Scope and Design of the Clinical Trial of the Nucleus Multichannel Cochlear Implant in Children Dianne J. Mecklenburg, PhD; Marilyn E. Demorest, PhD; Steven J. Staller, PhD Cavale Consulting, Boulder, Colorado (0. J. M.); Department of Psychology, University of Maryland Baltimore County, Baltimore, Maryland (M. E. D.) and Cochlear Corporation, Englewood, Colorado (S. J. S.)

THE UNITED STATES Food and Drug Administration (FDA) is charged by law with determining whether medical devices or drugs that potentially pose a significant risk have been scientifically scrutinized to determine their safety and effectiveness in the target population before being approved for marketing and general distribution. Devices implanted within the body are among the most highly regulated medical devices (Class 3)* and, as such, must undergo multicenter clinical trials. The data gathered during these trials are reported to the FDA in the form of a premarket approval application (PMA), which is reviewed by an advisory panel of experts in related fields. This advisory panel recommends whether the FDA should approve general marketing of the medical device based on the safety and effectiveness data provided. Once approved, FDA continues to monitor the manufacture and use of the device to ensure its continued safety. As a Class 3 implantable device, the cochlear implant falls under F D A jurisdiction. As of 1985, the single-channel 3M/House and the 22-channel Nucleus implants had been approved for use in postlinguistic adults. The research and development of the 22-channel implant originated in the Department of Otolaryngology at the University of Melbourne (Melbourne, Australia) under the direction of Professor Graeme Clark (see Patrick & Clark, Chap. 1). Since its inception, the primary focus of the developmental program for the 22-channel device was to provide benefit for profoundly deaf children. Initial experience was gained through the ‘Class 3 devices under FDA regulations are considered to pose significant risk and are purported to be for use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health. All implantable devices are considered class 3 and are subject to premarket approval regulations.

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implantation of a teenager in Australia in January of 1985. An adolescent was chosen as the first “pediatric” candidate because older children could be more reliably tested, communicate their experiences more effectively, and accommodate the size of the internal portion of the implant, which at that time was too large for young children. In addition, the implantation of young deaf children was controversial. After 1 yr of careful observation and investigation in Australia, an initial protocol for adolescents ( 10- 17-yr-olds)was developed and submitted to the FDA in the United States. An investigational device exemption (IDE) was granted, allowing the initiation of clinical trials in the United States shortly after FDA approval of the implant for adults (October, 1985). At the beginning of 1986, 20 investigational sites across the U.S. were recruited, and in February 1986, the first teenagers in the United States were implanted with the multichannel device. A complete chronology of the implantation of children is listed in Table 1. A smaller version (Mini-22) of the standard Nucleus 22-channel cochlear implant became available in September 1985 (see Patrick & Clark, Chap. I), allowing the implantation of younger children. In addition to its smaller size, the Mini-22 incorporated an internal magnet that eliminated the cumbersome headset which was inappropriate for small children. Professor Clark and his associates at the University of Melbourne implanted the device in the first young child (5.4yr of age) on March 15, 1986. Development of an investigational protocol for younger children required input from a variety of sources. The experience and recommendations of colleagues at the University of Melbourne were taken into consideration (Niehuys, Musgrave, Busby, Blarney, Nott, Tong, Dowell, Brown, & Clark, 1987),along with advice and feedback from implant centers in the United States. Input also was sought from a wide spectrum of researchers and clinicians. Cochlear Corporation sponsored a 2 day conference on cochlear implants in children in the winter of 1986. The participants included over 40 experts from a variety of specialty areas within speech, language, hearing, psychology, education, medicine, statistics, and engineering. Their deliberations

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0196/0202/91/1204-001OS$03.00/0 * EARAND HEARING Copyright 0 1991 by Williams & Wilkins Printed in the U.S.A.

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Table 1. Chronology of the patients implanted.

