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Executive Summary

Clinical testing of drugs for the treatment of Alzheimer's dementia must demonstrate efficacy on both the Alzheimer's Disease Assessment Scale (ADAS-COG) and some version of the Clinical Interview-Based Impression of Change (CIBIC), FDA's Peripheral & Central Nervous System Drugs Advisory Committee concluded on Feb. 14. The advisory committee met on Feb. 13 and 14 to review draft guidelines for the clinical assessment of antidementia drugs; the guidelines have been in circulation since November 1990. On the first day of the meeting, the committee heard comments on the guidelines from experts in industry and academia, all of whom urged the committee to be flexible in defining which instruments would be acceptable to measure the meaningfulness of any changes found on the cognitive performance-based ADAS-COG ("The Pink Sheet" Feb. 17, p. 13). While giving top billing to the CIBIC assessment, the committee responded to the experts' calls for flexibility by leaving the door open for companies sponsoring antidementia drug trials to employ a variety of instruments to measure a drug's clinical utility. At the meeting's conclusion, FDA Office of Drug Evaluation I Director Robert Temple, MD, said: "Ordinarily, the two choices one should use as a second instrument [in evaluating the utility of an Alzheimer's dementia drug in clinical trials in addition to the ADAS] are the CIBIC and the CIBIC-plus," a hybrid devised by the committee. Temple added, however, that "a strong case could be made for" other assessments as well. Unlike an ordinary CIBIC, the CIBIC-plus allows the clinician assessing the patient to interview the patient's caregiver. Underlining the latitude provided by the committee's decision, Committee Chairman Leon Thal, MD, Veterans Affair's Medical Center, San Diego, said the other studies that would be accepted as evaluations of clinical utility include the Clinical Dementia Rating and Global Deterioration scales. Other acceptable measures could include the Activities of Daily Living scale (ADL) or Instrumental Activities of Daily Living scale (IADL), Thal suggested. "All of the above would be acceptable and it's up to the sponsor which one to gamble on," provided that the choice is "specified in advance." The committee's endorsement of both the CIBIC and CIBIC-plus appear to be a compromise between Division of Neuropharmacological Drug Products Director Paul Leber, MD, and the majority of committee members, who did not seem to share Leber's doubts about the feasability of combining caregiver assessments with the CIBIC. The CIBIC, which was created by Leber's FDA division, is an attempt to standardize the clinician's global assessment of a patient by specifying the sources of information clinicians should use to evaluate dementia patients. Leber said the CIBIC was created "when we found out that there was tremendous variability" in "the way global evaluations were being done." The division's concerns and an outline of the CIBIC are contained in a Nov. 18 letter sent by Leber to companies interested in antidementia drugs (see excerpts p. 15). The letter also requires sponsors of trials that are completed or well under way to report who performed the clinical global assessment and what information was available to that person. For clinical trials that have not yet begun or recently began, "all sponsors are asked to include the CIBIC in every clinical investigation." Leber cautioned at the advisory committee meeting that the agency still may not consider the CIBIC or CIBIC-plus and ADAS-COG sufficient to measure clinical utility. He said that secondary tests might also be required, noting: "That doesn't mean that we would not also want you to do the other instruments as well." The expense of performing such secondary tests "may be the price that we think is necessary to understand what's going on in a very formative stage," Leber added. The CIBIC, as defined by the Leber letter, "is intended to be based entirely upon information collected during an interview with the patient." The letter explains: "Prior to the initial baseline interview, the clinician who is to perform the CIBIC should familiarize him or herself with all sources of information available about the patient, including but not limited to, the medical history, the results of physical examinations, laboratory and special tests, as well as reports of interviews with significant others, family, caregivers, and results of psychometric tests." After the baseline interview, however, "the clinician providing the CIBIC assessment may not consult these or any other sources." The clinician performing the CIBIC rates the subject on a seven-point scale for improvement or worsening of memory, praxis, orientation and other mental functions, with four meaning "no change," five to seven denoting various degrees of worsening, and