Informed Consent & Research Ethics Discussed at WIRB Annual Training Seminar

October 2, 2011

Seminar on Informed Consent and Research Ethics

WIRB Training Seminar was Held in Seattle, WA

“Obtaining consent does not make an unethical study ethical,” Dr. Marjorie Speers told the Annual Training Seminar of the Western Institutional Review Board (WIRB). Speers is the President and CEO of AAHRPP (Association for the Accreditation of Human Research Protection Program). She pointed out that, although many IRBs focus on the informed consent process, protocol design is an equally important ethical consideration. The focus of this year’s seminar was informed consent and the speakers’ presentations led to some lively discussion on consent forms, protocol design, research in the developing world, and financial disclosure.

The seminar, which WIRB opens to research professionals in the Puget Sound, features national experts on bioethics and the regulation of IRBs. Among the speakers were Dr. Speers; Dr. Jerry Menikoff, Director of the Office of Human Research Protections (OHRP); Dr. Vincent Ahonkhai, Senior Regulatory Office, Bill and Melinda Gates Foundation; and, Dr. Jeremy Sugarman, Professor of Bioethics and Medicine, Johns Hopkins University. The University of Washington and the Fred Hutchinson Cancer Research Center co-sponsored the seminar with WIRB.

informed consent and research ethics

Simplifying the Informed Consent Process

A recurring theme was the need to shorten consent forms to make them more accessible to research subjects. Dr. Speers referred to most of the required elements of informed consent a “required disclosures,” stating that “disclosures” was a preferrable term. During discussion periods there were several comments that the disclosures had more to do with legal concerns than with involving the research subject in an informed consent process. Dr. Speers stressed that, “too much information is no information.”

Dr. Speers spoke of the need to involve communities as well as the individual research participants. “Communities can be harmed and benefitted by the research,” maintained Speers. “Generally, the public does not understand the drug development process,” Speers said, the aim of gaining new knowledge.

The seminar discussed some humorous examples of researchers not understanding sensibilities in the developing world. For example, informed consent forms frequently use units of measure such as a teaspoon or quarter cup of blood taken for laboratory analysis. However, when the research was in sub-Saharan Africa, because researchers were using units of measurement most common in cooking, potential subjects assumed that the blood was going to be cooked, not analyzed. This led to worries about witchcraft, which was clearly not the intent of the researchers.

WIRB invited a research participant, Debbbie, to address the seminar. Debbie had participated in many cystic fibrosis studies in the past 20 years. She talked about how access to healthcare and money were her primary motivations for participating in a clinical trial. She had lost her health insurance a few months before enrolling in the study. Then she developed pneumonia. During the run-in phase of the study there was a “cleanout” using antibiotics, a common practice in CF studies. Participating in the clinical trial directly benefitted her healthcare. One of the reasons she enjoyed research participation was the access to healthcare and cutting edge developments in the treatment of cystic fibrosis.

The Influence of Money on Research Ethics

Money was a major topic of conversation, as always at a meeting discussing bioethics. Debbie was asked, “how much of a factor is it?” Quite a lot, she replied. Speakers discussed the question from the perspective of financial disclosure. Dr. Speers said that any financial interest by a member of the research team should be an expected disclosure. Others pointed out that the only type of financial relationship that significantly affected potential research participants was when the researchers had an equity interest in the research drug. But not always in ways you might expect. One potential subject said that when learning the PI owned stock in the company sponsoring the research, they thought, “the drug must work,” and wanted to participate.

There was one embarrassing moment for quality assurance professionals during a talk by Dr. Maria Greenwald, a researcher from California. She had recently been audited by a sponsor QA auditor who cited her for failing to report “protocol violations” to the IRB. The protocol required periodic laboratory tests for calcium levels, which were a concern for the investigational product.

Research Ethics and Audit Findings on Calcium Levels

Elevated Calcium Levels

When blood tests revealed significantly increased calcium levels for one research subject, Dr. Greenwald ordered laboratory tests at every study visit, more frequently than the protocol required. She considered this necessary for patient safety using her medical judgment, as required by the Form FDA 1572. The auditor disagreed and insisted that she had violated the protocol.

I remember my own inspection training in the FDA Bioresearch Monitoring program. “Never argue the practice of medicine with an MD,” I was told. When Dr. Greenwald said that she ordered the lab tests for patient safety according to her medical judgment, the auditor should have accepted it and merely noted it in her report.

