1. The Informed Consent Process: From Rules and Regulations to the Protective Value of Ethics
Kimberly Summers, PharmD
Deputy ACOS for Research
South Texas Veterans Health Care System
Research & Development Service

2. Purpose of Consent Process
Research subject will…
Understand nature of the research
Be continually informed of purpose, risks, benefits, and alternative therapies
Make a voluntary decision about participation or continuation

3. Significant Historical Events in the Development of Informed Consent
Nazi atrocities in World War II drew attention to the lack of international standards on research with human participants and led to the formulation of the Nuremburg Code (1948).
The thalidomide disaster led to the adoption of the "Kefauver Amendment" (1962) to the Food, Drug and Cosmetic Act, requiring drug manufacturers to prove to the FDA the safety and effectiveness of their products and physicians to obtain informed consent from potential subjects before administering investigational medications.
The Declaration of Helsinki drafted by the world Medical Association in 1964 (most recently updated in 2000) builds on the Nuremberg Code and is the basis for Good Clinical Practices used today.
The National Research Act (1974) passed primarily in response to the syphilis study, codified the requirement that human participants in research must be protected and set the stage for the issuance of the Belmont Report.

4. Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects in Research
Respect for Persons
Individuals should be treated as autonomous agents
Individuals with diminished autonomy are entitled to protections
Beneficence
Do not harm
Maximum possible benefits, and minimize potential harms
Justice
Fair distribution of burdens and benefits of research

5. Informed Consent: Application of Respect for Persons
Initiated before any forms are signed
Continues through the completion of the subject's involvement in the study
The consent document is only a confirmation of the consent process
Responsibility of the Principal Investigator
Even if obtaining signed informed consent is delegated to another study team member

6. Main Components of Informed Consent
Selecting participants – Are only those subjects who meet inclusion criteria enrolled? Does the consent form clearly indicate that participation in the research is voluntary?
Information - Does the consent form provide all the information necessary for the individual to make a reasoned decision?
Comprehension - Is the consent form crafted in language understandable to the potential participant?

7. Selecting Participants
Recruitment of participants needs to be done in a nonbiased and non superior to subordinate setting
Participants should never feel that if they do not participate they will be penalized
Participants should understand why they are being approached for enrollment in the research protocol

8. Example
One requirement of Psychology 101 is participation in a study on learning practices.
Does this violate the principle of autonomy?
Autonomy means a person must have the right to decide not to be in a study. Participation should not be a class requirement.

9. Recruitment: Boundaries Between Practice and Research
The distinction between practice and research is often blurred because many times they occur together
The researcher and the participant must be able to distinguish practice from research
The purpose of clinical research is to gain knowledge, not to treat a condition
Therapeutic Misconception
Misunderstanding that being in a clinical trial is automatically “good” for you

10. Information to Subjects: Describing the Research
Research Purpose
Research Procedures
Risks
Benefits
Compensation
Alternatives
Confidentiality
Disclosure of Potential Conflict of Interest
Research-Related Injury
Contact Information
Withdrawal

11. Informed Consent Document (ICD)
IRB template for the ICD covers information required to describe the research to potential research subjects
Only the most recent IRB approved and stamped consent form can be used to consent subjects
A signed ICD is required prior to any protocol-specific testing being conducted
If protocol specific testing is done the same day as signed informed consent is obtained, must be clear documentation of the chronological order in the medical record

12. Comprehension: Ensure Readability of the ICD
Direct the ICD at an eighth-grade reading level
Use simple, straightforward sentences
Use commonly recognizable terms and measurement amounts
Avoid the use of jargon or technical language
Explain terms that may not be easily understood

13. Comprehension: Assessing Participant Understanding
Ensure that prospective participants understand the extent of their role in the research protocol
Read through the consent document with participants
Discuss participation prior to their involvement in the research protocol
Answer questions and ask open-ended questions

14. Example
The principal investigator outlines the risks and benefits to a participant. The participant wants to know of her other options. The investigator does not know of any other options and states this to the potential participant.
Is this the correct response to the participant's request?
If there are no clear alternatives to participation, the investigator should simply note nonparticipation as an alternative.

15. Example
The principal investigator asks a participant to be in her study. The participant agrees, and the investigator has him sign a piece of paper and tells him she will put it in his file. The investigator also says she will mail him information about the study specifics.
Does this violate the principle of autonomy?
Potential participants must be given information they will need before they decide whether or not to enter a study.

16. Signatures on the ICD
FDA 21CFR 50 – The patient or authorized representative shall sign and date the informed consent
OHRP 45 CFR 46 - …signed by the patient or legally authorized representative
ICH GCP E …the informed consent should be signed and personally dated by the subject or legally authorized representative
VHA Handbook use of a written consent form approved by the IRB and signed and dated by the subject or the subject's legally-authorized representative

17. Witnessing the Informed Consent Process
When do you need a witness?
When presenting the ICD verbally
Use of a short form
If required by the IRB
For all VA research involving an ICD
Who can be the witness?
ICH GCP: An impartial witness – a person who is independent of the trial, who cannot be unfairly influenced by people involved in the trial, who attends the informed consent process
VHA Handbook : role is to witness the subject’s or the subject’s legally-authorized representative’s signature

