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GUIDELINES FOLLOWED IN THE PROTECTION OF SUBJECTS The Nuremburg and Helsinki guidelines were regarded by the investigators and their supervisors as appropriate constraints in studies performed on volunteers, although this was not clearly arti- culated in official memoranda until the mid 1960~. The provision of accurate, informative explanations of what was planned and what might be expected was regarded as essential to the continuance of the pro- gram. Written consents, witnessed by medical staff members, were required from the outset and became more elaborate with time. How- ever, minutes of hearings conducted by the U.S. Senate Subcommittee on Health and Subcommittee on Administrative Practice and Procedure, September 10-12, 1975, stated that the consent information was inadequate by current standards. INVESTIGATORS When BZ studies were begun in 1960, the need for a psychiatrist with biologic training and interest was recognized and one was assigned to the program in January 1961. Physicians trained in internal medicine, anesthesiology, cardiology, surgery, dermatology, ophthalmology, neurology, and other specialities were assigned as the program proceeded. Many were research-oriented and have since gained excellent reputations in academic medicine at leading universities. SELECTION OF DOSES FOR ~ TESTS Subthreshold doses based on estimates from animal potency stu- dies were used in the first few subjects. For example, the earliest exposures to BZ, one of the anticho~ nergic test compounds, were at doses between 0.l and 0.5 ~g/kg, which was less than one-tenth the incapacitating dose (ID) ultimately established at approximately 5.5 ~g/kg. The intravenous route was preferred initially, but other routes of administration were also used. Inhalation studies were sometimes undertaken after a compound had been thoroughly studied by one of these parenteral routes. Oral and percutaneous studies were performed when effectiveness via these routes was of interest. As the program developed, it became customary to test agents at dose increments of 40 percent, once the approximate effects of the lower doses were known. Placebos were used in some studies, but the cost with respect to subject confinement time, staff workload, and delay in achieving estimates of potency made this impractical except in special casses ~ e . g., evaluation of antagonists ~ . Instead , low and high doses were assigned in a randomized manner by someone not involved in an experiment. Placebo responses were minimal. Signs of drug effects at all but the lowest doses were sigh ficant and made the value of placebo or "no treatment" inconsequential. -256-
RANGE OF DOSES Rarely did the intramuscular or intra~rer~ous doses exceed l. 5 times the incapacitating dose. Inhalation doses were higher, but potencies were lower by this route (usually about 60 percent of that by the intravenous or intramuscular route). Compared with doses de scribed in the scient if ic literature on atropine coma therapy i8-23 or Scopolamine therapy,\9 the BZ doses to which volunteers were exposed appear modest. As much as 20 times the IDso of atropine and 30-40 times the ID,o of scopolamine have been administered in the past by c~inicians--often to older and less robust patients. Many patients received multiple exposures of this magnitude over a period of days or weeks. These therapeutic procedures, reported several decades ago in refereed journals, actually stressed and advocated the benef its of such treatment, despite occasional deaths (most of which appear to have been caused by hyperthermia). SAFETY MARGIN The safety margin of a drug is defined as the ratio of the lethal dose (LD) to the effective dose (ED) . Sometimes, ratio of the LDso to EDEN is used, although a more Conservative approach favors the use of the ratio of LD, to EDgg ~ standard margin of safety) . In the case of incapacitating agents, much reliance is placed on extrapolation from animal experimentation, and estimation of the LD1 is generally unreliable. Many other extrapolation techniques have been used in manipu~a- tion of animal lethality data in an effort to generate a reasonable human estimate. By taking a conservative approach with data on deaths at low doses, one can derive estimates for man that are modest and in keeping with clinical judgement. Such methods depend on pro- cedures developed and applied in toxico] ogy. -257
APPENDIX A Part 2. Clinical Research Department, SOP No. 5, August 12, 1968 (Revised) VOLUNTEER SCREENING AND SELECTION The purpose of this SOP is to provide guidelines for the psycho- logical/paychiatric selection of volunteers. There are several standard forms used for this purpose and each will be discussed. I. Screening Data form (medical history). A "yes" answer on any item without a recommendation of a medical officer for acceptance will reject the individual. 2. When the GT score is available a very low score (below 90 or 80) will reject the individual. 3. HOPI. These are "rules of thumb." Lacking a scientific basis for choosing, these represent advice rather than dogma, but should be followed if possible. A. Clinical Scales (Hs, D, Hy, Pd. Mf, Pa, Sc, Ma and Si) I. Operas profile. Reject if any five of the above scales are over 65. 2. Mark profiles borderline and carefully examine family history for indication of psychological problems if- a. L and K both exceed F by at least 15 scale points. b. F exceeds both L and K by at least 15 scale points. 3. P&, Pa, Sc Pattern (psychoticism) a. Reject if any two of these three are among the two highest Scores on the clinical scales. b. If Pa or Sc is above SO, and mark as border- 1ine if either exceeds 70. c. Reject if Pa and Sc are both above 65 and are also both above Ha, D, and Hy. -258-
