Department of Veterans Affairs 

Office of Inspector General 

Healthcare Inspection 

Human Subjects Protections 

in One Research Protocol 

VA Medical Center, Washington, DC 

Report No. 08-02346-191 August 28, 2008

VA Office of Inspector General 

Washington, DC 20420 
To Report Suspected Wrongdoing in VA Programs and Operations 

Call the OIG Hotline – (800) 488-8244 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

Contents 

Page 

Executive Summary ..............................................................................................i

I. Introduction .....................................................................................................1 

Purpose........................................................................................................................... 1

Background .................................................................................................................... 1

Scope and Methodology ................................................................................................ 4

II. Results and Conclusions ...............................................................................5

Issue 1. Patient Notification of FDA Communications Concerning Chantix®............. 5

Issue 2. Adequacy of Informed Consent....................................................................... 9

Issue 3. Psychiatric Adverse Events and Serious Adverse Events in Patients Enrolled 

in the Smoking Cessation Study Receiving Chantix® ................................................. 11 

Issue 4. Alleged Documentation Irregularities in the Smoking Cessation Study at 

VAMCDC .................................................................................................................... 12 

Conclusions.................................................................................................................. 13

Recommendations........................................................................................................ 14 

Appendixes

A. Under Secretary for Health Comments.................................................................. 16

B. OIG Contact and Staff Acknowledgments............................................................. 26

C. Report Distribution................................................................................................. 27

VA Office of Inspector General 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

Executive Summary 

On June 17, 2008, the Office of Inspector General received a letter from Representative 

Steve Buyer, Ranking Member of the House Committee on Veterans’ Affairs, requesting 

an investigation into the circumstances surrounding the use of a medication called 

varenicline (Chantix®) in a particular research study sponsored by the Veterans Health 

Administration (VHA). This complaint followed an incident in which a veteran treated at 

the VA Medical Center in Washington, DC, (VAMCDC) alleged that Chantix® caused 

him to become aggressive and engage in inappropriate activities. The Food and Drug 

Administration (FDA) had reported the possibility of an association with changes in 

mood, behavior, or suicidal thoughts and Chantix® on November 20, 2007. The FDA 

upgraded this warning to a public health advisory on February 1, 2008. 

To respond to this complaint, we conducted an investigation at VAMCDC, focusing on 

the timeliness of patient notification following warnings from FDA related to this study, 

on the adequacy of the informed consent process, and on the reporting of adverse events 

at the VAMCDC. During the course of our investigation, we also received allegations of 

inappropriate documentation in connection with this study at the VAMCDC, which are 

also described in this report. 

We found that the VAMCDC Pharmacy Service responded appropriately to FDA 

communications concerning Chantix® in November 2007 and in February 2008 in 

notifying providers of these newly defined risks. However, we found that the Research 

Service did not ensure that patients with post-traumatic stress disorder (PTSD) who were 

also enrolled in a smoking cessation study received adequate and timely notice of these 

risks. We further found that the facility failed to ensure that patients in this study who 

had taken Chantix® signed an addendum to the consent form disclosing these risks. 

While the facility mailed information letters to participants in late February or early 

March 2008, we also noted that the facility did not document or ensure that participants 

actually received this notification. 

The Association for the Accreditation of Human Research Protection Programs, Inc. 

(AAHRPP), the organization responsible for accrediting VA facilities conducting human 

subjects research, noted significant deficiencies in informed consent processes and 

procedures at the VAMCDC as a whole during an October 2007 site visit. We further 

found that the facility’s research compliance program did not conduct protocol audits in 

accordance with current VHA policy. Finally we found that in at least one instance, a 

form designed to describe a clinician’s interview with a subject was completed from 

other data rather than from a direct patient interview. Numerous documentation 

irregularities related to this study at this site were also reported to the Coordinating 

Center for this study. 

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Therefore, we made the following recommendations: 

Recommendations 

Based upon these findings, we made the following recommendations. 

Recommendation 1: The Under Secretary for Health will ensure that all patients who 

currently take Chantix® have been informed of the possible association between Chantix®

and suicidal thoughts. 

Recommendation 2: The Under Secretary for Health will develop a formal mechanism 

for ensuring that Institutional Review Boards are directly notified of FDA 

communications concerning medications when they are responsible for protocols 

involving those medications. 

Recommendation 3: The Under Secretary for Health will ensure that all patients 

involved in the smoking cessation study are informed of risks associated with Chantix®

by VHA study personnel and given the opportunity to sign the addendum to the informed 

consent disclosing those risks. 

Recommendation 4: The Under Secretary for Health will take appropriate 

administrative action, to include a research misconduct inquiry, based upon the findings 

contained within this report. 

Recommendation 5: The VISN 5 Director will require that the smoking cessation study 

data collected at VAMC Washington, DC, be validated to ensure its accuracy. 

Recommendation 6: The VISN 5 Director will require the medical center director to 

audit a representative sample of all active protocols involving human subjects for 

compliance with VHA informed consent requirements, including whether an informed 

consent can be located for each study participant. 

Recommendation 7: The VISN 5 Director will require the medical center director to 

ensure that protocols are being audited in accordance with VHA Directive 2008-014. 

VA Office of Inspector General ii 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

Comments 

The Under Secretary for Health concurred with the recommendations in this report and 

submitted acceptable improvement plans to implement all recommendations. In addition, 

the Under Secretary made extensive comments concerning the report findings. (See 

Appendix A, pages 16–25, for the full text of these comments.) Following a careful 

review of the Under Secretary’s comments and VHA’s action plan to implement our 

recommendations, we stand behind the findings, conclusions, and recommendations as 

stated in this report. We will follow up on all corrective actions until the plan has been 

fully implemented. 

 (original signed by:)

JOHN D. DAIGH, JR., M.D. 

Assistant Inspector General for 

Healthcare Inspections 

VA Office of Inspector General iii 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

Part I. Introduction 

Purpose 

The purpose of this inspection was to determine whether the Veterans Health 

Administration (VHA) protected human research subjects appropriately following 

notification from the Food and Drug Administration (FDA) of potentially harmful effects 

associated with the drug varenicline (Chantix®).

Background

On June 17, 2008, the Office of Inspector General received a letter from Representative 

Steve Buyer, Ranking Member of the House Committee on Veterans’ Affairs, requesting 

an investigation into the circumstances surrounding the use of Chantix® in a particular 

research study sponsored by VHA. Chantix® is a medication approved by the Food and 

Drug Administration (FDA) for use in helping patients to quit smoking. The request 

followed an incident reported in the media in which a veteran taking Chantix® while 

enrolled in a research study at the VA Medical Center in Washington, DC, (VAMCDC) 

allegedly experienced an episode of agitated and/or aggressive behavior. The research 

study enrolling the veteran compared the effectiveness of smoking cessation treatment 

administered by mental health providers to that administered by primary care providers in 

patients with post-traumatic stress disorder (PTSD); it will hereafter be referred to as “the 

smoking cessation study” or “the study.” 

The protocol, a written document describing the method for conducting the smoking 

cessation study, stated that patients assigned to mental health providers for their smoking 

cessation therapy would receive medications for smoking cessation unless 

contraindications existed. While Chantix® was not available when this research study 

began in 2004, the protocol was modified on January 17, 2007, to include circumstances 

under which Chantix® could be used. Specifically, the protocol indicated that Chantix®

would be provided, “at the discretion of prescribing clinicians for subjects who cannot 

tolerate or who have failed adequate trials of other smoking cessation medications.” 