The public seminar concluded with David Forster, the Chief Compliance Officer for WIRB pointing out a three-page informed consent form approved by WIRB during the first year of its existence. It had all of the required elements, or disclosures, and was simple and to the point. He challenged WIRB board members to see if it was possible to return to a clear, simple consent form. Most appeared up to the challenge.

Carl Anderson
GxP Perspectives
02 October 2011

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Good Documentation Practice: Thanks to Jerry Chapman at IPQ Publications for this useful resource list for GDP Guidance Canon

Information about IPQ Publications

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Next Week: Veteran GCP educator, David Montgomery opines on the
FDA Draft Guidance on Risk-Based Monitoring

Six Weeks Left to Comment on Risk-Based Monitoring!

How to comment to FDA? Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!

Location of Monitoring guidance FR

The Federal Register Docket Number is FDA-2011-D-0597

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Just released– FDA Draft Guidance for Medical Devices: De Novo Classification Process (Evaluation of Automatic Class III Designation)
Read the Federal Register Announcement

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You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives and the discussion on risk-based monitoring. I also encourage you to get an email subscription (on the sidebar to your right) or join the GxP Perspectives LinkedIn Group (below).

clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the Draft FDA Risk-Based Monitoring guidance document and on protocol deviations. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

GxP Perspectives LinkedIn Group

Follow GxP Perspectives on twitter: @GxPPerspectives

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Pacific Regional Chapter SQA Fall Training 10-11 November at Allergan in Irvine, CA. The training will feature a debate which should be an interesting development in training workshops: Debi Garvin, MS, RQAP-GLP and Paula Parsons: Debate: The role of CAPA in a GLP environment.

PRCSQA Fall Training


FDA Guidance on Risk-Based Monitoring, Part II

September 17, 2011

FDA risk based monitoring

New FDA Draft Guidance Document

FDA’s new draft Guidance for Industry: Oversight of Clinical Investigations — A
Risk-Based Approach to Monitoring (August 2011) is the subject of a great deal of discussion among clinical trial professionals. On the GCP LinkedIn group some have written about their concerns that “centralized monitoring” would severely limit a sponsor’s involvement with clinical sites. Others have pointed out that the emphasis on developing a monitoring plan should ensure that appropriate resources are tageted to where they are needed.

Two weeks ago GxP Perspectives published a Guest Commentary by Lorraine Ellis on the new draft guidance. This Guest Commentary by Judith Lynn, continues the discussion about the new draft guidance. She looks at FDA Warning Letters in developing her review and analysis.

Guest Commentary: A Risk-Based Approach To Monitoring

I reviewed the Recent Draft Guidance From FDA- A Risk-Based Approach To Monitoring with several information points in mind:

• Warning letters from FDA, including the JNJ /ICON letter of 8/10/09
• My own experiences reviewing Clinical Study Reports, conducting TMF review and mock audits
• FDA Compliance Program Guidance Manual 7348.811, Clinical Investigators

I try to view the instruction as meant to be helpful rather than another obstacle to overcome. I found that much of the draft guidance centers on managing your study, having a sampling plan, and ensuring quality. FDA mentions that both good protocol and CRF design is critically important, as well as having a monitoring plan that takes into account the specific study, and sponsors prior experience with the investigational product.

Onsite monitoring:

FDA risk based monitoring guidance

Seriously Ill or Vulnerable Populations

I am not convinced that onsite monitoring will go away. The sponsor obligation is to ensure the protection of human subjects, that sites conduct trials appropriately, and the data is auditable and accurate. Note the point in the draft guidance under section IV/ C, Factors to consider when developing a monitoring plan: that “a population that is seriously ill and/or vulnerable may require more intensive on-site monitoring to be sure appropriate protection is being provided”. This point speaks volumes as to the value FDA places in onsite monitoring.

Early phase monitoring:

The guidance states “For a product that has either a significant safety concern or for which there is no prior experience in humans, may require more intensive monitoring to ensure appropriate investigator oversight.” It is interesting that FDA specifically encourages sponsors to be onsite in earlier phase studies, when the Agency does not typically send their own investigators- remember, they investigate either for cause or pre-approval.

