by intratracheal administration of elastase, neutrophil extracts, or by recruitment of neutrophils in bronchial airways. In fact, a large number of neutrophils and high concentrations of active proteases are known to exist in the sputum of patients with COPD. By varying the doses of instilled elastase, experimental models of COPD with or without emphysematous changes can be produced. In animals, secretory cell metaplasia, a large number of atypical cilia, and impaired mucociliary clearance are usually observed in bronchial epithelium. Models based on the stimulation of hypersecretion based on demonstrated cause-effect relationship are the most appropriate ones.

CLINICAL FEATURES AND EvALUATION PARAMETERS

Biochemical Data Mucus present in normal airways is composed of 95% water, 2% glycoproteins (mucins) , 1% ions, 1% lipids, and 1% other proteins and proteoglycans. In conditions characterized by mucus hypersecretion, the relative proportion and the amount of mucus constituents are altered; the nature of the glycoproteins is altered and the protein content increased in noninfected mucoid sputum. In purulent sputum, DNA is present; a greater increase in proteins and lipids is also observed. Chemical and biochemical changes in mucus composition are correlated with the rheologic properties and mucociliary clearance. The evaluation of biochemical markers is appealing as they may be directly related to the proposed mechanism of action of a given drug ; hence, they may be useful for proof of concept. Indeed, mucoactive drugs can modify the biochemical nature of mucus either directly by acting on glycoprotein disulfide bonds and/ or on secretion of glycoproteins, lipids, other proteins and water content and / or indirectly by preventing the effect of inflammatory products on mucus secretion . Some mucoactive drugs, being reducing substances, may exert an antioxidizing effect. Because of complex interaction between clinically defined features and biochemical markers, their evaluation in clinical trials complicates their sole use as end points. In the expectorations, the following biochemical data can be usefully investigated: total solids content; glycoprotein concentration; protein concentration and nature; lipid concentration and nature; immunoglobulins; and DNA concentration. In certain circumstances it may be of value to characterize the glycoproteins (ie, fuco , sialo, and sulfomucins). It is important to use properly validated assays to measure the above-mentioned parameters.3 In the case of biochemical studies, it is critical to control the method of sputum collection; salivary contamination should be minimized, and time of collection and subsequent storage conditions should be standardized. As new biochemical parameters and techniques are identified, it may be essential to include them in the range of measurements attempted.

Rheologic Function Since the rheologic properties of mucus are known to correlate with transport rate on a ciliated epithelium, they represent a useful means of evaluating the activity of drugs. However, it is important to use properly validated techniques that will produce information derived within the linear viscoelastic CHEST I 106 I 5 I NOVEMBER, 1994

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region. Methods which destroy the mucus gel during measurement are of no use. The techniques which can produce useful data are, for example, creep compliance and dynamic (oscillatory) testing, as well as appropriate tensiometers. The moduli obtained by these methods will give an indication of transport of the mucus on a ciliated epithelium. In disease states, elasticity and viscosity and adhesiveness of mucus are known to be altered, and mucoactive drugs are intended to normalize these parameters. However, results from clinical trials are often confounded by large interpatient and intrapatient variation in terms of rheologic measurements, and it is therefore very important to ensure that patient groups are as clinically homogeneous as possible.

Pulmonary Function Lung function tests are used in the diagnosis as well as in the assessment of severity and prognosis of COPD. Whereas their role in the assessment of therapeutic intervention particularly with bronchodilators is well established, their role for evaluating clinical efficacy of mucoactive drugs is controversial. Airway obstruction is a distinctive feature of COB and COPD and may be assessed by conventional spirometry and/ or flow-volume curves (FEV 1 , VC, FVC, Vmax at a given lung volume, including peak flow ).4•5 Measurements of airway resistances by whole body plethysmography or helium dilution method 5 may be an additional index of airway obstruction. Lung volumes-functional residual capacity (FRC) , residual volume (RV), and total lung capacity (TLC) which can be measured by whole body plethysmography or helium-dilution method, are characteristically increased in COPD. Diffusion capacity (transfer factor) and diffusion coefficient can be measured by different methods of which the single breath technique is the most widely used. 5 Ventilation/ perfusion mismatch can develop with increasing severity of the disease, leading to variations in gas exchange; hence, the expired minute ventilation and the ratio of dead space to tidal volume together with blood gases should be measured to monitor such changes. Since a direct effect of mucoactive drugs on pulmonary function is not expected, measurement of pulmonary function should not represent a primary end point. Although statistically significant changes can be demonstrated, their clinical relevance should be carefully addressed. Mucoactive drugs are supposed to exert an indirect effect on such lung functions, probably mediated by a change in mucus clearance. The rate of mucus clearance can be measured in vivo in human subjects using inhaled radiolabelled aerosols and monitoring loss of radioactivity from the chest over time or by monitoring movement of inert particles deposited in 1534