Subjects enrolled were required to have the diagnosis of PTSD and to be actively 

receiving treatment for that disorder. Subjects could not be enrolled if they had a 

psychotic disorder not in remission, were at imminent risk for suicide or violence, or had 

severe psychiatric symptoms. 

The Cooperative Studies Program (CSP) provided us with a list of 101

 different VA 

medical centers which enrolled patients receiving Chantix® in this smoking cessation 

study. The various sites were overseen by the Cooperative Studies Program (CSP), a 

VHA program designed to coordinate research occurring at multiple facilities. CSP 

 

1

 Houston, Hampton, Minneapolis, New Orleans, Philadelphia, Portland, Providence, San Diego, Tuscaloosa, and 

Washington, DC. 

VA Office of Inspector General 1 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

maintains five coordinating centers, a clinical research pharmacy, four epidemiological 

research and information centers, and a health economics resource center. The 

coordinating centers provide statistical and methodological guidance to VA researchers 

involved in clinical trials. CSP trials have resulted in numerous important contributions 

to research, including demonstrating the efficacy of a vaccine for shingles and 

coordinating multiple trials involving cardiovascular treatments that resulted in major 

innovations in the treatment of hypertension and coronary artery disease. 

The research protocol in question utilized the Palo Alto CSP Coordinating Center (the 

Coordinating Center). The Coordinating Center received all study data from the sites. It 

forwarded information pertaining to serious adverse events (SAEs) to the Albuquerque 

Pharmacy Coordinating Center. In an e-mail of June 20, 2008, CSP reported that as of 

June 18, 2008, there were 158 subjects nationwide who had received Chantix® while 

enrolled in the research study. This CSP data was based on self-reporting by research 

subjects during the course of the study. VHA indicated that there is no single data source 

that can completely and accurately portray actual Chantix® use by those in this study. In 

addition, VHA reported to us that there was a total of 945 subjects in the study 

nationwide. 

CSP had also reported in the June 20, 2008, e-mail that 11 of the VAMCDC subjects 

received Chantix®. However, the senior researcher (also known as the senior investigator 

(SI)) conducting the smoking cessation study at VAMCDC informed us on June 19 (the 

date of our first onsite visit), that there were a total of 109 subjects in the study at 

VAMCDC and that 12 of those 109 subjects received Chantix®. Following chart review 

for these 12 subjects, we found that 1 patient had never actually taken Chantix®. Later, 

on June 27, 2008, the SI informed us of an additional 4 patients at VAMCDC who 

received Chantix® at some time during the course of the study; this made a total of 

15 patients who received Chantix® as part of this study at VAMCDC. It is these 15 

patients whom we discuss throughout this report. 

VAMCDC is part of the VA Capitol Health Care Network (Veterans Integrated Service 

Network (VISN) 5). In addition to acute care services, it maintains a 120 bed long-term 

care unit and four Community Based Outpatient Clinics. It is affiliated with three 

medical schools and is a medical readiness partner with three Department of Defense 

facilities. The VAMCDC also has an active research program, with 70 researchers and 

185 active protocols as of June 27, 2008. It also maintains one of two VA War Related 

Illness and Injury Study Centers. 

A. FDA Notifications Pertaining to Chantix®

The FDA approved Chantix® on May 10, 2006, as an aid for smoking cessation. During 

pre-marketing studies, more than 4,500 people received Chantix®. Recorded adverse 

psychiatric reactions included frequent anxiety, depression, emotional disorders, 

VA Office of Inspector General 2 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

irritability, and restlessness. Initial product labeling did not include any warning 

regarding any suicidal ideation. VHA added the product to its National Formulary as a 

third line agent, following failure of nicotine replacement strategies and buproprion, 

another medication for smoking cessation. 

As additional information became available during post-marketing studies, the sponsor 

modified the patient package insert on November 20, 2007, to include possible adverse 

reactions such as depression, suicidal thoughts, and agitation. At this time, the FDA 

issued an “Early Communication About an Ongoing Safety Review” because of postmarketing cases involving suicidal ideation and behavior. This communication specifies 

that the FDA had not concluded that a causal relationship existed, nor did they advise 

health care professionals to discontinue the product. On January 31, 2008, in response to 

additional reported adverse events, the FDA requested that all advertising materials be 

modified to reflect the additional risks. On February 1, 2008, the FDA issued a public 

health advisory stating that “. . . it appears increasingly likely that there may be an 

association between Chantix® and serious neuropsychiatric symptoms.” 

B. Human Subjects Protections in Research 

Determining if and to what extent this public health advisory altered the relative risks and 

benefits of the smoking cessation study was the responsibility of the facility’s 

Institutional Review Board (IRB). Each facility in VHA conducting research involving 

human subjects must have an IRB, which is a committee vested with the responsibility of 

protecting human research subjects. The IRB is composed of scientists, physicians, and 

community members. In the VA, the IRB is a subcommittee of the Research and 

Development (R&D) Committee. Any research project must have both IRB and R&D 

Committee approval. 

In research protocols conducted at multiple sites, each site’s IRB must approve the 

protocol, as well as any substantive modifications. In approving the protocol, the IRB 

must determine that the potential benefits outweigh any risks to subjects involved in the 

research. Further, the IRB must approve any modifications to informed consent and 

ensure that each protocol has an adequate plan for monitoring the safety of subjects 

enrolled in the protocol. 

IRBs are required to meet regularly and to maintain minutes of those meetings. They 

must review all protocols at least annually. IRB Chairpersons may unilaterally approve 

minor changes to previously approved research using expedited review procedures, 

providing that the IRB reviews these actions at the next regularly convened meeting. 

In addition, IRBs review adverse events (AEs) and serious adverse events (SAEs) 

occurring during the course of research studies. AEs are defined as “any untoward 

occurrence (physical, psychological, social, or economic) in a human subject 

participating in research.” SAEs include “death; a life threatening experience; 

VA Office of Inspector General 3 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

hospitalization (for a person not already hospitalized); prolongation of hospitalization (for 

a patient already hospitalized); persistent or significant disability or incapacity; 

congenital anomaly and/or birth defects; or an event that jeopardizes the subject and may 

require medical or surgical treatment to prevent one.” 

IRBs do not, however, routinely review files maintained by the researchers, including 

whether there is a signed informed consent for each research subject. This type of 

information would be gathered through protocol audits, a process of reviewing the actual 

implementation of the protocol in accordance with human subjects protections. VHA 

Directive 2008-014, dated March 12, 2008, mandated that facilities perform such audits. 

Audit requirements included an evaluation of informed consent. Prior to this Directive, 

facilities were not required to fully audit research protocols. Rather, IRBs were only 

required to have a procedure for conducting such audits. 

IRBs in VHA are evaluated as part of an accreditation process in VHA. VHA contracted 

with the Association for the Accreditation of Human Research Protection Programs, Inc. 

(AAHRPP) to accredit its human subjects protection programs. Accreditation Standards 

used by AAHRPP include multiple measures of IRB compliance with Federal regulations 

and VHA policy. They conducted a site visit at the VAMCDC from October 30, 2007 – 

October 31, 2007. Accreditation was not granted. The facility received a status of 

Accreditation-Pending and was given the opportunity to submit an Improvement Plan. 

Scope and Methodology 

To address the concerns regarding the use of Chantix® in this research study, we chose to 

focus our review on issues of informed consent, patient notification of potential adverse 

effects associated with Chantix®, and the tracking and reporting of adverse events 

occurring during the course of this research study. The scope of this review is limited to 

the VAMCDC. Our first site visit to VAMCDC was on June 19, 2008. While 

conducting our inspection, we received allegations of potential inappropriate 

documentation, which we also reviewed. 