Nucleus Cochlear ImDlant Device First adults implanted' First teenager implanted' Final FDA approval: adults" Investigational device exemption (10-17 yr olds) accepted" Cochlear's Durango conference First US. teenager implanted** First young child implanted' Investigational device exemption (2-9 yr olds) accepted" First young child implanted in US." Final FDA approval: all children**

9/82 1/85 10185 11/85 2/86 2/86 3/86 11/86 2/87 6/90

University of Melbourne. ** United States.

and conclusions (Mecklenburg, 1986) were influential in the final design of the FDA clinical trial protocol. The remainder of this chapter discusses subject selection, the chronology and content of evaluation and testing, the tests and materials administered, and the data analytic methods used in assessing safety and performance of the Nucleus multichannel cochlear implant system in children. SELECTION OF SUBJECTS

To be included in the FDA clinical trial, subjects had to meet several selection criteria. Subjects were selected between the ages of 2 and 17 yr with profound deafness bilaterally. The younger limit of 2 yr was chosen to allow time for sufficient skull growth (Mangham & Luxford, 1986) and to have reasonable expectations that reliable audiologic evaluations could be performed. Subjects were evaluated to ensure that little or no benefit from alternative sensory aids was obtained. To satisfy this criterion, only children who showed no ability to recognize open set speech or identify segmental aspects of speech were included. Children were required to be enrolled in an educational program that included an auditory-oral component. Medical contraindications for intracochlear electrode placement or inappropriate expectations on the part of the family or the child were considered to be exclusionary criteria. Adolescents were encouraged to actively participate in the decision-making process and a psychological consult was included in the evaluation protocol to determine their desires and expectations before undergoing the surgical procedure. Candidates were further required to have received consistent exposure to auditory stimulation and to possess a desire to participate in the hearing environment. Also, for children aged 2 through 9 yr, selection criteria included a willingness of the child and the family to participate in pre- and postoperative training and assessment procedures. Initially, children with single-channel implants that had failed were considered appropriate candidates. Ear and Hearing, Vol. 12, No. 4, Supplement, 1991

These children were known to have received auditory stimulation through the implant and had undergone rehabilitation directed toward facilitating the best use of their listening skills (Mecklenburg, 1987b). To be more conservative, this provision was later dropped from the FDA selection criteria for young children. TEST PROTOCOL

Chronology The clinical trial was designed to compare each child's performance under a variety of experimental conditions over several data collection periods (Mecklenburg, 1987a). A six-stage program was formulated. Its essential features are listed in Table 2. A unique aspect of the first stage of the program was an 8 week preoperative training period used to assess auditory perceptual performance and speech production in each child before implantation. The training period ensured that each child was appropriately fitted with sensory aids and allowed assessment of the effects of training independent of the implant. Evaluation and training of skills necessary for programming the speech processor after implantation were also performed during this period.

Skills Tested The children's performance was assessed in several different areas, some of which demonstrated direct benefits of implantation (primary) and others that were indirectly related to the sensory input provided by the implant. Primary benefits focused on demonstrable changes in performance that are related to the perception of segmental and suprasegmental speech stimuli. They are directly dependent on the information provided by the cochlear implant (See Table 3). Secondary benefits are those that are obviously influenced by many factors in addition to the sensory input provided by the implant. Because of the large number of uncontrolled intervening factors (such as cognition, language competence, experience, communication mode), most secondary benefits cannot easily be attributed to any single cause. Moreover, secondary benefits probably depend on the cumulative effects of auditory stimulation interacting with other factors (such as training) over long periods of time. Because of the difficulty of assessing secondary benefits within the Table 2. Stages of the FDA clinical trials through which each child proceeded during the investigation.

Stage

Procedure

I

Initial testing, &week training period, post-training evaluation Cochlear implant evaluations Surgery and recuperation Fitting the speech processor Return to normal environment post-implanttraining Postoperativeassessment

II 111 IV

V VI

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Table 3. Range of benefits provided by multichannel implants in children. Primary benefits represent perceptual skills directly affected by implantation. Secondary benefits represent skills that are indirectly influenced by improvements in perceptual abilities. They are mediated by factors in addition to cochlear implantation (habilitation,cognition).