the trachea via fiberoptic bronchoscopy. It is important that the deposition of the radiolabelled or inert particles is comparable at the beginning of the clearance measurement. 3

Clinical Signs and Symptoms Chronic bronchitis is characterized by chronic cough and expectoration, chest discomfort, and in the case of associated airway obstruction, by progressing dyspnea. Increase in airway secretion reduces mucociliary transport together with cough frequency and efficiency; it alters the ciliated epithelium leading to airways congestion and chest discomfort. Patients may complain of difficulty in bringing up airway secretions and of recurrent bronchial infections. A frequent complication of CB is acute exacerbation characterized by worsening of symptoms, such as an increase in cough severity and frequency, an increase in airway secretions, alteration in macroscopic appearance (purulence) and physical properties, and chest discomfort often associated with dyspnea because of increased airway obstruction, sometimes also associated with malaise and/ or fever. Acute exacerbations result from various etiologies, such as viral and bacterial infections, and are influenced by environmental factors, such as air pollution. Depending on the severity of the underlying respiratory disease and airway obstruction, respiratory failure and pulmonary hypertension may occur. When designing clinical studies, the suggested clinical criteria, described in "Clinical Studies," should be considered. METHODOLOGJC ISSUES

Study Design Human pharmacodynamic studies involving the evaluation of biochemical, rheologic, and/or pulmonary function parameters are intended to provide information on surrogate markers of pharmacologic activity in clinical trials. Double-blind placebo-controlled randomized studies should be performed. A crossover design may be suitable for short-term trials. In long-term trials, parallel group design should be considered since in these studies, crossover designs do not generally provide reliable results due to the progressive and unstable nature of the disease. Inclusion/ exclusion criteria should be specified according to the aim(s) of the study. Similarly, baseline and frequency of measurements should be defined and justified.

Target Population For the purpose of this document, two patient populations have been considered as follow : (a) those with acute episodes; and (b) those receiving longterm treatment. Acute episodes are defined as the appearance of

Clinical Trial Guidelines of Mucoactive Drugs in Chronic Bronchitis and COPD (Tabusso et aQ

sputum changes and aggravated cough, general malaise or fever, or increased mucus production and consistency.6 Long-term treatment involves patients in an intercritical phase of the disease. Basic Inclusion Criteria: It is advisable that patients admitted to clinical trials be well characterized (as to pulmonary function ; duration of disease, clinical history , life habits, episodes of exacerbation, etc .) to reduce as much as possible heterogeneity and multiple etiologies of chronic bronchitis. Different end points may require different suitable eligibility criteria, with the aim of reducing individual variability as much as possible and facilitating significant outcomes. Patients with concomitant illnesses and treatments may be admitted, provided that confounding factors influencing the assessment of results are not introduced. Particular attention should be paid to the concomitant use of bronchodilators, antibiotics, and to physiotherapy. If concomitant therapy is needed , its dosage should not be changed during the whole study period. Group stratification must be considered prospectively, taking into consideration the following: age (more than 40 years of age) ; disease duration; special habits (eg , smokers and exsmokers, smoking exposure); documented history of chronic mucus hypersecretion; and particular features of clinical history (eg, number of bronchitic exacerbations in a defined period) . Practical limitations to patient inclusion should be specified. For trials related to acute episodes, the following additional inclusion criteria may be considered: presence / absence of airway obstruction; presence/ absence of respiratory failure; severity scores; nutritional status; and inpatients or outpatients. Since a large percentage of the population affected by CB and COPD fall into an age range over 65 years, it is also important that the study population includes geriatric subjects so that results can be extrapolated to the actual population likely to use the drug. Basic Exclusion Criteria: Patients suffering from asthma ,1 cystic fibrosis , or assessed diagnosis of bronchiectasis, pneumonia, or other chronic severe diseases which can interfere with the outcome should be excluded. Patients receiving antitussive drugs, other mucoactive compounds, or patients using inhaled and oral steroids and beta2-agonists for a short time before study start must be excluded.