We addressed issues of informed consent by obtaining study records for the research 

subjects who we were told received Chantix® during the course of the study at 

VAMCDC. We compared these records to the patients’ electronic medical records. As 

discussed on page 2 of this report, we had identified 15 patients who had received 

Chantix® at some time during the research. We then attempted to contact 14 of the 15 

patients by telephone to determine when and if they had consented to enrollment in a 

smoking cessation study. As of June 30, 2008, we have been able to speak with 10 of 15 

patients; 1 of the 10 was hospitalized and could not be interviewed. An 11th patient was 

deceased as the result of an unrelated illness. We have called 3 patients whom we have 

been unable to contact. Therefore, we interviewed 9 of 15, spoke to 1 we could not 

interview, and were unable to reach 3 of 15; 1 of 15 was deceased as a result of unrelated 

causes, and 1 we did not attempt to contact. 

VA Office of Inspector General 4 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

In addition, we reviewed IRB files, files maintained by the SI at the VAMCDC, e-mail, 

and pharmacy correspondence pertaining to this protocol. We interviewed the SI, 

Associate Chief of Staff (ACOS) for Research and Development, the IRB Administrator, 

study personnel, the research compliance officer, and the Acting Chief of Staff. We 

obtained and reviewed records from the CSP Coordinating Center in Palo Alto, 

California, and interviewed staff located at that facility. We reviewed CSP policies and 

procedures, adverse event reports, and numerous documents from VHA’s Office of 

Research and Development pertaining to the smoking cessation study as conducted by 

VAMCDC. We also asked the FDA for an opinion regarding whether the November 20, 

2007, early communication should have prompted a modification to the protocol. As of 

the date of this report, we have not received this opinion. 

In this report we did not review or comment upon the medical care provided to individual 

veterans. We reported our findings only in the aggregate form. We performed the 

inspection in accordance with the Quality Standards for Inspections published by the 

President’s Council on Integrity and Efficiency. 

Part II. Results and Conclusions 

Issue 1: Patient Notification of FDA Communications 

Concerning Chantix®

The CSP Coordinating Center and the facility’s Pharmacy Service appropriately notified 

providers following the FDA’s Early Communication of November 20, 2008. However, 

following the February 1, 2008, Public Health Advisory, we found that the facility’s 

research service did not ensure that patients involved in the smoking cessation study were 

notified of the risk of suicidal thoughts or behavior in a timely manner. 

The November 20, 2007, Early Communication from FDA 

The VAMCDC IRB approved the smoking cessation study on August 16, 2004. The 

R&D Committee there initially approved the smoking cessation study on August 27, 

2004. R&D Committee minutes describe the study as a greater than minimal risk study 

involving patients with PTSD. The study further required monitoring of PTSD and 

depression symptoms to determine whether smoking cessation would worsen these 

conditions. 

The IRB re-approved the study under continuing review procedures on July 11, 2005; on 

May 15, 2006; and on April 9, 2007. The R&D Committee also re-approved the study 

annually, with the last such approval occurring on April 24, 2008. On April 30, 2007, the 

IRB approved an amendment to the study, adding Chantix® as a study medication. 

VA Office of Inspector General 5 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

Further, the consent form was amended to reflect the risks of Chantix® which were 

known at that time; these included insomnia, unusual dreams, headache, and constipation. 

On November 20, 2007, the FDA issued its early communication notifying health care 

professionals of post-marketing cases involving suicidal ideation and occasional suicidal 

behavior. The Associate Chief of Pharmacy at the facility received this alert the same 

day via e-mail through a subscription to a service informing health care professionals of 

medication alerts. E-mails describing the risks were sent to providers at the facility on 

November 21, 2007. The Associate Chief of Pharmacy generated lists of patients by 

prescriber between November 23, 2007, and November 26, 2007, and indicated that these 

lists were distributed. They were paper rather than electronic, because all the providers at 

the facility do not have encrypted e-mail to ensure the privacy and security of the 

patients’ personal information. The Chief of Primary Care confirmed that these lists were 

distributed. 

CSP conducted three conference calls with site researchers between November 20, 2007, 

and December 31, 2007. The first of these conference calls occurred on November 26, 

2007. These minutes record the following statement: “...because this is not a drug study, 

it is not necessary to take action on this [the FDA communication] unless your local IRB 

requires that you report it to them.” On December 3, 2007, minutes reiterate that it was 

considered the decision of the local IRB as to what actions should be taken following an 

FDA warning. On December 4, 2007, minutes state the following: 

Given that this is not a drug study and use of varenicline is optional, the 

Chairs don’t feel that sites need to inform their IRBs of this issue unless 

particular subjects report adverse events related to the medication. 

On January 18, 2008, a communication from the VHA Pharmacy Benefits Management 

Service to health care providers stated the following: “FDA’s preliminary assessment 

indicates that many cases presented with new-onset of depressed mood, suicidal ideation, 

and behavior and emotional changes within days to weeks of starting varenicline 

[Chantix®].” Further, the communication described a warning from the European 

Medicines Agency of suicidal ideation and suicidal attempt in some patients taking 

Chantix®. The communication recommended that providers “monitor patients taking 

varenicline for changes in mood and behavior.” We could find no documentation that the 

SI formally reported this to the IRB, or that the IRB addressed any of the events related to 

the November 20, 2007, communication. Documentation supplied regarding CSP 

conference calls between November 20, 2007, and December 31, 2007, make it clear that 

the CSP believed that local IRBs should decide whether this communication warranted 

action. 

This lack of action is concerning, because it is evident that the pharmacy service 

considered the November 20, 2007, communication important information requiring 

dissemination to providers and the creation of lists of patients on this medication. This 

VA Office of Inspector General 6 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

was particularly important in the smoking cessation study, as it by definition enrolled 

only those veterans who had PTSD. Because not all the research subjects in the smoking 

cessation study received their medications from VA providers, and because all providers 

prescribing Chantix® for patients involved in the study were not listed on the protocol, we 

were unable to determine whether all providers notified patients of these events. 

The February 1, 2008, Public Health Advisory

The CSP Coordinating Center and the IRB reacted following FDA’s Public Health 

Advisory of February 1, 2008. Minutes from a February 5, 2008, conference call 

between study coordinators and assessment technicians and Coordinating Center staff 

indicated that the new safety information should be passed along to site clinicians to 

ensure patient notification. The Human Rights Committee at Palo Alto sent a 

memorandum to the Director of the Coordinating Center on February 8, 2008. This 

memorandum stated that, “it is appropriate that veterans who are or who might be 

prescribed this medication while participating in the study be informed, and given the 

opportunity to discuss alternative treatments with their provider.” This memorandum 

also contained the following statement: 

The proposed procedure is that all participants be given the information at 

their next follow up visit; this will be documented by their signature on the 

addendum. While this is acceptable for participants who are not receiving 

the medication, those who are taking varenicline should be notified more 

urgently. 

The CSP Coordinating Center sent a memorandum dated February 13, 2008, to 

researchers at the VAMCDC stating that patients currently on Chantix® “will receive a 

copy of the consent addendum in the mail, along with a cover letter explaining the reason 

for the addendum.” The Center provided a draft of the letter. The letter described risks 

of “anxiety, nervousness, tension, and depression as well as untoward changes in 

behavior.” It did not contain any information regarding increased risks of suicidal 

thoughts or behavior. While the letter did not describe these risks, the informed consent 

addendum did state that side effects included “thoughts of suicide, and attempted and 

completed suicide”. However, CSP indicated that patients could sign the addendum at 

their next study visit. The SI at each site was responsible for ensuring that the letters 

were sent following IRB approval. 

