Minutes of the Meeting of the Human Subjects Research Review Board, 9 November 1992

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DEPARTMENT OF THE ARMY OFFICE OF THE SURGEON GENERAL MEMORANDUM FOR THE SURGEON GENERAL SUBJECT: Minutes of the Meeting of the Human Subjects Research Review Board, 9 November 1992 1. Pursuant to AR 40-7, 4 January 1991; OTSG Regulation 15-2, 11 January 1989; AR 40-38, 1 September 1989 and AR 70-25, 25 January 1990, a meeting of the Human Subjects Research Review Board (HSRRB) was held at 1300 in Room 640, 5109 Leesburg Pike, Falls Church, VA, on 9 November 1992. The HSRRB is the principal body of the Office of The Surgeon General (OTSG) f o r the assessment of practices and procedures by which DA employs human subjects in research and clinical investigation activities. a. Voting members present were: (2) COL Ariel Rodriguez, MC, TSG Surgical Consultant, Investigation Consultant, HSHN-I, U.S. Army Health Services (6) COL James P. Wilson, TSG Pharmacy Consultant, (7) LTC John F, Glenn, MS, Executive Assistant to the and Pastoral Care, Walter Reed Army Medical Center. and Regulatory Affairs Office, USAMRDC.

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SUBJECT: Minutes of the Meeting of the Human Subjects Research - Review Board, 9 November 1992 Materiel Development Activity. (12) CSM Johnny M. Williamson, Command Sergeant Major, Institute of Infectious Diseases. b. Also present were: Research and Development Command. (2) LTC David N. Taylor, MC, Walter Reed A r m y Institute (3) MAJ Victor McGlaughlin, MC, Womack Army Medical Regulatory Affairs Office, USAMRDC. Affairs Office, USAMRDC (Recorder). 2. After determining that a quorum of eight was present, COL Jennings opened the meeting at 1302. 3. The minutes of the 14 October 1992 meeting of the HSRRB were presented f o r Board examination and comment (encl 1). 4. The minutes of the 23 October 1992 meetfng of the HSRRB Subcommittee for Review of Materiel Test Plans and Protocols were presented for information (encl 2). 5. A list of protocols administratively approved as reported by the Human Use Review and Regulatory Affairs Office since the 14 October 1992 HSRRB meeting was presented (encl 3). 6. Annual reports were presented f o r the following INDs:

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- SUBJECT: Minutes of the Meeting of the Human Subjects Research Review Board, 9 November 1992 b . BB-IND 1114 - Bolivian Hemorrhagic Fever Immune Globulin d. IND 30726 - Ketoconazole and Pentostam (encl 7 1. 7. A report of an incident related to the protocol entitled "Active Immunization of Early HIV Infected Patients with Recombinant gp160 HIV Protein: Phase XI Clinical Efficacy," was presented for information (encl 8). The Human Use Review and Regulatory Affairs Office was directed to obtain a copy of the additional consent form used f o r the subject involved in this incident and a copy of the modification to the protocol to allow continuation of a female volunteer who becomes pregnant during course of the study. Questions were raised concerning ( a ) the right of the mother to consent for her unborn child and ( b ) whether the father should have the opportunity/responsibility to read and sign the informed consent in cases such as this. The investigator should explain whether the human use committee at Womack Army Medical Center was notified of this incident. T h e . USAMRDC Command Judge Advocate will be consulted on the legal 8. Report of incident related to protocol entitled "Serologic Response to Anthrax and Botulism Vaccines," submitted by The investigator should explain whether the human use committee at Womack Army Medical Center was notified of this incident. The USAMTC Command Judge Advocate will be consulted on the legal implications of this action. 9. The following protocols A-D ( e n d s 10-13) were acted upon by the Board. The appropriate review committees will review these studies annually unless otherwise stated. NOTE: The question of whether or not t h e HSFtRB's current policy regarding storage of donated blood/tissue/body fluid products samples is adequate was discussed in relation to all the protocols presented at this meeting. Since the legal representative was unable to be present at this meeting, he will be consulted on this matter and the subject will be discussed at the December meeting of the Board. a. Protocol A - "Phase I Study of Vinblastine Plus