Clinical Studies Acute Episodes: Aims of mucoactive therapy in acute episodes of bronchitis include the following : ease of expectoration ; decrease in volume of sputum ; decrease in cough (frequency and severity) ; short-

ened duration of the acute episode; and reduction in concomitant medications (eg, antibiotics) . Therefore , in clinical trials, the following primary end point(s) should be pursued: (1) ease of expectoration; (2) cough frequency / severity; and (3) shortened duration of acute episode, more relevant for inpatients than for outpatients. The following secondary end points may be considered: (1) sputum volume; (2) shorter duration of episode for outpatients; (3) patient's global assessment; (4) physician's global assessment; (5) reduction in concomitant medications; (6) dyspnea ; and (7) pulmonary function . Evaluations should be recorded in diary cards according to standardized and validated methods and scales, whenever available, for example : ease of expectoration;7•8 dyspnea using visual analog scale, Borg, Sadoul, or Cotes scales;9 shortened duration of acute episodes by a quoted number of days;10 and cough by frequency , intensity, and efficiency.11 Frequency and timing of measurements should take into account the following: variable to be measured; chronobiological variations; mechanism of action of the drug; kinetic and pharmacodynamic profile; route of administration; and ethical considerations. A rational justification of frequency and timing should be provided for the proposed evaluation schedules. Symptoms and signs should be recorded on a daily basis, ensuring that morning and night symptoms are properly reported , as well as concomitant medication. The hospital visits will include at least a complete initial and final assessment. In this acute condition, a study duration of at least 2 weeks is suggested, according to the characteristics of the drug under investigation. Long-term Treatment: In principle, all the recommendations relevant to the acute episodes also apply to chronic treatment. In chronic treatment , two therapeutic objectives may also be considered : (a) symptomatic relief; and (b) modification of the natural history of disease. Symptomatic relief- Therapeutic aims include improvement of symptoms such as cough (frequency / severity) and difficulty in expectoration. In clinical trials, the following primary end point( s) should be pursued: (1) cough frequency and severity; (2) ease of expectoration; (3) chest discomfort; (4) dyspnea; (5) patient's global assessment; and (6) physician's global assessment. Secondary end points for symptomatic relief should take into account: (1) pulmonary function parameters; and (2) quality of life and economic factors. Measurements of signs and symptoms should be recorded daily on diary cards using validated score CHEST / 106 / 5 / NOVEMBER, 1994

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systems. Diary cards should be designed to allow reporting of day and night symptom scores; hospital visits should occur at the start of the study and at least at monthly intervals until completion . Treatment should last at least 3 months. A run-in period is recommended in order to ensure adequate training of patients in filling-in diary cards and to enable the investigator to define a baseline for an appropriate categorization of patients prior to randomization. Modification of natural history of disease- The therapeutic aim is to influence the natural course of the disease, in particular, the incidence of acute exacerbations. In clinical trials, the following primary end points should be pursued: (1) incidence of acute exacerbations; (2) morbidity evaluated by frequency and duration of acute exacerbation; and (3) concomitant medication (eg, antibiotics and bronchodilators). Secondary end points include: (1) cough frequency , severity, and efficiency; (2) ease of expectoration; (3) chest discomfort; (4) dyspnea; (5) quality of life; (6) economic factors ; (7) patient's global assessment; (8) physician's global assessment; (9) pulmonary function parameters; (10) exercise pulmonary function ; (ll) blood gases; (12) biochemical or other surrogate markers; and (13) sleep dysfunction and nocturnal oxygen saturation. Measurements are based on the number of acute exacerbations. Hospital visits should be performed at a maximum of 3-month intervals, depending on the duration of the study which should last at least 6 months. Pulmonary function should be assessed by lung volumes, spirometry, exercise studies, ventilation perfusion isotope studies at 6-month intervals according to the standardization of tests of the American Thoracic Society 4 and of the European Community for Coal and Steel. 5 A run-in period is essential in order to establish baseline data and to familiarize the patient with the study procedure.