The IRB at VAMCDC subsequently met on March 3, 2008. Minutes from that meeting 

document that the IRB Chair and Administrator met with the SI on February 29, 2008, to 

discuss patient notification issues following that advisory. The IRB Chair approved the 

addendum to the consent form addressing these risks by expedited review on the same 

day. The SI was to notify all study participants by mail with the letter in addition to the 

informed consent addendum. The SI planned to notify all study participants, whether or 

VA Office of Inspector General 7 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

not they were on Chantix®. The minutes include the following sentence: “The FDA 

states that some patients on varenicline [Chantix®] have an increased risk of depression 

and suicidality.” Minutes also state that patient notification issues were reported to the 

research compliance officer for followup. 

We interviewed the SI, IRB Administrator, IRB Chair, and study coordinator for the 

smoking cessation trial at VAMCDC. The IRB Administrator and Chair indicated that it 

was the SI’s responsibility to actually send the letters. The SI stated the letters were sent 

to all 109 participants. The study coordinator reported assisting in this task. The letters 

were not sent with any return receipt requested, or with any other means of verifying 

delivery to the appropriate individuals. There was no consistent documentation in the 

electronic medical record that such letters were sent. We interviewed nine of the patients 

by phone. Three of these patients recalled receiving a letter. The study coordinator 

indicated that a few letters came back, but we were unable to locate documentation of any 

follow-up actions to address these returned letters, or exact numbers of how many were 

returned. 

While we believe these letters were sent, we have no reliable way of determining how 

many of the veterans actually received notification. Further, we concluded that the letter 

did not adequately explain the risks associated with Chantix® at that time. We were told 

that the informed consent addendum was included with the letter when the letters were 

mailed, but we were unable to find any documentation of sending these items to all 

affected veterans. Therefore, we found that the notification procedures for patients in the 

smoking cessation study at the VAMCDC following the February 1, 2008, Public Health 

Advisory did not adequately ensure that all patients were notified of this risk in a timely 

manner. 

On May 30, 2008, VHA’s Pharmacy Benefits Management Service sent an e-mail to 

VISN formulary leaders and pharmacy chiefs asking them to distribute a letter to veterans 

taking Chantix® that informed them of the risk of suicide associated with the medication. 

Two of the six veterans who did not recall receiving the initial letter from the SI recalled 

getting this letter recently. 

While the facility’s Pharmacy Service appropriately notified providers of the risks 

associated with Chantix, we do not find that the research service ensured that subjects 

enrolled in the smoking cessation study were notified of these risks. We therefore 

concluded that the facility notified providers of the adverse effects of Chantix® in an 

appropriate and timely manner but did not ensure that patients enrolled in the smoking 

cessation study received this information. 

VA Office of Inspector General 8 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

Issue 2: Adequacy of Informed Consent 

Federal informed consent regulations govern the use and participation of human subjects 

in research. The purpose of the regulations is to safeguard the welfare of humans and to 

assure that the subjects are given enough information about the research so that they may 

make informed decisions about whether or not to participate. 

Patients enrolling in the smoking cessation study were initially required to sign two 

consent forms. The first indicated the patient’s consent to be screened for the study to 

determine whether they were eligible. If a patient was found eligible for the study, the 

patient would then sign a second consent form to participate in the research and be 

informed of any medications which might be used in the study. Over time there were 

three versions of this second consent form. The first version, we call “the original second 

consent form.” The second version of this form we refer to as the “revised consent 

form”; it introduced Chantix® to the study and informed the patients of the earliest known 

risks. The third version of this form we refer to as “the addendum”; it disclosed the 

greater risks of Chantix® as of February 2008. 

Thus, the “original second consent form” to participate in the study contained 

information pertaining to the risks of nicotine patches, nicotine gum, and buproprion, 

another medication used for smoking cessation. The original second consent did not 

contain a mention of Chantix®, which at that time had not yet received FDA approval and 

was not a part of the research study. 

On April 9, 2007, the IRB approved a new second consent form to participate in the 

study, which is referred to here as the “revised consent” form; it replaced the original 

second consent. This revised consent form included information on the risks of Chantix®

that were known at that time, to include changes in dreams and nausea. We reviewed all 

the consent forms for all 15 patients identified by the SI as being on Chantix® at some 

time during the course of the study. We could locate the revised consent form for only 

5 of the 15 patients on Chantix®. The SI indicated that patients entering the study after 

April 9, 2007, were to sign that revised consent form, but that individuals who had 

already signed the original second consent form were not re-consented during the 

research study. 

Following the February 1, 2008, FDA Advisory, an addendum was created and added to 

the revised consent form to include information about the risks of suicidal thoughts or 

behavior for patients taking Chantix®. In this report, we refer to the addendum to the 

informed consent, which is essentially the third version of the second consent form, as 

“the addendum.” The addendum was initially approved through expedited review on 

February 29, 2008, and disclosed that Chantix® could cause “changes in behavior, 

anxiety, nervousness, tension, depression, thoughts of suicide, and attempted or 

completed suicide.” The SI stated that she mailed the addendum to all patients within the 

study, not just to those on Chantix®. On April 1, 2008, minutes from a CSP conference 

VA Office of Inspector General 9 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

call between study personnel and the Coordinating Center indicated that the study 

coordinator and assessment technician from the VAMCDC site reported that “a number 

of patients have signed the consent addendum.” 

Chantix® next appears in the VAMCDC IRB minutes of May 5, 2008. These minutes 

document a discussion between a patient who experienced an episode of aberrant 

behavior while on Chantix® and the SI and the Chief of Psychiatry. The patient wanted 

to withdraw from the study and a letter to that effect was signed by these parties and 

witnessed by the IRB Chair. On May 6, 2008, another CSP conference call occurred in 

which VAMCDC study personnel stated that they were “actively approaching subjects 

about the varenicline (Chantix®) addendum and obtaining signatures.” 

We reviewed only those charts of the 15 patients identified as having taking Chantix® at 

some time during the course of the review. We could locate signed addendums including 

information about the risks of suicidal thoughts or behavior for only 6 of these 15 patients 

as of June 23, 2008. Of these 6, only 2 were signed prior to June 20, 2008. We do note 

that, of the patients without a signed addendum in their chart, one had died as the result 

of an unrelated illness and another had moved out of the area. Medical records 

demonstrate that 11 of the 15 patients had visited the medical center between March 3, 

2008, and June 20, 2008. 

Despite evidence that study personnel at the VAMCDC reported that the consent process 

was going well on numerous occasions, we found that the facility failed to obtain patient 

signatures on the addendum to the informed consent describing the risk of suicidal 

thoughts in patients taking Chantix®. Patients also were not re-consented with the 

April 9, 2007, consent form, which added Chantix® to the list of medications already 

utilized by study prescribers and disclosed risks known to be associated with the drug at 

that time. Minutes from a June 2, 2008, conference call between CSP and research 

personnel at the VAMCDC once again record that VAMCDC told the CSP that “[T]he 

varenicline [Chantix®] consent process is going well.” 