In my experience with both bioavailability and first in man studies, the value of being on-site to observe unexpected safety and protocol issues, and make immediate decisions regarding study conduct, has been critical. Examples:

• safety issues a healthy subject (recent army recruit) collapsed at a blood draw (was excluded); a site had urine/blood test machine not work and had to test offsite, affecting dosing times/schedules
• dose issues, a nasal sprayer malfunctioned for an intranasal product; patches expected to be study for 12-24 hours fell off almost immediately

Electronic Data

risk based monitoring FDA guidance

Electronic Case Report Forms

Using electronic CRFs is a great boon to the industry. It gives almost instant access to data that used to take months to enter, review, check for consistency and plausibility.

Data Checks that used to come only at the end of a study are available throughout: such as missing forms; out of window visits; other inconsistencies. Immediate data availability can be used to track study progress, investigator compliance (with visits, data entry, inclusion/exclusion), and detect possible troublesome data fields/labels for a single site or throughout a protocol. However, only the data entered is available for central review (remote).

Use data to identify anomalies:

FDA risk based monitoring guidance

Questions Raised During Data Review

During an audit for a sponsor preparing for an FDA inspection, I focused on 2 critical efficacy evaluations (a 20 minute physician evaluation and MRI scan, done at select study visits). I requested data management to calculate the number of procedures performed on the same day at a specific site. I found it very interesting when data management responded:

• 22 physician evaluations were performed on a single day (by the same physician)
• 15 MRI scans were performed on one day.

None of the monitoring visit reports mentioned this kind of scheduling, the requirements for calibrating MRI machines, or whether there was more than 1 machine at a site.

It may be worthwhile to spend more time during the study reviewing available study data. You may need to create customized reports to follow the metrics on your study. Consider the value of team review rather than individual review, in order to understand what your data may be indicating.

FDA warning letters often include observations that may be found during onsite monitoring:

fda

FDA Warning Letters

• Problems with original signatures on informed consent documents. Informed consent documents are not usually submitted to sponsors/monitors, but are reviewed during onsite visits.
• Non-serious adverse events were present in source documents that were not reported to the sponsor. Without onsite review, the sponsor cannot know what is missing.
• Inadequate records, including remarks regarding inappropriate delegation (unqualified person performing procedure or not signed/dated by investigator). Many sites around the world have paper records, and without onsite review, the sponsor cannot be aware of inadequacies.
• Inadequate accountability of the test article.

Monitoring plan considerations:

You may decide to reduce the number of onsite visits. Do this wisely. Ideally the monitoring plan is another tool that helps confirm the validity of your study data. Have your monitors perform activities onsite that cannot be performed remotely.
Source data: Often, only limited source data is available remotely for centralized review.

Finally, remember what the FDA is instructing their inspectors to do, and develop your plan in anticipation. The FDA inspection manual requires inspectors to:

• review logs of onsite monitoring visits
• describe the investigators source documents for legibility and completeness
• review the informed consent process.

Ideally the sponsor will not be surprised what is found when a Regulatory agency goes to the study site.

Judith Lynn, Pharmaceutical Consultant, September 2011

Read the Draft Guidance Document

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How to comment to FDA: Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!

Location of Monitoring guidance FR

The Federal Register Docket Number is FDA-2011-D-0597

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Pacific Regional Chapter SQA Fall Training 10-11 November at Allergan in Irvine, CA. The training will feature a debate which should be an interesting development in training workshops: Debi Garvin, MS, RQAP-GLP and Paula Parsons: Debate: The role of CAPA in a GLP environment.

PRCSQA Fall Training

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Tufts Center for the Study of Drug Development: Article on Protocol Amendments: One Third can be avoided.

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Training Opportunity:

training GxP

Audits & Risk Management

GxP Audit & Risk Management Congress: 20-21 October 2011, Philadelphia, PA. This conference combines both GMP and GCP tracks to maximize the opportunity for cross training, shared best practices, and networking. Two members of the GxP Perspectives LinkedIn group, Janice Wilson and Adi Lampmann, are among the faculty. The conference is sponsored by ExL Pharma and GxP Perspectives is a media partner.

GxP Audit & Risk Management Brochure

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You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives and the discussion on risk-based monitoring. I also encourage you to get an email subscription (on the sidebar to your right) or join the GxP Perspectives LinkedIn Group (below).

