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Office for Human Research Protections
Office for Human Research Protections
6100 Executive Boulevard, Suite 3B01
July 19, 2001
Edward D. Miller, M.D.
Dean and Chief Executive Officer
Johns Hopkins Medicine
Johns Hopkins University School of Medicine
School of Medicine Administration Building
720 Rutland Avenue
Baltimore, MD 21205-2196
Chi Van Dang, M.D., Ph.D.
Vice Dean for Research
The Johns Hopkins University
School of Medicine
School of Medicine Administration Building
720 Rutland Avenue Baltimore, MD 21205-2196
Gregory F. Schaffer, M.S.
The Johns Hopkins Bayview Medical Center
4940 Eastern Avenue
Baltimore, MD 21224
RE: Human Subjects Protections Under Multiple Project Assurance (MPA) M-1011
Research Project: Mechanisms of Deep Inspiration-Induced Airway Relaxation
Project Number: AAC00-07-26-02
Principal Investigator: Dr. Alkis Togias
HHS Project Number: R01 HL61277 (Principal
Investigator: Dr. Solbert Permutt)
Dear Dr. Miller, Dr. Dang, and Mr. Schaffer:
As you know, the Office for Human Research Protections (OHRP) conducted an on-site evaluation of (i) the circumstances surrounding the death of ahealthy volunteer subject who participated in the above referenced researchproject, and (ii) the human subject protection system at the Johns HopkinsSchool of Medicine (JHUSOM), the Johns Hopkins Bayview Medical Center(JHBMC), and the other signatory institutions covered by MPA M-1011 on July16-18, 2001. The evaluation, conducted by 5 OHRP staff and with theassistance of 3 expert consultants and a representative from the U.S. Foodand Drug Administration (FDA), included meetings with senior institutionalofficials, the three Chairpersons of the Institutional Review Boards (IRBs),21 IRB members, all IRB administrative staff, and several researchinvestigators, including the principal investigator and co-investigators forthe above-referenced research project. The evaluation involved review ofIRB files for over 60 protocols, all available minutes of the IRB meetingssince 1998, and the audiotapes of two recent JHUSOM IRB meetings.
In the course of the OHRP review, the IRB chairs, IRB members, and IRBadministrative staff displayed a sincere commitment to the protection ofhuman subjects. Furthermore, the volume of research reviewed and the amountof time and effort devoted to IRB activities by the IRB Chairs and staffindicate great dedication to the mission of the IRBs. Investigatorsdemonstrated a culture of respect for the IRB process. The IRBAdministrator and staff were very helpful and accommodating to OHRP duringthe site visit. In particular, OHRP greatly appreciates the efforts of theIRB Administrator and staff to extend the site visit schedule and make alarge volume of IRB records available to OHRP on very short notice.
OHRP Findings Regarding Research Protocol Number AAC00-07-26-02, Mechanisms of Deep Inspiration-Induced Airway Relaxation
Based upon its review of your institutions' reports dated May 17, June 6,June 22, June 26, June 29, and July 13, 2001, as well as additionalinformation obtained during the site visit from records reviewed andinterviews with investigators and IRB members and staff, OHRP makes thefollowing findings regarding the above-referenced research.
(1) Department of Health and Human Services (HHS) regulations at 45CFR 46.111(a)(1) and (2) require that in order to approve research an IRBshall determine that the risks to subjects are minimized by using procedureswhich are consistent with sound research design and which do notunnecessarily expose subjects to risk, and that risks to subjects arereasonable in relation to anticipated benefits, if any, to subjects and theimportance of the knowledge that may reasonably be expected to result. OHRPfinds that the JHBMC IRB and the investigators conducting the researchfailed to ensure that risks to subjects were minimized and reasonable, asrequired by HHS regulations at 45 CFR 46.111(a)(1) and (2). In particular,OHRP notes the following:
(a) Prior to the research being approved by the IRB, theinvestigators and the JHBMC IRB failed to obtain published literature aboutthe known association between hexamethonium and lung toxicity. Such datawas readily available via routine MEDLINE and Internet database searches, aswell as recent textbooks on pathology of the lung.