Benefits of Pediatric Cochler Implantation Primary Detection of sound at comfortable loudness levels Improved identification of the prosodic elements of speech Improved speech perception for closed- and open-set speech stimuli Enhanced lipreading skills

Secondary Improved voice quality Improved speech production (accuracy) Increased phonological repertoire Improved single-wordreceptive vocabulary

scope of a single clinical trial, the study placed greater emphasis on primary benefits: detection of sound, identification of prosodic features of speech, speech perception (assessed with both closed- and open-set test materials), and enhancement of lipreading. Performance Comparisons The test protocol for each subject involved preimplant testing and training, and postimplant evaluations at 6 mo intervals. Preoperative auditory performance was either evaluated with a hearing aid, a vibrotactile device, or a combination of the two, whichever proved most useful. This was defined as the child’s best aided condition and served as the basis for all preoperative testing. Postoperatively, evaluations were conducted with the cochlear implant alone, even though some children continued to wear a hearing aid in the contralateral ear. This methodology provided a strict prepostoperative comparison, because effectiveness of implantation could only be shown if statistically significant improvements were demonstrated by the child in the implanted (typically worse preoperative) ear compared to the best aided preoperative condition described above. Lipreading and some speech production tests were administered in a “device on” and “device o f f paradigm. These postoperative tests permitted evaluation of instantaneous changes in performance that occurred when children received adjunctive sound (lipreading) and were able to monitor their own voices (speech production). Although the latter was initially conceptualized as a secondary benefit of stimulation (see Table 3), the data reported by Tobey and Hasenstab in Chapter 6 suggest that in some cases the benefit may be rather immediate and direct.

deafened adults or to evaluate less profoundly hearingimpaired children. To accommodate the wide range of ages and linguistic abilities of deaf children, a large number of potential test instruments were assembled for the protocol. Many tests had not been standardized for children and there were few published psychometric studies to support their reliability and validity in this population. Nevertheless, the protocol represented the state of the art for assessing the skills of interest. Clearly, at the outset of the clinical trial, it was not known which tests would prove to be most useful. Once the clinical trial was underway, however, a hierarchy of test procedures evolved so that more appropriate testing could be applied to each child (Staller, 1990), resulting in more consistency across children in the actual tests administered. The test battery currently in use is discussed in detail by Beiter, Staller, & Dowel1 (Chap. 4). Categorization of Benefits, Tasks, and Materials The variety of tests and materials used to assess performance changes were categorized according to the complexity of the stimuli and the perceptual skills assessed (Erber, 1982). Figure 1 provides an overview of the categorization scheme for assessing primary benefits. Four experimental tasks were performed in an auditory only condition: detection, discrimination between two alternatives, closed-set identification, and open-set recognition. These four tasks were combined with four categories of materials. The first category consisted of nonspeech stimuli, suprasegmental aspects of speech, and environmental sounds. The remaining three categories contained stimuli including phonemes, words, and sentences, respectively. For the lipreading tasks, materials were administered under conditions of lipreading without the device and lipreading with sound. The FDA protocol design required at least one test ASSESSMENT OF PRIMARY BENEFIT TEST MATFR!ALS

PROSODIC/ ENVIRON. SOUNDS PHONEME

WORD

SENTENCE

BENFFIT 1. Detection

2. Discrimination

3. Identification 4. Recognition

5. Lipreading

EVALUATION TOOLS

Selection of Tests and Materials Most of the tests and materials available for this study had been designed, originally, to evaluate profoundly 12s

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Enhancement Figure 1. Categorization of test materials used to evaluate primary benefits provided by implantation. The clinical protocol required at least one test within each cell to be administered. Tests were either inappropriate or unavailable for the cross-hatched cells.