18. Documenting the Informed Consent Process
A statement that the protocol procedures and the informed consent document were reviewed with the participant
Review of the risks and benefits of the study
Time for questions to be asked and answered
Alternative treatment options discussed
Description of the participant’s decision
Copy of ICD provided to participant

19. Enrollment Consent Template: Research Consent / Enrollment Note
Must be entered into the subject’s health record (CPRS) after IC has been obtained
Template in CPRS flags patients Medical Record in postings
Template contains all the required information for documentation of consent process
Template must be used in order to scan IC document
Note must indicate if the study involves the use of investigational medications

20. Consent Document Revisions
Study participants must be informed of any new and important information that might affect their willingness to continue participation
If new information, knowledge, or an adverse event has been discovered, it must be communicated to the subjects
The Principal Investigator must evaluate the new information to decide if a revised consent document is required
Evaluate if future participants are affected
Evaluate what information should be given to former or current subjects
May be a requirement of the IRB

21. Auditing vs Monitoring
Audits are in addition to the more detailed monitoring of studies by the research team and sponsor
Audits are an independent evaluation by someone who is not directly associated with the research

22. VA Research Compliance Office
Conduct audits and reviews to ensure compliance with all VA and other Federal requirements for the conduct of research
Conduct annual audits of all active studies to insure that informed consent has been properly obtained and documented for each subject since the previous audit 22

23. Components of the VA Compliance Audit of Informed Consent
Was ICD used for participant the most current IRB approved and stamped document at time of enrollment?
Is a ICD present in the participant’s medical record?
Is witness’s signature and date present?
Is person’s who obtained consent signature and date present?
Was delegation of authority to obtain consent appropriate?
Do all dates on the consent match?
Is the informed consent process documented in progress note?

24. STVHCS Research Compliance Most Recent Audit Summary
Feb – May ,376 ICD reviewed
Identified deficiencies
Witness signature missing
Consent not scanned into CPRS
No documentation of consent process in CPRS
Missing HIPAA authorization
Study procedures performed prior to subject signing ICD
Failure to use most current IRB approved and stamped ICD

25. FDA Inspections and Informed Consent Statistics
2007 – 11% of the clinical investigators/sites inspected were cited for informed consent related issues
2007 – 32% of the investigators/sites who received Official Action Indicated letters included informed consent citations

26. VA Inspector General (IG) Report
VA enrolls a total number of 361,042 human research subjects in its studies
Of those, an estimated 110,230 have noncompliant informed consent documentation
IG investigators estimate that over 107,000 consent forms have missing or incomplete witness signatures

28. Jesse Gelsinger
18 year old participant in a gene therapy trial conducted at the University of Pennsylvania
Suffered from ornithine transcarbamylase deficiency (OTC)
X-linked genetic disease of the liver
At the time of enrollment was doing well on a restricted diet and medications
Enrolled in a trial to test the safety of a procedure to inject gene therapy with an adeovirus vector
Procedure was being developed for treatment of infants born with OTC
No direct benefit was expected to current participants
Jesse died 4 days after initiation of the procedure due to a massive immune response triggered by the adenovirus vector

29. FDA Investigation
Concluded scientists involved, including the lead investigator and the University broke several basic ethical principals

30. Failure to Recruit Based on Inclusion Criteria
Participant enrolled despite elevated ammonia levels that met exclusion criteria
Jesse’s liver deficiency was worse than any of the previous seventeen research subjects

31. Failure to Fully Describe the Research: Potential Risks
The consent form approved by the NIH notified participants that monkeys had died from similar treatments
The final consent form distributed to volunteers enrolled at U Penn omitted any mention of the monkey deaths
Jesse and his parents were not aware of the monkey deaths associated with similar treatments

32. Failure to Fully Describe the Research: Research Procedures
The protocol had a dose ranging component
Jesse was the first participant assigned to the largest dose group
Jesse was not informed that he may receive a dose larger than that given to any previous subject

33. Failure to Revise Informed Consent Document
Previous subjects in this trial had experienced severe elevated liver enzymes and serious adverse reactions
These adverse effects had not been reported to federal regulators
The consent form had not been amended to include these reactions
Protocol procedures continued with increasing dosages despite warning signs

34. Failure to Disclose Potential Conflicts of Interest
The lead investigator and the University are reported to have had financial stakes in the research
Financial conflicts of interest for the investigators and/or the institution were not disclosed in the informed consent process

35. Failure to Assess Participants Understanding
Statement by PAUL GELSINGER:
“Jesse was doing exceptionally well on his medications, and nothing should have prevented him from living a full and happy life. He believed, after discussions with representatives from Penn, that the worst that could happen in the trial would be that he would have flu-like symptoms for a week. He was excited to help.”

36. Was Jesse able to make an informed decision regarding his participation in this trial?

37. Statement by Paul Gelsinger
I still support our need for clinical trials, but with this caution: Informed consent is only possible if all facets of the research endeavor are ethical and in the open. Because of the secretive and conflicting influences on clinical research, the average research subject has little hope of understanding and giving truly informed consent. All research subjects really want is to be able to trust the system. If we can somehow get that system to apply Jesse's Intent... not for recognition and not for money, but only to help... then research will get all it wants and more; they'll get research right and have a real prosperity, one they never imagined possible. Until that happens I am so very grateful that we had a legal recourse that enabled us to draw attention to the problems currently inherent in clinical research.

38. Questions? Kimberly Summers, PharmD Office: (210) 617-5300 ext 15969