(b) Use of hexamethonium is not currently approved by theFDA for use in humans, and has never been approved by the FDA foradministration via inhalation.
(c) Prior to approving the research, the JHBMC IRB failed toobtain sufficient information regarding the source, purity, quality, andmethod of preparation and delivery of the hexamethonium used in theresearch.
(d) The hexamethonium bromide used in the research wasobtained by the investigators from Fluka US and was labeled "[f]orlaboratory use only, not for drug, household, or other uses." The JHBMC IRBwas not aware of this information before the investigators administered thehexamethonium to three subjects and the hospitalization of the thirdsubject.
(e) Prior to its approval of the research, the JHBMC IRB didnot receive or request from the investigators (i) any information regardingthe pharmacology and toxicity of inhaled hexamethonium in animals; or (ii)sufficient information regarding the safety of inhaled hexamethonium inhumans.
(2) HHS regulations at 45 CFR 46.108(b) require that, except when anexpedited review procedure is used, the IRB must review proposed research atconvened meetings at which a majority of the members are present, includingat least one member whose primary concerns are in nonscientific areas. OHRPfinds that the JHBMC IRB failed to review the research, which was noteligible for expedited review under HHS regulation at 45 CFR 46.110(b), at aconvened meeting [see finding (8) below]. As a result, the JHBMC IRB failedto ensure that all criteria required for IRB approval under HHS regulationsat 45 CFR 46.111 were satisfied.
(3) HHS regulations at 45 CFR 46.103(b)(4) and 46.108(a) requirethat the IRB review and approve all proposed changes in a research activity,during the period for which IRB approval has already been given, prior toinitiation of such changes, except when necessary to eliminate apparentimmediate hazards to the subjects. OHRP finds that the following changes tothe research protocol were implemented by the investigators without IRBapproval:
(a) The investigator initially changed the diluent for thehexamethonium solution from normal saline to distilled water starting withthe first subject, and then further modified the solution by adding sodiumbicarbonate in order to neutralize the pH starting with the second subject.
(b) The investigators failed to perform a Limulus test oneach solution prior to administration to subjects as required by theIRB-approved protocol.
(c) The investigators changed the aerosol delivery systemafter the second subject's first administration.
(4) HHS regulations at 45 CFR 46.116 stipulate that no investigatormay involve a human being as a subject in research unless the investigatorhas obtained the legally effective informed consent of the subject or thesubject's legally authorized representative. HHS regulations at 45 CFR46.116(a) stipulate basic elements for such informed consent.
(a) OHRP finds that the informed consent document approvedby the JHBMC IRB for the research failed to adequately describe the researchprocedures to be followed or identify procedures which were experimental, asrequired by HHS regulations at 45 CFR 46.116(a)(1). In specific, OHRP notesthe following:
(i) The informed consent document failed to indicatethat inhaled hexamethonium was experimental and not approved by the FDA.OHRP is particularly concerned that the hexamethonium was referred to as a"medication" in the informed consent document.
(ii) The informed consent document failed todescribe the plan for escalating the inhaled methacholine dose during thescreening phase of the research.
(b) OHRP finds that the informed consent document approvedby the JHBMC IRB failed to adequately describe the reasonably foreseeablerisks and discomforts associated with the research, as required by HHSregulations at 45 CFR 46.116(a)(2). OHRP finds that the investigatorsfailed to provide a description of the possible pulmonary toxicity ofhexamethonium to the subjects.
(5) HHS regulations at 45 CFR 46.116(b)(1) and (2) require that,when appropriate, the following additional elements of informed consent beprovided to each subject:
(a) A statement that the particular treatment or proceduremay involve risks to the subjects which are currently unforeseeable.
(b) A description of anticipated circumstances under whichthe subject's participation may be terminated by the investigator withoutregard to the subject's consent.
OHRP finds that it would have been appropriate for the informedconsent document for the research to include these elements.