Setting and Observations Due to the characteristics of the diseases, studies are usually performed in outpatients. The range of intrasubject variability for defined parameters such as rheology, should be identified before study start. It is essential that instrumentation and equipment used in different studies produce comparable results. Whenever possible, conversion tables should be provided. This will permit comparison of results and meta -analysis. Patients should be properly instructed in the recording of observations following descriptive standardized scales of efficacy parameters. Patient's compliance to study procedures and to the study treatment should be ascertained and demonstrated. 1536

STATISTICAL ISSUES

Methods of Assigning Patients to Treatment Scientifically sound study designs require unbiased assignment of patients to treatment regimens. Prestudy randomization, preferably centralized for multicenter studies, should be planned. Stratification of subgroups should be taken into account, as well as blocking procedures for multicenter studies.

Removal of Patients From Study or Analysis Criteria for removal of patients should be prospectively defined and reported in the final report or publication. Criteria for entrance into statistical evaluation should be given. Statistical and Analytical Plans The sample size should be defined prestudy, preferably in terms of power to detect a difference in the primary variable or end point. If practical limitations exist, they should be stated. Large studies require multicenter trials which present obvious advantages but introduce an extra source of variation, ie, variation between centers which should be taken into account when analyzing data. The statistical analytical plan depends upon the trial design and should be based on intention-to-treat; it should be the simplest possible and supported by relevant data. Known confounding factors should be dealt with the appropriate statistical methods (covariate and interaction analysis); suspected confounding factors should be taken into account. If there is more than one primary end point (multiple end points), or if there are multiple treatment groups or subsets of patients being examined, statistical analysis should take these into account. The role of concomitant therapy should be properly evaluated. In case subgroup analysis was not decided a priori, results therefrom are to be considered exploratory and not confirmatory .

Demographic and Baseline Features The above should be clearly defined, and variables used to assess disease severity at baseline should be properly recorded. If the study population shows nonhomogeneous characteristics, stratification should be considered. QUALITY OF LIFE

Quality of life (QoL) definition and measurement have become major dependent variables in clinical trials, particularly those concerning chronic progressive diseases such as COPD where effective interventions are difficult to quantify in terms of outcomes. While some measures of QoL are derived from general health questionnaires, it is desirable that trials include measures from disease-specific QoL

Clinical Trial Guidelines of Mucoactive Drugs in Chronic Bronchitis and COPD (Tabusso et alj

instruments. Such measures must be reliable, sensitive, and internationally valid . To ensure scientific credibility in multinational trials with mucoactive drugs, QoL questionnaires or procedures not employing questionnaires have to overcome problems of cross-culture translation equivalence and intergroup differences. Equating items for variations in cultural perceptions of meaning and value presents the major psychometric challenge. Work in related areas, such as asthma, has demonstrated that problems of comparison in the UK and Italy have been resolved satisfactorily.l 2 When a QoL measure is a dependent variable that is assumed to be subject to influence by a treatment, for example, a drug regimen that is independently varied, decisions about the size of sample necessary to reveal a significant treatment effect may have to be made. The following attributes of QoL are relevant and should be available from the literature that describes the QoL instrumentation. Apart from subscale means and standard deviations, the most important aspect of a valid scale is its reliability. In order to place individuals accurately on a scale, internal consistencies (coefficient alpha) and testretest reliabilities should be greater than .90. For group comparisons, reliabilities of .85 or more are adequate. Finally, sample sizes must take into account corrections for multiple scale comparisons when the same subjects are being used to test the significance of treatment variations on more than one outcome variable. One should, in such comparisons, have regard to effect size, as well as significant values. PHARMACOECONOMICS