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-UBJECT: Minutes of the Meeting of the Human Subjects Research Review Board, 9 November 1992 review f o r scientific merit and review and approval by the Fox Chase Institutional Review Board must be submitted. Before resubmission f o r reconsideration by the HSRRB, the following additional information must be provided and revisions made to the protocol and consent form: ( a ) The name and curriculum vitae of the medical monitor must be provided. (b) A copy of all case report forms must be provided. (c) With regard to the protocol: 1 Since the use of cyclosporin in this study is not the approved indication for the product, has an Investigational New Drug (IND) application been filed? What is the source of the 2 It is noted that renal toxicity is not being monitored in this study? Has consideration been given to the effect of escalating doses on renal toxicity? 3 o-( of reproductive potential must have a negative serum pregnancy test within 48 hours prior to each drug administration (no more - r P3- Page 7, Section 3.18, change to read "Female patients 4 Page 11, Section 7.2, Pregnancy test, an " X " should also be placed on the pregnancy test line under the "Every 4 5 . Page 14, Section 10.0, if females will be removed from the study fn the event they become pregnant, this should be stated here and in the consent form. 6 The Human Use Review and Regulatory Affairs Office, USAMRDC, should be included in Section 11.4 on page 15 as an agency to be notified of adverse reactions occurring during the conduct of this study. ( d ) With regard to the consent form: 1.The complete title "Phase I Study of Vinblastine Plus Cyclosporin and Quinine as Modulators of Multidrug Resistance (MDR)" should be listed on the consent form.

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- SUBJECT: Minutes of the Meeting of the Human Subjects Research Review Board, 9 November 1992 2 The location of the study and the principal investigator's name should be listed after the title. 3 The statement under Purpose on page 1 should be rewritten as follows: The purpose of this research study is to determine the best dose of CSA or the dose associated with the fewest unfavorable effects or greatest improvement when given in combination with quinine and vinblastine, "pneumothorax" should be expressed in lay terms, understand the blood, biopsy tissue and urine samples which I am providing may also be used in other research studies. be personally identified in any publication of the results of these other research studies. In addition, I agree to waive all property rights to these blood/tissue/body fluids, date and initial all but the last page of the consent form. 2' Page 2, paragraph 1, line 2, delete '*(by vein); " line 3, change "disease" to "tumor;" line 7, change the second occurrence of the word "day" to "dose." In paragraph 2, the total amount of blood to be drawn during the entire study should be noted in lay terms, 8 It is stated in paragraph 2 on page 2 that tests will 5 The following should be added to the consent form: I . Suggest the volunteer and witness be instructed to be decided by the patient's physician. shows a schedule of routine tests to be performed. If these tests will be routine, the patient should be informed of the type, duration and frequency of these tests. read "...tumor increases in size, and if I have a lump...;" line "proceeded" in line 13 should be changed to "preceded." Page 11 of the protocol 9 Page 2, paragraph 3, line 6, change the sentence to

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SUBJECT: Minutes of the Meeting of the Human Subjects Research -. Review Board, 9 November 1992 LQ The word "of" should be inserted after the phrase " ... has been used extensively in treatment ..." in line 1 under Vinblastine Toxicity on page 3. L l Page 3, under Risks, add the risks associated with I2 Page 4, paragraph 5 states other alternatives are available. However, it is understood these patients will have exhausted all known treatments before enrollment in this protocol. Please clarify. In paragraph 6, add representatives of the U.S. Army Medical Research and Development Command as those eligible to review research records. In paragraph 7, fourth through sixth sentences should be replaced with "I understand that I will be provided all necessary medical care for injury or disease which is the proximate result of my participation in this research. Other than medical care that may be provided, I will not receive any compensation for my this is not a waiver of my legal rights." . participation in this research study; however, I understand that l3 Page 5, paragraph 8, line 2, the word "in" is misspelled. In paragraph 9, delete the second sentence. In paragraph 10, include criteria for removal from the study that are listed on page 14, Section 10.0 of the protocol. 14 What procedures will be followed for obtaining consent in the event the patient becomes comatose during the study? Will third party consent be obtained or will the patient be withdrawn from the study? This should be explained in the consent form and the form should be modified to accommodate third (2) BOARD'S VOTE: Twelve in favor (COL Tomlinson not Verapamil as a Modulator of Multidrug Resistance in Metastatic ( 1 ) COMMENTS: Board members questioned whether the terminally Ill patients to be enrolled in this study should be asked to participate in a study to determine toxic dose levels rather than to receive therapeutic benefit. Also, members were frustrated by the overall imprecision of this protocol.