(6) OHRP finds that the investigators failed to promptly report anunanticipated problem involving risks to subjects to appropriateinstitutional officials, the IRB, OHRP, and the head of the sponsoringagency as required by HHS regulations at 45 CFR 46.103(a) and (b)(5). Inspecific, the investigators failed to promptly report the cough, shortnessof breath, and a decrease in pulmonary function experienced for 8 days bythe first subject exposed to hexamethonium. OHRP is particularly concernedthat the investigators continued to expose additional subjects to inhaledhexamethonium before the symptoms in the first subject were resolved andbefore reporting the event to the JHBMC IRB.
(7) OHRP acknowledges and concurs with the following conclusionsfrom your Report of Internal Investigation into the Death of a VolunteerResearch Subject provided to OHRP on July 13:
(a) "[A]n adequate evidence base did not exist for the IRBto be confident that inhaled hexamethonium was safe for use in researchsubjects."
(b) "[T]he consent form [for the research] should not havebeen approved by the IRB."
(c) "[T]he death [of the third subject exposed to inhaledhexamethonium] was most likely the result of participation in thehexamethonium phase of the experiment."
OHRP Findings Regarding Human Subjects Protections Under MPA M-1011
(8) HHS regulations at 45 CFR 46.108(b) require that, except when anexpedited review procedure is used, the IRB must review proposed research atconvened meetings at which a majority of the members are present, includingat least one member whose primary concerns are in nonscientific areas. OHRPfinds that the JHUSOM and JHBMC IRBs (the IRBs) fail to review at convenedmeetings most research undergoing initial review that is not eligible forexpedited review. As a result, the IRBs fail to ensure that all criteriarequired for IRB approval under HHS regulations at 45 CFR 46.111 aresatisfied. Of note, the minutes and audiotapes of IRB meetings, and ourdiscussions with IRB members and administrators, indicate that no reviewtakes place at convened meetings for most protocols undergoing initialreview. Most protocols are neither individually presented nor discussed ata convened meeting of any IRB.
(9) As OHRP noted in its letter of October 3, 2000 to yourinstitutions, OHRP reiterates that continuing IRB review of research must besubstantive and meaningful. In conducting continuing review of research noteligible for expedited review, all IRB members should at least receive andreview a protocol summary and a status report on the progress of theresearch, including (a) the number of subjects accrued; (b) a description ofany adverse events or unanticipated problems involving risks to subjects orothers and of any withdrawal of subjects from the research or complaintsabout the research; (c) a
summary of any recent literature, findings obtained thus far,amendments or modifications to the research since the last review, reports on multi-centertrials and any other relevant information, especially information aboutrisks associated with the research; and (d) a copy of the current informedconsent document. Furthermore, the minutes of IRB meetings should documentseparate deliberations, actions, and votes for each protocol that requirescontinuing review by the convened IRB.
OHRP finds that continuing review of research by the IRBs is notsubstantive nor meaningful. As with initial review of research, nearly allprotocols undergoing continuing review are neither individually presentednor discussed at a convened meeting by the IRBs.
(10) HHS regulations at 45 CFR 46.115(a) require that aninstitution, or when appropriate, an IRB, shall prepare and maintaindocumentation of IRB activities, including minutes of IRB meetings.Furthermore, HHS regulations at 45 CFR 46.115(a)(2) require that suchminutes be in sufficient detail to show attendance at the meetings; actionstaken by the IRB; the vote on these actions including the number of membersvoting for, against, and abstaining; the basis for requiring changes in ordisapproving research; and a written summary of the discussion ofcontroverted issues and their resolution. OHRP finds that:
(a) For the JHUSOM IRBs, minutes of IRB meetings do not yetexist for 18 of the last 21 meetings dating back to October 2000.
(b) The minutes of meetings for all the IRBs often failed todocument the basis for requiring changes in research. OHRP notes that IRBactions were not documented separately for each individual protocol. Inaddition, OHRP's review of protocols and IRB records revealed that someprotocols had unresolved concerns following review by the IRB subcommittee,but there was no record in the minutes of IRB meetings of these concernsbeing addressed by full IRB.