Further, we found that the facility’s research compliance program failed to appropriately 

monitor the adequacy of the informed consent process at the facility. The research 

compliance officer obtained her current position in October of 2007. Since that time, she 

told us she has “been in training mode.” She reviewed the consent forms for this study 

but did so only from the perspective of whether the informed consent process was 

documented appropriately. She did not verify that there were consents for all patients 

enrolled in this study. AAHRPP noted several deficiencies relating to the informed 

consent process in its October 2007 visit. Standards described as “NOT MET” by 

AAHRPP included: 

(1) Researchers “develop an informed consent process and method of documentation 

appropriate to the type of research and the study population, emphasizing the 

importance of participant comprehension and voluntary participation.” 

VA Office of Inspector General 10 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

(2) The Research Review Unit has and follows “written policies and procedures 

requiring that the investigator has and follows a procedure for properly 

documenting informed consent.” 

(3) The Research Review Unit “reviews the content of the consent process including 

the consent document, and the process through which informed consent is 

obtained from each participant, focusing on measures to improve patient 

understanding and voluntary decision-making.” 

We do note, however, that the facility did not receive a copy of the Final Site Visit 

Report from AAHRPP until March 19, 2008. AAHRPP did not accredit the VAMCDC; 

rather, they gave it a status of Accreditation Pending. An Improvement Plan is due to 

AAHRPP on July 14, 2008. 

Issue 3: Psychiatric Adverse Events and Serious Adverse 

Events in Patients Enrolled in the Smoking Cessation Study 

Receiving Chantix®

We also reviewed whether the VAMCDC appropriately monitored AEs and SAEs 

occurring during the course of the smoking cessation study. Our review of SAEs was 

limited to psychiatric events occurring at the VAMCDC in patients who had taken 

Chantix® at some time during the course of the study. We did not evaluate all adverse 

events from the VAMCDC or SAEs from any of the other sites. 

At the VAMCDC, we found reports for 4 SAEs relating to psychiatric hospitalizations for 

3 of the 15 patients; 1 of those patients was on Chantix® at the time. Three SAEs were 

dated in early 2007; the fourth was in early 2008. 

We then sought to determine whether the Coordinating Center had evaluated the 

communications from FDA in terms of the study results nationwide. We did find that 

they considered this problem. They initially decided not to change reporting 

requirements of AEs following the November 20, 2007, communication. Prior to the 

February 1, 2008, warning, sites were required to report SAEs but not all AEs. However, 

following the February 1 warning, sites were required to report AEs and SAEs. The Data 

and Safety Monitoring Board for the nationwide Chantix® study met on February 27, 

2008. Minutes from this meeting contain the following statements: 

[A Board member] reported that the number of SAEs [includes all SAEs, 

not just psychiatric SAEs] continues to be high. Often one or two lifethreatening events are reported in a day, but most are not study related. . . 

The study chose to include varenicline [Chantix®] when it became 

available. [The Board member] noted that the original [market-related] 

studies [on Chantix®] did not include people with active mental disorders, 

so we are starting to see the affect [sic] now in our population. We are 

VA Office of Inspector General 11 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

asking sites to report these side effects on the SAE forms even if they are 

only AEs [adverse events]. 

Also on February 27, 2008, the human rights committee at the CSP Coordinating Center 

in Palo Alto met and discussed Chantix®. Minutes reflect a discussion of the fact that the 

initial Chantix® studies evaluating its safety did not include subjects with comorbid 

mental health diagnoses. Minutes state that the “study Co-Chairs agreed to check with 

sites and review how those participants who are taking varenicline, but are not in therapy, 

are being monitored.” We were not provided with any written documentation regarding 

if or when this occurred. 

Study results provided to us described 25 serious adverse events of a psychiatric nature 

which occurred while patients were enrolled in the study nationwide. This did not mean 

that these events were related to the study or that they occurred while the patient was 

actually taking Chantix®. By definition, all patients in the study had pre-existing mental 

illness. The 25 events disclosed included 16 patients with suicidal ideation; 1 who 

attempted suicide; and 1 who had homicidal thoughts. 

We are concerned, however, by the comment in the Data Safety and Monitoring Board 

minutes stating that we are seeing the effects now “in our population.” This made the 

human rights committee decision to review how patients taking Chantix® were to be 

monitored all the more important. However, we do note that data provided reflected that 

only a single possible Chantix®-related event occurred during the course of this study 

nationwide. Interpreting nationwide data for this study, however, is expressly beyond the 

scope of this review. 

Issue 4: Alleged Documentation Irregularities in the Smoking 

Cessation Study at VAMCDC 

During the course of our review, we received allegations that study personnel had 

falsified certain study records at VAMCDC. The smoking cessation study required study 

personnel to fill out a number of written documents based upon direct patient interviews. 

One such document was the Clinician Administered PTSD Scale (CAPS) form. This is a 

structured interview used in part to assess the severity of PTSD symptoms in study 

participants. At VAMCDC the study coordinator could not complete this form because 

he was not a clinician. The assessment technician typically completed these forms at the 

VAMCDC. 

On June 24, 2008, the ACOS for R&D notified ORO of allegations he received regarding 

inappropriate documentation of information contained on the CAPS form for two patients 

associated with the smoking cessation study. It was reported that the study coordinator 

completed these forms based on information contained in other documents, rather than 

from a direct patient interview. 

VA Office of Inspector General 12 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

We reviewed the CAPS forms, and interviewed the study coordinator. We were unable 

to interview the assessment technician because of reported health problems. The study 

coordinator admitted that in two instances, he completed these forms from information 

obtained from other forms. He further stated that he had the assessment technician on the 

telephone who offered advice as to how to complete these forms. We verified that in at 

least one of these instances, the assessment technician was on leave without pay on the 

day of the patient’s visit. 

Based upon this information, we conclude that the CAPS form in at least one instance 

was not completed by a clinician during a direct patient interview as required by the 

protocol. Further, we were told that this particular record was faxed to the Coordinating 

Center along with the other data collected at this site. We therefore found that this 

employee did not complete the form in accordance with the protocol, and we question the 

accuracy of the data contained on that form. 

In addition, we reviewed quality control reports sent from the Coordinating Center 

concerning their evaluation of study data submitted from the VAMCDC. These reports 

were provided on a weekly basis. The Coordinating Center reports contain numerous 

entries concerning VAMCDC’s missing pages, missing data, and inconsistent data. 

While data entry errors are exceedingly common, we are concerned about these reports in 

light of the information described above. 

Conclusions 

The actions of study personnel regarding the completion of the smoking cessation study 

records suggest that the accuracy of such records may be in dispute. Data used in the 

type of important trials described in this report may be used to define the standard of care 

for PTSD patients who want to stop smoking. The quality control reports reflect that 

CSP monitored data submissions regularly. However, the Coordinating Center could not 

be expected to detect whether the CAPS form was appropriately completed from a direct 

patient interview or extrapolated from other study data. These kinds of documentation 

irregularities may affect the credibility of study results. While in this case we have no 

reason to believe that the problem is not remediable, it reinforces the need for monitoring 

of data collection and researcher records at a local level. 

The human rights committee at the Coordinating Center suggested special monitoring for 

study subjects taking Chantix® and not receiving therapy. We were not able to locate 

documentary evidence that this recommendation was ever implemented at VAMCDC. 

Further, the VAMCDC did not initially supply us with an accurate number of patients 

having ever taken Chantix® during the course of the study, suggesting that local sites may 

not have been tracking which patients were and were not taking Chantix. This makes it 

unlikely that they ever identified the subgroup of those patients who were not actively 

receiving therapy while taking Chantix®. 

VA Office of Inspector General 13 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

In addition, the absence of signed informed consent addendums describing the effects of 

Chantix® after they were known to researchers at the VAMCDC is also of concern. 