4. Pd. Mf, Ma Pattern (Sociopathic Deviate; "Acting Out") a. Reject if Pa and Ma are both above 65, and there is a history of "acting out." b. Re ject if Pa is above 70, and there is a history of "acting out." - c. Reject of Mf is above 80 in combination with P6, Pa, or Sc above 65. 5. Ha, D, Hy, Pt. Si Pattern (neuroticism) a. Reconsider overall picture, history, etc., if any four of these are above 70. b. Reconsider overall picture, history, etc., if any two of these are above 80. c. Reconsider overall picture, history, etc., if Pt is above 80. The most common exception to these rules is the active, ambi- tious, college graduate with Ed and Ma above 65, but no history of acting out. In all but the most extreme cases it is well to obtain corroborating evidence from the Family History. 4. Family arid Developmental History. The Family History (SMIJEA Form 6-85) contains information about a wide range of the potential volunteer's activities, as well as tapping various levels of consciousness. For routine screening certain items are useful. Troub1 e in school, with the civilian police, or Article 15~. A pattern of this sort is indicative of an "acting out" type of person. 2. Interviews with a psychiatrist for anything other than routing screening, e.g., peace corps selection, etc. 3. A history of fighting after heavy drinking, especially with a bad temper. 4. Blatant and diffuse expressions of hostility on the Picture Frustration Test pp 15-16. Other items: Blow rate of promotion, lack of clear cut goals, excessive depreciation of self value, and generally bizarre answers -25g-
on the Sentence Completion may be clues but must be interpreted to relation to other information available. The screening on the basis of the MMPI is usually done by the psychologist or psychiatrist. The Family Histories are read by the Medical Officers in Psychopharmacology with each officer reading his share. Durlug this phase of the screening only those histories that have survived the preceding steps are read. lthe purpose of this screening is to pick those volunteers chosen to come to Edgewood for any type of test. Af ter all this material has been read and the volunteers rated , a list is furnished the administrative office of about SO first choice names and SO alternates. These names are usually given to the administrative office by the tenth of the month which precedes the month they are to report to Edgewood. When the volunteers arrive at Edgewood they are interviewed by the officers in the Psychopharmacology Branch. At the time of the screening interview, on the basis of the interview, history, questionnaire (sentence completion and Picture Frustration tests) and MMPI scores a rating will be applied to each candidate to separate out the following groups and an entry will be made upon the Physical Examination sheet opposite the heading "Psychiatric" characterizing the candidates qualification for drug testing, as follows: Rating A B C D Qualification (on PE form) l OK for psychochemical testing Low-dose psychochemicals only No p~ychochemicals Equipment only The ratings are to be defined as follows: A. No apparent or overt paychologic problems and no tendency to somatize or act-out intra-paychic tension. Many assets, few liabi- lities. Flexible. Good ego strength. Age - appropriate maturity and responsibility. A clear sense of identity. Such conflicts as are evidenced are few in number, situational, and usually conscious. Normal MMPI and Family History. An exceptionally well adjusted candidate who impresses the interviewer by his flexibility and ease in handling anxiety and hostile or aggressive imputes should be rated A+. These men will be used for such psychochemical tests as are considered to be of greater than usual stress. -260-
/ B. well. . . . Adequate, flexible, good ego strength. Gets along fairly An appropriately mature and responsible person. History is good out may nave one or more negative items such as: a very minor offense for which an Article 15 is given or a civilian arrest for a minor, non-occurring matter (symptomatic of immaturity). Minor per- sonality distortions which do not interfere with optimum functioning. These men are not optimal candidates for psychochemical testing but the interviewer expects they would suffer at most negligible psychic trauma from experience with the effects of psychochemicala. C. Any tendency to psychosomatic reactions or aggressive physi- cal acting-out should drop a candidate at least to this group. These men are good cooperative subjects who, however, are not candidates ~ ~ ~ . ~ . . ~ ~ _. : :or _ may be somewhat dull or non-verbal, have obvious neurotic traits, immaturity, rigidity or other apparent liabilities, but with good reality assessment and no borderline or psychotic tendencies at pre- sent or at any time in past history does not include bizarre circum- stances or severe and cont inued traumatization. _ Psycuocnem~ca1 tests out may De used for other drum tests. they D. These men fall into the lower end of a scale of group whose characterization agrees roughly with those rated as C. Some definite emotional pathology is tolerated in this group as well as some bizarre or unusual responses on the questionnaire tests and border- line or aberrent scores on some MMPI scales. Numerous but minor offenses (2 or 3 Article 15~. These men may be used for equipment testing and at the discretion of the responsible medical officer may be used for local drug testing but should not be subjected to any systematic drug. Hysterical, or schizoid personalities and any but minor tendencies towards somatization should drop a candidate to this group. Some men who arrive at Edgewood with diagnosible physical or emotional disorder may be allowed to participate in the program but with D rating and their participation in any particular test must be OK'd by the responsible physician. Such mere who are untrustworthy, sociopathic, grossly disturbed or pathologic or have criminal history or a history of recurrent, severe or recent psychotic episodes should not be selected as volunteers and if they arrive at Edgewood, should be returned to their home station. This decision should ordinarily be made during the initial screening upon the basis of severe distortion of MMPI scores or very bizarre or unappropriate items on the history or questionnaire tests. Under no circumstances should this SOP be construed to supplant or replace the judgement of the medical officers in the selection procedures, who may deviate from these guidelines at their discre- tion. Deviation from the SOP may et so be done in a systematic way 261
if adherence would interfere with the accomplishment of a particular investigation, as, for example, a study of the effects of psycho- chemicals upon depressed subjects. But the conditions of such an experiment would demand an unusual attention to the safety and well- being of the volunteers selected. -262-