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to be attempted within each cell category. This test plan was designed to sample perceptual skills broadly and over a wide range of difficulty. As noted above, at the outset of the clinical trial it was not known which specific tests and materials would be most appropriate. Therefore, investigational teams were instructed to select measures for which the child had the prerequisite cognitive, linguistic, and perceptual abilities. One outcome of this “freedom of choice” was that not all children received the same tests or the same number of tests. There are three reasons why, in principle, these differences in the specific tests administered to each child should have minimal impact on the interpretation of the data: first, all skill-referenced measures assessed a common perceptual ability; second, statistical comparisons for a given child were performed between two scores on the same test; and third, the major hypotheses concerning benefit were tested using a single-subject design. For secondary benefits (i.e., those that could not be directly attributed to the cochlear implant alone), the same approach was taken. A number of tests were chosen, a matrix developed, and a protocol designed to account for the measurement of speech production and changes in language level. Because language competence is known to be confounded with many other variables, measurements were used only to estimate whether children’s language abilities were being affected adversely by cochlear implantation. However, imitative and spontaneous speech production were used as both a direct and an indirect method of measuring reception. Thus, changes in the characteristics of speech were evaluated for both clinical and statistical improvement. Finally, subjective evaluations of benefit were systematically collected through diary reports from children and parents, clinician reports, physician reports, and forms filled out by the children’s teachers. These data were used to supplement findings from the objective measures and provided a more complete picture of how the child was interacting on a day to day basis. RESEARCH STRATEGY AND DATA ANALYSIS

The Problem of Heterogeneity It is clear that the target population for cochlear implants is heterogeneous and that variability in outcomes is to be expected. Although clinical experience has demonstrated that this is certainly true for adults, it is an even more important fact when the target population is children of different ages with very different cognitive skills and initial levels of performance. It was essential, therefore, that the research design explicitly recognize this variability, and acknowledge that each subject represented a unique combination of sensory, cognitive, linguistic, educational, demographic, and other variables. Given these considerations, the strategy selected for design and analysis was to consider the multiple measurements made on each subject over time and across Ear and Hearing, Vol. 12, No. 4, Supplement, 1991

experimental conditions to be a single-subject experiment (case study). This produced a multivariate, singlesubject, repeated measures design. Because of the structured test protocol, it was possible to perform statistical analyses of the data for each subject individually and to evaluate benefit in each perceptual area for each child. The primary strength of this type of design is that it leads to statistically supported conclusions for each individual subject. Data Analytic Models The multistage protocol and the quantitative nature of the performance measures permitted three types of comparisons to be made: (1) performance on a particular measure compared with chance-level performance; (2) best preimplant performance compared with performance 12 mo postimplant; and 3 ) performance in a device off condition compared with performance in a device on condition. In the latter two comparisons, the subject served as his or her own control. For the first comparison, it was necessary to specify chance performance on each measure. For closed-set tests this was generally straightforward, with chance performance equal to the number of items in the test divided by the number of response options per item. For open-set tests, the chance score was set at zero. A binomial test was then used to determine whether the obtained score significantly exceeded the chance score (i.e., a one-tailed statistical model was used). For comparisons 2 and 3 , the binomial model, as presented by Thornton and RaEn (1978), was used to test for significant differences either pre- versus postoperatively or in aided versus unaided conditions. Twotailed statistical tests were performed, even for those analyses where one-tailed tests could have been justified. When more than two scores were compared, Chisquare tests derived from loglinear models (Bishop, Fienberg, & Holland, 1975) were used. Aggregation of Results Across Tests Extensive data were gathered on each child, which permitted a detailed and comprehensive evaluation of the nature and degree of benefit for each subject. In context of the premarket approval application to the FDA, an extensive report was developed for each child as a single experiment with comprehensive preoperative and postoperative data. The clinical data sections of that application were extensively detailed, occupying 4, 2’12 in. volumes. In order to gauge the pattern of results for a given child and the generality of the findings across children, an aggregation strategy had to be developed. First, for each cell in Figure 1, outcomes of the statistical analyses for a given child were examined across the different test measures. The chapters by Staller, Dowell, Beiter, and Brimacombe (Chap. 5 ) and Tobey and Hasenstab (Chap. 6) in this monograph present individual preoperative and postoperative data on selected measures that were most widely adminisNucleus Cochlear Implant in Children