While the SI at the VAMCDC did send out a letter in late February or early March 2008 

to at least some participants in the study, we have no documentary evidence of who 

received it or when. This prevents us from ensuring that patients were notified in a 

timely fashion once side effects of Chantix® were known. We also did not find that the 

letter contained sufficient warning regarding the possible risk of suicidal thoughts or 

actions, but note that this information was in the enclosed addendum to the consent form. 

We also found that the pharmacy service provided timely notification to clinical care 

providers, including lists of patients on the medication. The VA sent letters dated 

May 30, 2008, to identified patients on Chantix® to alert them to medication side effects. 

We believe that this was sufficient for the general population of patients in the facility 

taking Chantix®. However, research subjects, who by definition had active PTSD, 

represented a group uniquely susceptible to neuropsychiatric side effects. We believe 

that the Coordinating Center recognized this in deciding to modify the informed consent 

and mail letters to patients. The local implementation of this directive, however, is at 

issue in that the VAMCDC did not ensure that these patients signed informed consent 

addendums or received letters notifying them of the additional risks. 

Finally, the deficiencies involving informed consent identified in the AAHRPP review 

suggest that the VAMCDC may not be adequately monitoring the informed consent 

process on a systemic scale. The scope of this review prevents us from making a 

definitive statement with regard to the VAMCDC’s research program overall, but 

deficiencies identified in the AAHRPP report suggest that some issues may be systemic 

in nature. Therefore, we make the following recommendations: 

Recommendations 

Recommendation 1: The Under Secretary for Health will ensure that all patients who 

currently take Chantix® have been informed of the possible association between Chantix®

and suicidal thoughts. 

Recommendation 2: The Under Secretary for Health will develop a formal mechanism 

for ensuring that Institutional Review Boards are directly notified of FDA 

communications concerning medications when they are responsible for protocols 

involving those medications. 

Recommendation 3: The Under Secretary for Health will ensure that all patients 

involved in the smoking cessation study are informed of the risks associated with 

Chantix® by VHA study personnel and given the opportunity to sign the addendum to the 

informed consent disclosing those risks. 

VA Office of Inspector General 14 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

Recommendation 4: The Under Secretary for Health will take appropriate 

administrative action, to include a research misconduct inquiry, based upon the findings 

contained within this report. 

Recommendation 5: The VISN5 Director will require that the smoking cessation study 

data collected at VAMC Washington, DC, be validated to ensure its accuracy. 

Recommendation 6: The VISN 5 Director will require the medical center director to 

audit a representative sample of all active protocols involving human subjects for 

compliance with VHA informed consent requirements, including whether an informed 

consent can be located for each study participant. 

Recommendation 7: The VISN 5 Director will require the medical center director to 

ensure that protocols are being audited in accordance with VHA Directive 2008-014. 

 

VA Office of Inspector General 15 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC

Appendix A 

Under Secretary for Health Comments 

Department of 

Veterans Affairs Memorandum

Date: July 30, 2008 

From: Under Secretary for Health (10) 

Subj: OIG Draft Report, Healthcare Inspection – Human Subjects 

Protections in One Research Protocol, VA Medical Center, 

Washington, DC, Project No. 2008-02346-HI-0140 (WebCIMS 

408201) 

To: Assistant Inspector General for Healthcare Inspections (54) 

1. I have reviewed the draft report, and I concur with the 

recommendations. While I strongly believe that VA has an outstanding 

research program, it is evident that the circumstances involved in this case 

have resulted in veterans who believe that they have been improperly 

treated, and I regret the extent to which our actions may have contributed to 

that belief. This draft report cites valuable opportunities for improvement, 

and I will utilize your recommendations to ensure the best, most ethical and 

safest scientific inquiries into the health care needs of our Nation’s 

veterans. 

2. While I concur with the recommendations, there are a number of 

comments I would like to make concerning the report findings. First, in 

considering the events surrounding this study, it is important to emphasize 

that this research project is not a drug study. It is an examination of the 

most effective treatment for heavy smokers who have post-traumatic stress 

disorder (PTSD), using medications approved by the Food and Drug 

Administration (FDA). The specific drug that is the focus of your report, 

Chantix®, is in fact considered to be the most effective medication 

available for smoking cessation. Any veterans receiving Chantix® in the 

study, or anywhere in VA, have been prescribed this drug by their doctors 

following an individual doctor-patient decision, with continued monitoring 

of the patient's health status. When information suggested that some 

patients taking Chantix® experienced potential psychological side effects, 

VA promptly notified its clinical providers. VA also sent letters discussing 

possible side-effects to every individual participating in the study, as well 

VA Office of Inspector General 16 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC

as to every veteran prescribed Chantix® by VA. Within this letter, VA 

encouraged all patients to contact their provider immediately if they 

experienced side effects and assured them that VA will help them find 

another way to quit smoking if they are concerned about Chantix® or are 

experiencing side effects. As far as I am aware, VA is the only health care 

organization that notified patients following issuance of FDA's Public 

Health Advisory on February 1, 2008, despite no requirement to do so. 

3. I am also concerned that your presentation of particular findings in the 

report may lead readers to misinterpret VHA’s actions related to this 

research protocol. The draft report concludes that the Washington, DC VA 

Medical Center (VAMCDC) did not ensure that patients with PTSD, who 

were also enrolled in a smoking cessation study, receive adequate and 

timely notice of the risks associated with Chantix®. 

FDA did not require that notifications be made to patients on Chantix®; 

nevertheless, given the vulnerability of the patients in the study, the 

VAMCDC Research Service took positive action to notify patients of the 

risks involved. The senior investigator (SI) and study coordinator 

conducting the smoking cessation study at VAMCDC indicated that they 

mailed out letters and informed consent addendums describing the risks 

associated with taking Chantix® to all 109 participants in the study, 

including the 16 patients who were prescribed Chantix®. You 

acknowledged that you believe VA did send out these patient notifications. 

4. Your report also finds fault with the adequacy of our patient notification 

and concludes that the notification procedures following the FDA February 

1, 2008, Public Health Advisory did not adequately explain the risks 

associated with Chantix®. Your conclusion is based upon the finding that 

while the letter described risks of anxiety, nervousness, tension, and 

depression as well as untoward changes in behavior associated with taking 

Chantix®, only the informed consent addendum contained information 

regarding increased risks of suicidal thoughts or behavior. While the 

argument that inclusion of information regarding increased risks of suicidal 

thoughts or behavior in both the letter and the informed consent addendum 

would have resulted in a stronger notification may have some validity, I 

believe that since the addendum included the information and the 

addendum was a part of the notification package, our notification was 

appropriate. 

5. Additionally, the draft report finds fault with the timeliness of our 

patient notification and concludes that while VAMCDC's Pharmacy Service 

appropriately and timely notified providers of the risks associated with 

Chantix®, the facility did not ensure that patients enrolled in the study 

VA Office of Inspector General 17 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC

received this information in a timely manner. Following the FDA's 

February 1, 2008 Public Health Advisory, by February 13, 2008, the 

Cooperative Studies Program (CSP) Coordinating Center drafted the 

notification letter and informed consent addendum for submission to the 

facility's Institutional Review Board (IRB), which has sole authority to 

approve any modifications to informed consent and patient 

communications. Realizing the importance of this notification, the IRB 

Chair and Administrator met with the SI on February 29, 2008, to expedite 

review and approval of the notification letter, addendum, and subsequent 

patient notification. The SI mailed out the notifications on March 3, 2008. 