(11) During its record review, OHRP found several protocolapplications in which the IRB failed to receive or consider sufficientinformation for the IRBs to make the determinations required for approval ofresearch under HHS regulations at 45 CFR 46.111(a). For example, certainIRB applications provided only minimal information regarding (a) subjectrecruitment and enrollment procedures; (b) the equitable selection ofsubjects; (c) provisions to protect the privacy of subjects and maintain theconfidentiality of data; and (d) the local context for research conducted ininternational settings.
(12) HHS regulations at 45 CFR 46.111(b) require the IRB to ensurethat additional safeguards have been included in research to protect therights and welfare of vulnerable subjects. OHRP finds that IRB recordsfailed to demonstrate consistently the consideration of such safeguards.
(13) HHS regulations at 45 CFR 46.107(e) stipulate that no IRBmember may participate in the IRB's initial or continuing review of aproject in which the member has a conflicting interest, except to provideinformation requested by the IRB. OHRP found instances in which IRB membersinappropriately participated in the initial and continuing review ofprotocols for which they had a conflicting interest. As noted in OHRP'sOctober 3, 2000 letter, OHRP strongly recommends that IRB members absentthemselves from the meeting room when the IRB votes on research in whichthey have a conflicting interest, and such should be noted in the IRBmeeting minutes.
(14) HHS regulations at 45 CFR 46.110(b)(2) permit use of expeditedprocedures for review of minor changes to previously approved research.OHRP finds that the IRBs routinely employed expedited procedures to reviewchanges that exceed this limitation.
OHRP recommends that institutions adopt policies describing thetypes of minor changes in previously approved research which can be approvedby expedited review in accordance with HHS regulations at 45 CFR46.110(b)(2).
(15) HHS regulations at 45 CFR 46.116(a) delineate specific elementsrequired for informed consent.
(a) OHRP found multiple instances where (i) requiredelements were omitted or inadequate; and (ii) there were discrepanciesbetween the protocol application and the informed consent documentsregarding the purpose, risks, and benefits of the research.
(b) OHRP is concerned that the IRBs encourage investigatorsto limit the length of informed consent documents, and as a result,important information is being excluded.
(16) HHS regulations at 45 CFR 46.116(b) require that, whenappropriate, additional elements of informed consent be provided to eachsubject. OHRP found numerous instances where it would have been appropriatefor the informed consent document to include one or more of these additionalelements. In particular, the elements at 46.116(b)(2), (4) and (5) were theadditional elements most frequently overlooked.
As previously stated in OHRP's letter of October 3, 2000, OHRP againstrongly recommends that the informed consent document boilerplate used bythe IRBs and checklist be modified to include the additional elements at 45CFR 46.116(b).
(17) HHS regulations at 45 CFR 46.116 require that the informationprovided in the informed consent documents be in language understandable tothe subject. OHRP is concerned that the informed consent documents approvedby the IRBs often appeared to include complex language that would not beunderstandable to all subjects.
(18) OHRP is concerned that the boilerplate informed consentdocument is difficult to understand and contains information that may beirrelevant for certain research projects.
(19) OHRP is concerned that the current membership of the IRBsappears to lack the diversity, including consideration of race and culturalbackgrounds and sensitivity to such issues as community attitudes, topromote respect for its advice and counsel in safeguarding the rights andwelfare of human subjects, as required under HHS regulations at 45 CFR46.107(a).
(20) With respect to the JHUSOM IRBs, OHRP is concerned that many ofthe above findings may be indicative of IRBs overburdened by the largevolume of research for which it has oversight responsibility. It is OHRP'sexperience that such a large volume of human subjects research warrants morethan two fully functional IRBs.