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tered and that represented competence in a particular skill area. In addition, the more customary method of summarizing results for specific tests, by examining the performance of the entire group of subjects tested, is also presented. Although these group data facilitate comparison of the present results with normative data and with data from other clinical populations and intervention strategies, they do not allow characterization of the entire experimental sample of implanted children because no single test was administered to all subjects. A final aggregation strategy was adopted based on the model developed by Geers and Moog (1987) at the Central Institute for the Deaf. This aggregation method, described in detail by Staller et a1 (Chap. 5 ) , assigns children to one of five hierarchical speech perception categories ranging from simple detection (category 1) to open-set speech recognition (category 5 ) according to skill-referenced criteria. Using this method, inferences could be drawn regarding the perceptual capabilities preoperatively and postoperatively, of all children included in the study, irrespective of the particular test battery administered. Comparisons of pre- and postoperative test scores, comparisons of aided and unaided performance, and comparisons over time postimplant, are based on ttests for related measures or repeated measures analysis of variance. In order to gain additional insights, the group data were also used in exploratory multiple regression analyses of the correlates of performance outcome. SAFETY

The safety of the 22-channel implant was addressed by carefully monitoring surgical and postsurgical complications throughout the study on all children implanted worldwide. Findings from English speaking and foreign speaking subjects were pooled for evaluation of implant safety. This was possible because a11 centers worldwide used the same device and followed a common protocol, including criteria used to select subjects and sign patient consent forms. To investigate whether the presence of otitis media in implanted children might increase the possibility of secondary infections in the middle and inner ear, a questionnaire was sent to all U.S. clinical trial sites. The survey was analyzed and was included as supportive evidence for the safety of the device (see Clark, Cohen, & Shepherd, Chap. 3). All safety data, including the total number of electrodes inserted compared to any electrode failures, internal device failures, flap infections, surgical misplacement of the electrode, and so forth, were cumulatively tracked on a central database. Complications were di-

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vided into three categories: surgical incidents, adverse reactions, and device-related problems. The primary focus in an analysis of safety is the probability that an individual will experience a particular type of complication or adverse reaction. The basic datum for estimating this probability is the proportion of the study sample experiencing that particular reaction. However, because the estimate is subject to sampling error, it is customary to construct a 95% confidence interval around the sample value. The upper limit of the confidence interval is typically reported to the FDA because it provides a conservative estimate of the true probability of that reaction in the target population. It is unlikely that the true probability is higher than this value. SUMMARY

Although much has been learned in the 5 yr since the first child received a multichannel cochlear implant, we remain at the very early stages of this endeavor. The current evaluation procedures and performance data detailed in subsequent chapters represent the continuation of the efforts described above. REFERENCES Bishop YM, Fienberg SE, and Holland PW. Discrete multivariate analysis. New York: Wiley, 1975. Erber NP. Auditory Training. Washington DC: Alexander Graham Bell Association, 1982. Geers AE and Moog JS. Predicting spoken language acquisition of profoundly hearing-impaired children. J Speech Hear Disord 198752~84-94. Mangham CA and Luxford WM. Cochlear prosthesis surgery in children. In: Mecklenburg DJ, Ed. Cochlear implants in children: Proceedings from a multidisciplinary colloquium. Semin Hear 1986;7(4):361-369. Mecklenburg DJ, Ed. Cochlear implants in children: Proceedings from a multidisciplinary colloquium. Semin Hear 1986;7(4):1-439. Mecklenburg DJ. Plane fur die Versorgung von tauben Kindern. In Lehnhardt E and Hirshorn MS, Eds. Cochlear Implants, Eine Hilfe f i r beidseitig Taube. Berlin: Springer-Verlag, I987a: 172-1 76. Mecklenburg DJ. The Nucleus children’s program. Am J Otol 1987b;8(5):436-442. Niehuys TB, Musgrave GN, Busby PA, Blarney PJ, Nott P. Tong YC, Dowell RC, Brown LF, and Clark GM. Educational assessment and management of children with multichannel cochlear implant. Ann Otol Rhino1 Laryngol, 1987;96:l(Suppl 128):80-82. Staller S. Perceptual and production abilities in profoundly deaf children with multichannel cochlear implants. J Am Acad Audio1 1990;l: 1-3. Thornton AR and Rafin MJ. Speech discrimination modeled as a binomial variable. J Speech Hear Res 1978;21:507-5 18. Acknowledgment: The majority of this chapter was presented at the Ear, Nose and Throat advisory panel to the FDA, November 13, 1989, Washington, DC. Address reprint requests to Steven J. Staller, Cochlear Corp., 61 lnverness Dr. E. #200, Englewood, CO 80112.

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