I believe that this timeline and expedited IRB approval process indicate that 

VAMCDC's Research Service acted appropriately and timely notified 

patients of the risks associated with Chantix®. 

6. In regards to your finding that VAMCDC failed to ensure that patients 

in this study who had taken Chantix® signed an addendum to the consent 

form disclosing these risks, I agree that a stronger effort to follow-up with 

these patients was warranted. Since the discovery that not all 16 veterans 

who were prescribed Chantix® at any time signed the addendum, 

VAMCDC has worked diligently to try to obtain the remaining signatures. 

To date, the facility has documented that 10 of the 16 veterans have signed 

the addendum. The facility also verified that none of the 16 patients have 

active Chantix® prescriptions, and has no reason to believe that any of 

these patients are currently taking the drug. Of the six patients that have 

not signed the addendum: one is deceased; one moved to Florida, but has an 

appointment to come to VAMCDC to sign the addendum when visiting the 

DC area in August 2008; one withdrew from the study on May 2, 2008; two 

have appointments to come to the VAMCDC and sign the addendum, but 

have not yet reported for those appointments; and one, VAMCDC has not 

been able to make direct contact with despite repeated phone call, emails, 

and letters. It is also important to note that for the two patients who have 

appointments to sign the consent addendum, there have been no study 

related visits since mailing of the information letter and addendum on 

March 3, 2008. VAMCDC personnel continue to work diligently to reach 

these remaining three individuals and obtain the signed addendums. 

7. Your report also states that the Association for the Accreditation of 

Human Research Protection Programs, Inc. (AAHRPP), the organization 

responsible for accrediting VA facilities conducting human subjects 

research, noted significant deficiencies in informed consent processes and 

procedures at the VAMCDC as a whole during an October 2007 site visit. I 

believe that the characterization of AAHRPP's review resulting in 

"significant deficiencies" is not an appropriate one. It would be more 

VA Office of Inspector General 18 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC

accurate to state that AAHRPP found deficiencies at VAMCDC related to 

the lack of certain elements of disclosure in the consent template, 

documentation of its informed consent processes, and the consistency of its 

informed consent policies. In response to the AAHRPP's review, 

VAMCDC revised all informed consent templates and policies to adhere to 

AAHRPP's recommendations and has addressed all previously-cited 

elements in the Improvement Plan that it submitted to AAHRPP on July 14, 

2008. 

8. The draft report further states that AAHRPP accreditation was not 

granted to VAMCDC, and that the facility received a status of 

Accreditation Pending. While this is a true statement per se, I believe the 

report does not provide enough context regarding VAMCDC's accreditation 

status to give the reader a full understanding. AAHRPP has four 

accreditation categories: Full Accreditation, Qualified Accreditation, 

Accreditation Pending, and Accreditation Withheld. It is important to point 

out that AAHRPP did not place the VAMCDC in its Accreditation 

Withheld category. Instead AAHRPP placed VAMCDC in its 

Accreditation Pending category. This is not uncommon as 62 percent of 

VA facilities receive Accreditation Pending status following an AAHRPP 

visit.1

 By assigning VAMCDC this category, AAHRPP indicates that the 

organization is able and willing to commit to take corrective actions to meet 

the criteria for accreditation within a reasonable time period. Thus, it 

would be more accurate for the report to state that VAMCDC's AAHRPP 

accreditation is still in process. 

9. Regarding, the report's conclusion that VAMCDC's research compliance 

program did not conduct protocol audits in accordance with VHA Directive 

2008-014, Auditing of VHA Human Subjects Research to Determine 

Compliance with Applicable Laws, Regulations, and Policies, I must point 

out that VHA issued this policy on March 12, 2008, and implementation of 

new policy requires an adequate period of time. This directive, as you 

correctly point out, mandates that facilities conduct protocol audits. Prior 

to issuance of this directive, there was no such mandate; the only 

requirement was that each IRB have a procedure for conducting such 

audits. In response to this previous requirement, VAMCDC has had a 

research compliance program and procedures for conducting protocol 

audits since 2003. VAMCDC conducted a full audit on this protocol on 

February 23, 2006, and found that all required original consents were 

present. Furthermore, VAMCDC has continuously audited consents as part 

 

1

 Figure provided by VHA Office of Research and Development Program for Research Integrity 

Development & Education (PRIDE). 

VA Office of Inspector General 19 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC

of an ongoing process, and previous consents have been found to be present 

for all participants in this protocol. Nonetheless, I agree that the Medical 

Center could improve how it monitors the adequacy of the informed 

consent process. I believe that VAMCDC leadership is taking the 

necessary actions to ensure that this takes place. Specifically, Medical 

Center leadership fully implemented VHA Directive 2008-014 on June 18, 

2008, and appointed the Chief of Staff, who oversees the Research 

Compliance Office, as the official responsible for the auditing program. 

10. In regards to the report's finding that in at least one instance, a form 

designed to describe a clinician’s interview with a subject was completed 

from other data rather than from a direct patient interview, I request that 

you acknowledge that this is an allegation at this time. After the SI became 

aware of this allegation, she promptly notified all of the appropriate VA 

authorities. In response, VHA Office of Research Oversight (ORO) 

instructed VAMCDC to initiate a Research Misconduct Inquiry in 

accordance with VHA Handbook 1058.2, Research Misconduct. 

VAMCDC initiated an inquiry on July 1, 2008, and will report its findings 

to ORO by July 31, 2008. 

11. Thank you for the opportunity to review the report. Attached is VHA’s 

complete plan of corrective action. If you have any questions, please 

contact Margaret Seleski, Director, Management Review Service (10B5) at 

(202) 461-8470. 

 (original signed by:) 

Michael J. Kussman, MD, MS, MACP 

Attachment 

VA Office of Inspector General 20 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC

VETERANS HEALTH ADMINISTRATION 

Action Plan 

OIG Draft Report, Healthcare Inspection: Human Subjects Protections 

in One Research Protocol, VA Medical Center, Washington, DC 

Project No. 2008-02346-HI-0140 

Recommendations/ Status Completion 

Actions Date 

We recommended that the Under Secretary for Health will: 

Recommended Improvement Action(s) 1: Ensure that all patients 

involved in the smoking cessation study who currently take Chantix® 

have been informed of the possible association between Chantix® and 

suicidal thoughts. 

Concur 

VA sent letters to every patient prescribed Chantix® by VA to inform them 

of the possible association between Chantix® and suicidal thoughts. 

Within this letter, VA encouraged all patients to contact their provider 

immediately if they experienced side effects and assured them that the VA 

will help them find another way to quit smoking if they are concerned 

about Chantix® or are having side effects. Currently, there are 40 study 

patients in VA who are currently taking Chantix®, and VA will continue to 

closely monitor all of them. 

 Completed 7/8/08 

Recommended Improvement Action(s) 2: Develop a formal 

mechanism for ensuring that Institutional Review Boards are directly 

notified of FDA communications concerning medications when they 

are responsible for protocols involving those medications. 

Concur 

VHA Office of Research and Development (ORD) is currently developing 

a directive that will address the direct notification of Institutional Review 

Boards (IRB) in the event of FDA communications concerning medications 

in which they are responsible for protocols involving those medications. 

After issuance of the directive, ORD will ensure that each medical center's 

VA Office of Inspector General 21 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC

Research Service, Pharmacy Service, and Institutional Review Board are 

fully aware of and understand the tenets of the new directive. 