three to one corresponding to different degrees of improvement. Referring at the meeting to the insensitivity of the CIBIC seven- point scale, Leber said: "If you got movement on it, you would know you had a large drug effect." He added, "if someone says they hit one over the left field fence wall, you'd like to know if it was in a Little League park or whether it's Yankee Stadium and [the CIBIC] is sort of the Yankee Stadium of all tests." Leber said he objected to the same clinician performing the CIBIC and interviewing a caregiver because such a composite test could "increase the chances for" breaking the double-blinds designed into the trial. Temple supported Leber, saying that "if you really want to know if someone can make a diagnosis, you send them in there blind and then go back." The rest of the committee did not appear to share Leber's and Temple's concern about compromising the trial's double-blind design. Herbert Weingartner, PhD, National Institute on Aging, observed that "most of us would agree that the data that you would get from [interviewing] the informant complements the data you would get from the patient [interview]" and should be therefore be done by the same person. Committee guest David Drachman, MD, University of Massachusetts, said: "You have to allow the clinician to take a history and the only available history here is from the family members." Without such information the clinician "is literally functioning like a technician without most of the clinical skills we usually regard as being of value." Based on this, Drachman referred to the isolated CIBIC as "a veterinary effort." Weingartner called the potential of blind breaking "a methodological issue" that had to be addressed during trial design. The committee also expressed doubts about using daily living assessments alone as the second instrument to evaluate Alzheimer's drugs. Committee guest Allen Raskin, PhD, Institute of Psychiatry and Human Behavior, Baltimore, said, "I do have a problem in using [ADL] as a primary part of a scale" because "there are racial differences and gender differences" that reduce the scale's reliability. He also pointed out that "the IADL is not intended for use with elderly patients." Committee Chairman Thal acknowledged that current tests for assessing daily living changes "do not have the appropriate psychometric properties and have never been validated in Alzheimer's patients." Leber noted that instruments specific to Alzheimer's study "are being worked on." While the panel acknowledged the importance of assessments of patients daily living skills, it also found that the clinician has to determine the reliability of information given by caregivers. Drachman observed that "we know that family members either over or under report deficits among their relatives" and "that's exactly what we are about as clinicians -- we serve as both a funnel and a filter [for caregiver information]." At the end of the meeting, Leber still advocated a pure CIBIC, saying, "I am still stuck with a problem that I can't get past... there really is no independent measure that I know of in the possession of the physician to know whether or not" a caregiver is reliable. "I know they believe they have that capacity. Talk about things that are unvalidated and unknown, how good is the physician at doing this?" Weingartner responded: "Being able to make a judgement about a caretaker -- this is something that a clinician should be able to do." On his remaining concerns about possible unblinding if clinicians performing the CIBIC also perform caregiver assessments, Leber stated: "I guess we'll just have to be guided by [the committee's] advice." Concerning trial length, the panel concluded that a minimum of three months would be required to demonstrate efficacy, but did not rule out shorter or longer trials in the future, depending on the duration of a drug's effect and whether it was meant to treat only symptoms or to slow the progression of Alzheimer's. Thal said that a three-month minimum was needed because "looking at the current drugs that are being developed, we are talking about drugs that improve patients very little." Richard Mohs, PhD, Mt. Sinai School of Medicine, pointed out that "even if you could show an effect in six weeks, you'd want to know about three months" because "it maximizes your case." Referring to the panel's broad recommendation, Leber admitted that "nobody yet knows what to do" because the treatment of Alzheimer's is "in a formative stage." He said, "I don't want to see premature closure" on which instruments drug sponsors have to use. He noted that "many people are working on developing different instruments" so that "nothing is written in stone." He also admitted that "a lot of what we're asking regulated industry to do that looks excessive is a reflection of our uncertainty."

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