(21) HHS regulations at 45 CFR 46.103(b)(2) require thatinstitutions provide sufficient staff to support the IRB's review andrecordkeeping duties. OHRP is concerned that the level of staff supportprovided to the JHUSOM IRBs appears to be insufficient. It is OHRP'sexperience that the volume of human subjects research conducted by theinstitution warrants additional professional and clerical IRB staff members.
(22) HHS regulations at 45 CFR 46.404-407 require specific findingson the part of the IRB for approval of research involving children. OHRP'sdiscussions with IRB members and its review of IRBs documents reveal noevidence that the IRB consistently makes the required findings whenreviewing research involving children.
(23) HHS regulations at 45 CFR 46.305-306 require specific findingson the part of the IRB for approval of research involving prisoners. OHRP'sdiscussions with IRB members and its review of IRB documents reveal noevidence that the IRB makes the required findings when reviewing suchresearch.
(24) OHRP is concerned that the IRBs issue approval letters toinvestigators prior to receiving and confirming the adequacy of revisionsrequired by the IRBs.
(25) HHS regulations at 45 CFR 46.116(d) require that the IRB findand document four specific criteria when approving waiver or alteration ofsome or all of the required elements of informed consent. OHRP's discussionswith IRB members and its review of IRB documents reveal no evidence thatthe IRB consistently satisfies these requirements.
(26) OHRP is concerned that the Chairs and members of the IRBsappear to lack a detailed understanding of the specific requirements of theHHS regulations for the protection of human subjects. As a result, IRBdeterminations have sometimes deviated from these requirements.
(27) OHRP finds that the institution does not have written IRBpolicies and procedures that adequately describe the following activities,as required by HHS regulations at 45 CFR 46.103(b)(4) and (5):
(a) The procedures which the IRB will follow for determiningwhich projects need verification from sources other than the investigatorsthat no material changes have occurred since previous IRB review.
(b) The procedures for ensuring prompt reporting to the IRB,appropriate institutional officials, and Department or Agency head of (i)any unanticipated problems involving risks to subjects or others or anyserious or continuing noncompliance with 45 CFR Part 46 or the requirementsor determinations of the IRB; and (ii) any suspension or termination of IRBapproval.
(28) OHRP is concerned about the adequacy of the IRB's presentprocedures for ensuring prompt reporting, review, and evaluation ofunanticipated problems involving risks to subjects or others.
Additional OHRP Guidance
(29) As OHRP noted in its October 3, 2000 letter, OHRP againrecommends that documentation for initial and continuing reviews conductedutilizing expedited review procedures include the specific permissiblecategories (see 63 FR 60364) justifying the expedited review.
(30) Where HHS regulations require specific findings on the part ofthe IRB, such as (a) approving a procedure which alters or waives therequirements for informed consent [see 45 CFR 46.116(d)]; (b) approving aprocedure which waives the requirement for obtaining a signed consent form[see 45 CFR 46.117(c)]; (c) approving research involving prisoners (see 45CFR 46.305-306); or (d) approving research involving children (see 45 CFR46.404-407), the IRB should document such findings. OHRP strongly recommendsthat all required findings be fully documented in the IRB minutes, includingprotocol-specific information justifying each IRB finding.
(31) As OHRP noted in its October 3, 2000 letter, IRBs mustdetermine which protocols require continuing review more often thanannually, as appropriate to the degree of risk [see 45 CFR 46.103(b)(4) and46.109(e)]. OHRP recommends that the minutes of IRB meetings clearlyreflect these determinations regarding risk and approval period (reviewinterval).
In view of the above determinations and in order to ensure adequateprotections for human subjects at the covered institutions, in accordancewith HHS regulations at 45 CFR 46.103, OHRP hereby suspends the MultipleProject Assurance (MPA # M-1011) for the Johns Hopkins University School ofMedicine, the Johns Hopkins University School of Nursing, the Johns Hopkins Hospital, the Johns Hopkins Bayview Medical Center, the Gerontology ResearchCenter of the National Institute of Aging-Bayview Campus, theKennedy-Krieger Institute, and the Applied Physics Laboratory.