Pharmacoeconomics is increasingly becoming one of the factors affecting regulatory decisions, which can be influenced by cost-containment policies. It is therefore being addressed more frequently in clinical trials. This aspect is particularly relevant when incapacitating diseases are involved, such as CB and COPD. Variables found in the literature on mucoactive drugs which are relevant to pharmacoeconomic perspectives are the following: number of acute episodes; number of hospitalizations and reduction in hospital days because of acute episodes; days of illness per year due to acute episodes of bronchitis; lost working days; and reduction in antibiotic consumption (days of antibiotic therapy) during exacerbations. To introduce pharmacoeconomic factors into a clinical trial on mucoactive drugs, the following three components of economic analysis should be considered: (1) establishing effectiveness; (2) estimating QoL or utility; and (3) measuring direct, indirect, and

intangible costs. One discrete clinical outcome for mucoactive drugs is clinical effectiveness, specified as the number of exacerbations saved. This outcome becomes the denominator of the cost-effectiveness analysis. The marginal cost of using mucoactive drugs instead of placebo to gain a reduction in exacerbations should be calculated. Cost-utility analysis, requiring nonmonetary outcome measures such as quality adjusted life years or utilities, needs the evaluation of QoL as indicator. As to cost-benefit analysis requiring expression of therapy outcomes in monetary terms, the only parameter representing benefit appears to be that related to saving on costs, ie, cost correlated with working days gained, with hospital days saved, and with other medical therapies being avoided (eg, antibiotics, bronchodilators). Task group on mucoactive drugs: Stefano Capri, Milan, Italy; Giuseppe Gallus, Milan, Italy; Carlo Grassi, Pavia, Italy; Gerard ]. Huchon , Boulogne, France; Sidney H. Irvine, Plymouth, England; Maria Teresa Lopez-Vidriero, lngelheim Am Rhein, Germany; Maurizio Luisetti, Pavia, Italy; Giuseppe Lungarella, Siena, Italy; Christopher Marriott, London, England; Jean Marsac, Paris, France; Heinrich Matthys, Freiburg, Germany; Stephan I. Rennard, Omaha, Nebraska (USA); Giuliana Tabusso, Milan, Italy; ]osep Tor~ent, Barcelona, Spain. REFERENCES

1 American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987; 136:225-44 2 Medical Research Council. Definition and classification of chronic bronchitis for clinical and epidemiological purposes. Lancet 1965; 1:775-81 3 Braga PC, Allegra L. Methods in bronchial mucology. New York: Raven Press, 1988 4 American Thoracic Society,. Standardization of spirometry: 1987 update. Am Rev Respir Dis 1987; 136:1285-98 5 Report Working Party. Standardization of lung function tests: standardized lung function testing. Bull Eur Physiopath Resp 1983; 19(suppl5):1-92 6 Rasmussen JB, Glennow C. Reduction in days of illness after long-term treatment with N-acetylcisteine controlled release tablets in patients with chronic bronchitis. Eur Respir J 1988; 1:351-55 7 Petty T. The national mucolytic study: results of a randomized, double-blind, placebo-controlled study of iodinated glycerol in chronic obstructive bronchitis. Chest 1990; 97:75-83 8 Boman G, Backer U, Larsson S, Melander B, Wahlander L. Oral acetylcysteine reduces rate in chronic bronchitis: report of a trial organized by the Swedish Society for Pulmonary Diseases. Eur J Respir Dis 1983; 64:405-15 9 Stark RD. Dyspnoea: assessment and pharmacological manipulation. Eur Respir J 1988; 1:280-87 10 British Thoracic Society Research Committee. Oral N-acetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airways obstruction. Thorax 1985; 40:832-35 11 Irwin RS, Curley FJ, Pratter MR. The effects of drugs on cough. Eur J Respir Dis 1987; 7l(suppl153):173-81 12 Irvine SH, Wright DE, Hyland M, Recchia C, Dal Negro R, De Carli G. Quality of life and asthma: questionnaire: measurements and methods with Italian patients. Ita! J Chest Dis 1992; 47:273-77 CHEST / 106/5 / NOVEMBER, 1994

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