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SUBJECT: Minutes of the Meeting of the Human Subjects Research Review Board, 9 November 1992 (2) BOARD'S RECOMMENDATION: Deferred. Documentation of review for scientific merit and review and approval by the Fox Chase Institutional Review Board must be submitted. Before resubmission for reconsideration by the HSRRB, the following additional information must be provided and revisions made to the protocol and consent form: ( a ) The name and curriculum vitae of the medical monitor must be provided. (b) A copy of all case report forms must be provided. (c) Has an Investigational New Drug (IND) application been filed with the Food and Drug Administration (FDA) for the use of R-Verapamil? I f so, the name of the sponsor and the FDAassigned code number should be provided. Also, the investigational nature of the drug should be described in the the purposes to be investigated; it 1s not approved by the Food and Drug Administration f o r this purpose." ( d ) With regard to the protocol: 1 ,D-Verapamil and R-Verapamil are both referred to in the proposal. Please clarify whether these are two separate drugs or typographical errors (see pages 17 and 22 of the 2 The word "response" 'in 6 of paragraph 4 on page 7 3' Page 10, change Section 3.20 to read "Female patients should be changed to "respond." of reproductive potential must have a negative serum pregnancy test within 48 hours prior to drug administration (no more 4 Were the rounding rules used to determine the 360 5 References in Section 7.12 on page 12 to other drugs and references in Sections 7.4 and 7.5 on page 13 to "holding" or "discontinuing" drugs are unclear since their use is not mentioned in the protocol. With reference to Section 7.41 on page 13, what alternative to phenothiazine will be used to treat

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SUBJECT: Minutes of the Meeting of the Human Subjects Research .- Review Board, 9 November 1992 4 The reference to Verapamil in Section 7.7 on page 14 as a drug which "should not be taken" is unclear. Please 2 - Section 7.9 on page 14 should be deleted. 8 Page 16, Section 9.2, Pregnancy test, an " X " should also be placed on the pregnancy test line under the "Every 4 9 Section 9.4 should be rewritten. Time zero ("t=O") cannot indicate time prior to beginning treatment. Specify the range, i.e., -15 to -30 minutes. This error also occurs in other places in the protocol. Also, clarify the times f o r blood collection (Day 24 or at 24 hours). LQ Page 19, Section 12, if females will be removed from the study in the event they become pregnant, this should be stated here and in the consent form. ll The Human Use Review and Regulatory Affairs Office, USAMRDC, should be included in Section 14.4 on page 20 as an agency to be notified of adverse reactions occurring during the conduct of this study. (e) With regard to the consent form: 1. The complete title "Phase I1 Study of Vinblastine Plus R-Verapamil as a Modulator of Multidrug Resistance in Metastatic Breast Cancer" should be listed on the consent form. 2' The location of the study and the principal investigator's name should be listed after the title.

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SUBJECT: Minutes of the Meeting of the Human Subjects Research Review Board, 9 November 1992should be expressed in lay terms. 4 A copy of all other consent forms used in the study must be provided for approval. 5 Inform patients why their blood pressure may drop and how the use of Decadron will help. 6 The following should be added to the consent form: I understand the blood, biopsy tissue and urine samples which I am providing may also be used in other research studies. I will not be personally identified in any publication of the results of these other research studies. In addition, I agree to waive all property rights to these blood/tissue/body fluids. 2 Page 2 states that tests will be decided by the patient's physician. Page 16 of the protocol shows a schedule of the patient should be informed of the type, duration and frequency of these tests. In paragraph 4, the total amount of blood to be drawn during the entire study should be noted in lay changed to "tumor" and the sentence in that line should be changed to read"..,tumor increases in size, and if I have a . routine tests to be performed. If these tests will be routine, .1 terms. In paragraph 5, line 5, the word "disease" should be lump ..." In paragraph 5, line 11, insert "(1 teaspoonful)" after 8 Page 3, under Risks, add the r i s k s associated with 9' Page 4, under Benefits, the third sentence should read "If this does happen, I might feel better." Under Confidentiality, add representatives of the U.S. Army Medical Research and Development Command as those eligible to review research records. Under Certain Costs, the fourth through sixth sentences should be replaced with "I understand that I will be provided all necessary medical care for injury or disease which is the proximate result of my participation in this research. Other than …