The suspension of MPA M-1011 is effective immediately as of the date of thisletter and removes the Assurance required by HHS regulations at 45 CFR46.103(a) for all Federally supported research involving human subjects atthe above MPA signatory institutions.
As result, all Federally supported research projects at the coveredinstitutions must be suspended. For any project affected by thissuspension, enrollment of new subjects must cease immediately except inextraordinary cases approved in advance by OHRP (OHRP would expect requestsfor such approvals to be rare). Furthermore, research activities involvingpreviously enrolled subjects may continue only where it is in the bestinterests of individual subjects. No suspended Federally supported researchat these institutions may resume without OHRP reinstatement of the MPA, orapproval by OHRP of an applicable Assurance.
(1) JHUSOM, JHBMC, and all other institutions covered by MPA M-1011must develop the following corrective action plans as a condition for OHRPconsideration of reinstatement of the MPA:
(a) Satisfactory corrective action plans to address alldeficiencies and concerns described above. In order to be consideredsatisfactory, such corrective action plans must include a plan for theconvened IRB to review all research protocols not eligible for expeditedreview.
(b) A satisfactory plan to restructure the system forprotecting human subjects under MPA M-1011. In OHRP's experience, suchrestructuring would necessarily include an enhanced institutional commitmentto human subject protections, implementation of additional IRBs, andappointment of additional IRB Chairpersons.
(c) A satisfactory plan to ensure that all IRB members, allIRB staff, and all research investigators are appropriately educated, on animmediate and ongoing basis, about the regulatory requirements for theprotection of human subjects.
(2) By August 10, 2001, the above institutions covered by MPA M-1011must provide a complete list of all Federally supported research protocolsthat were suspended, including the project title, principal investigatorname, IRB project number, and the Federal department or agency projectnumber. The list should identify those projects for which it has beendetermined that research activities involving previously enrolled subjectsmay continue because it is in the best interest of the individual subjects.Please describe the procedures used to make such determinations.
OHRP encourages JHUSOM and JHBMC to develop the corrective action plansexpeditiously, and forward them to OHRP for review as soon as possible.OHRP is available to assist in the development and implementation of thesecorrective action plans. Do not hesitate to contact OHRP should you haveany questions.
Patrick J. McNeilly, Ph.D. Compliance Oversight Coordinator Division of Compliance Oversight
Michael Carome, M.D.DirectorDivision of Compliance Oversight
Mr. Ronald R. Peterson, President, The Johns Hopkins Hospital
Dr. Sue K. Donaldson, Dean, School of Nursing, JHU
Dr. Jacquelyn Campbell, School of Nursing, JHU
Dr. Gary W. Goldstein, President, Kennedy Krieger Institute
Ms. Karen Cox, Research Administrator, Kennedy Krieger Institute
Dr. Darrell R. Abernethy, Clinical Director, NIA
Dr. Vincent L. Pisacane, Director, Institute for Advanced Scienceand Technology in Medicine, Applied Physics Laboratory
Mr. David Grant, Applied Physics Laboratory
Ms. Barbara L. Starklauf, Administrator, Human Subjects Committees, JHUSOM
Dr. Lewis Becker, Chairman, JCCI -I, JHUSOM
Dr. David R. Cornblath, Chairman, JCCI-II, JHUSOM
Dr. Gary Briefel, M.D., Chair, JHBMC IRB
Dr. Solbert Permutt, JHUSOM
Dr. Alkis Togias, JHUSOM
Ms. Diann Shaffer, FDA Commissioner, FDA
Dr. David Lepay, FDA
Dr. James F. McCormack, FDA
Dr. John Mather, Director, Office of Research Compliance and Assurance, Veterans Health Administration
Dr. Greg Koski, OHRP
Dr. Melody H. Lin, OHRP
Ms. Susan Sherman, OHRP
Dr. Kristina Borror, OHRP
Mr. George Gasparis, OHRP
Dr. Jeffrey Cohen, OHRP
Ms. Roslyn Edson, OHRP
Mr. Barry Bowman, OHRP