 In Process 9/30/08 

Recommended Improvement Action(s) 3: Ensure that all patients 

involved in the smoking cessation study are informed of the risks 

associated with Chantix® by VHA study personnel and given the 

opportunity to sign the addendum to the informed consent disclosing 

those risks. 

Concur 

VA sent letters to every patient prescribed Chantix® by VA to inform them 

of the risks associated with Chantix®. Within this letter, VA encouraged 

all patients to contact their provider immediately if they experienced side 

effects and assured them that the VA will help them find another way to 

quit smoking if they are concerned about Chantix® or are having side 

effects. VA will continue to work diligently to obtain signed addendums 

for those patients prescribed Chantix® that have not yet signed the 

addendum. All study sites will inform VHA Office of the Deputy Under 

Secretary for Health for Operations and Management when this action is 

complete. 

 In Process 7/31/08 

Recommended Improvement Action(s) 4: Take appropriate 

administrative action, to include a research misconduct inquiry, based 

upon the findings contained within this report. 

Concur 

The Secretary of Veterans Affairs directed VHA Office of Research 

Oversight (ORO) to conduct a comprehensive review of CSP Protocol 

#519, Integrating Practice Guidelines for Smoking Cessation into Mental 

Health Care for Posttraumatic Stress Disorder (PTSD). This was 

completed on July 18, 2008. Furthermore, ORO is currently coordinating a 

comprehensive review of all VHA research studies involving individuals 

with PTSD. The purpose of this review is to ensure (a) appropriate 

sensitivity to the PTSD study population; (b) consideration of relevant Food 

and Drug Administration (FDA) or Sponsor advisories, alerts, and 

warnings; (c) appropriate subject notification regarding such advisories, 

alerts, and warnings; and (d) review of risks associated with medications 

VA Office of Inspector General 22 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC

likely to be used in the PTSD study population. This comprehensive 

review is projected for completion by August 25, 2008. 

Lastly, ORO is exercising oversight of formal Research Conduct 

proceedings in this case in accordance with VHA Handbook 1058.2, 

Research Misconduct. Washington DC VA Medical Center (VAMCDC) 

initiated this Research Misconduct Inquiry on July 1, 2008, and it is 

projected for completion by July 31, 2008. The Medical Center Director 

chartered a committee to conduct the inquiry. The committee will present 

the results of its inquiry to the VAMCDC Research Integrity Officer, 

Medical Center Chief of Staff, Veterans Integrated Service Network 

(VISN) Office, and Medical Center Director. ORO will also review the 

results. If the inquiry finds the allegation has substance, VAMCDC will 

conduct a full investigation, which they have 90 days to complete. If the 

investigation finds misconduct, the next step is adjudication by the VISN 

Director, followed by ORO Review. 

 In Process 12/15/08 

We recommended that the VISN Director will: 

Recommended Improvement Action(s) 5: Require that the smoking 

cessation study data collected at VAMC Washington, DC, be validated 

to ensure its accuracy. 

Concur 

Consistent with VHA Office of Research Oversight's (ORO) 

comprehensive review of all VHA research studies involving individuals 

with post-traumatic stress disorder (PTSD), the Director, Washington, DC 

VA Medical Center (VAMCDC), has appointed three voting members from 

the Institutional Review Board (IRB) Committee and/or Research and 

Development (R&D) Committee to validate the accuracy of all data from 

the smoking cessation study (CSP 519). This panel will present the results 

of its review to the VAMCDC Associate Chief of Staff for Research, IRB 

Committee, R&D Committee, Medical Center Chief of Staff, Veterans 

Integrated Service Network (VISN) Office, and the Medical Center 

Director. VAMCDC will complete its audit no later than August 1, 2008. 

VISN 5 will also perform an audit of the VAMCDC smoking cessation 

study for data accuracy. The VISN will complete its audit no later than 

August 15, 2008. VAMCDC and VISN 5 will report the results of the 

reviews to ORO upon completion. 

 In Process 8/15/08 

VA Office of Inspector General 23 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC

Recommended Improvement Action(s) 6: Require the medical center 

director to audit a representative sample of all active protocols 

involving human subjects for compliance with VHA informed consent 

requirements, including whether an informed consent can be located 

for each study participant. 

Concur 

The Director, Washington, DC VA Medical Center (VAMCDC), instructed 

the Institutional Review Board (IRB) Administrator to initiate a review of 

signed informed consents related to 548 research participants at VAMCDC 

for the period of January 1, 2007 – July 3, 2008. The IRB Administrator 

assembled an audit team and reviewed all research protocols. The IRB 

Administrator will present the results of this audit to the Associate Chief of 

Staff of Research, IRB Committee, Research and Development Committee, 

Medical Center Chief of Staff, Veterans Integrated Service Network 

(VISN) Office, and Medical Center Director. VAMCDC will complete its 

audit no later than August 5, 2008. VISN 5 will also perform an audit of 

the VAMCDC informed consent protocol for human subjects. The VISN 

will complete its audit no later than August 15, 2008. VAMCDC and 

VISN 5 will report the results of these reviews to VHA Office of Research 

Oversight upon completion. 

 In Process 8/15/08 

Recommended Improvement Action(s) 7: Require the medical center 

director to ensure that protocols are being audited in accordance with 

VHA Directive 2008-014. 

Concur 

Washington, DC VA Medical Center (VAMCDC) Research Compliance 

Officer will complete protocol audits in accordance with VHA Directive 

2008-014, Auditing of VHA Human Subjects Research to Determine 

Compliance with Applicable Laws, Regulations, and Policies, and will 

certify the conduct and results of all audits to the Medical Center Director. 

VAMCDC Research Compliance Officer began protocol audits on July 15, 

2008, and will present the results of existing protocol audits to the 

Associate Chief of Staff of Research, Institutional Review Board (IRB) 

Committee, Research and Development (R&D) Committee, Medical Center 

Chief of Staff, Veterans Integrated Service Network (VISN) Office, and 

Medical Center Director. VISN 5 will also perform an audit of 

VAMCDC's compliance with VHA Directive 2008-014. The VISN will 

complete its audit no later than September 15, 2008. VISN 5 will report the 

VA Office of Inspector General 24 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC

results of the reviews to VHA Office of Research Oversight upon 

completion. 

 In Process 9/15/08 and On-going 

VA Office of Inspector General 25 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC

Appendix B 

OIG Contact and Staff Acknowledgments 

OIG Contact Andrea Buck, M.D., J.D. 

Medical Consultant 

(202)-461-4669 

Acknowledgments Randall Snow, J.D. Associate Director, Washington, DC, 

Regional Office 

Donna Giroux, Healthcare Inspector 

Nelson Miranda, Director of Washington, DC, Regional 

Office 

VA Office of Inspector General 26 
Human Subjects Protections in One Research Protocol, VAMC Washington, DC 

Appendix C 

Report Distribution 

VA Distribution

Office of the Secretary 

Veterans Health Administration 

Assistant Secretaries 

General Counsel 

Non-VA Distribution

House Committee on Veterans’ Affairs 

House Appropriations Subcommittee on Military Construction, Veterans Affairs, and 

Related Agencies 

House Committee on Oversight and Government Reform 

Senate Committee on Veterans’ Affairs 

Senate Appropriations Subcommittee on Military Construction, Veterans Affairs, and 

Related Agencies 

Senate Committee on Homeland Security and Governmental Affairs 

National Veterans Service Organizations 

Government Accountability Office 

Office of Management and Budget 

U.S. Representative: Stephen Buyer 

This report is available at http://www.va.gov/oig/publications/reports-list.asp. 

VA Office of Inspector General 27