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FDA vs. Dr. Oz: Should you be drinking apple juice? Television personality Dr. Oz says that there are dangerous levels of arsenic in apple juice. The FDA disagrees. They point out that the tests Dr. Oz conducts are for total arsenic, inorganic and organic, and only inorganic arsenic represents a danger to public health. Read the FDA press release for a detailed explanation.

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On The Blogroll: PharmTech Talk discusses the Top Ten FDA 483 Observations for drug GMP inspections. Angie Drakulich reports that Numero Uno concerns Quality Control Units (QCUs).

My Perspective by Kathryn Davis, Clinical Development. In this new blog on WordPress Kathryn Davis discusses relevant issues including social media, GCP, and recruiting minorities in clinical trials.

The Dark Daily Laboratory and Pathology News

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FDA Clinical Investigator Course,
7-9 November 2011, Silver Springs, MD

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clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the Draft FDA Risk-Based Monitoring guidance document and on protocol deviations. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

GxP Perspectives LinkedIn Group

GxP Perspectives on twitter: @GxPPerspectives

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Please comment on the new draft guidance on Risk-Based Monitoring.


FDA Releases Draft Guidance for Monitoring Clinical Trials

September 4, 2011

FDA releases draft guidance document for monitoring clinical trials

FDA Draft Guidance Offers New Methods of Monitoring Clinical Trials

At long last, FDA has released a new draft guidance document for monitoring clinical trials. The previous FDA guidance document, Guideline for Monitoring Clinical Investigations (1988/1998) was withdrawn earlier this year. The new draft guidance document, FDA Guidance for Industry- Oversight of Clinical Investigations– A Risk-Based Approach (August 2011), discusses the changes in the way clinical trials are conducted and new methods of monitoring clinical trials. There is a 90-day comment period where members of industry, professional organizations, and the public can submit written commments to the agency for review and consideration.

In this Guest Commentary veteran monitoring specialist Lorraine Ellis gives her perspective on the new draft guidance for monitoring clinical trials.

Guest Commentary by Lorraine D. Ellis, MS, MBA

When I started monitoring, the Investigators completed CRFs from the source documents and there were few Clinical Research Coordinators (CRCs). Usually an office nurse or staff member would complete the forms when they had “free” time. Three decades later, sites, studies, and monitoring have changed significantly. Investigator sites must have significant study infrastructure (SOPs and facilities, etc) and trained/experienced staff to complete the complex trials of the 21st century. So it is significant that the 1988 Guidance document has been retired and the new guidance on monitoring describes FDA’s view on applying 21st century technology and methods to monitoring.

There are several key advances in this guidance. The guidance describes the term “centralized monitoring” for the many practices of using technology to review data off-site. This term and other FDA comments describe using “off-site” monitoring as one of the acceptable methods of monitoring data quality and study conduct. This guidance will intensify the discussions of “why do we need monitoring every 4 to 6 weeks with 100% source document verification” and “what is the best monitoring procedure for this study”. Also, FDA outlines more detailed monitoring plans as the risk based approach requires that monitoring approaches should be tailored to the trial.

clinical trial monitoring fda guidance document

Poorly Designed Protocols, CRFs, or Trial Instructions

FDA suggests a multi-factor approach to ensure data integrity, compliance and patient protection since there are many trial factors that can affect these trial elements besides monitoring. For example, poorly designed protocols, CRFs, or trial instructions could cause fatal trial errors despite extensive monitoring. Inadequate, incomplete or poor training of all involved in the trial, Investigators, staff, monitors etc., could also decrease study quality. The guidance encourages using various methods of study conduct review to assess these study elements as well as data quality.

The second half of the guidance provides information on monitoring plans and their expected content. Currently monitoring plan content and quality vary among Sponsors so this detailed section should increase monitoring plan quality and detail as it describes methods appropriate to the study. Since this guidance promotes custom monitoring plans based on variables of the study such as scope and complexity, these sections will assist Sponsors in designing and implementing those monitoring practices appropriate to the study.

FDA clinical trials guidance

"Greater Reliance on Centralized Monitoring"

One sentence will probably be surprising to some veteran monitors and Sponsors. “FDA encourages greater reliance on centralized monitoring practices than has been the case historically, with correspondingly less emphasis on on-site monitoring”. Many Sponsors that have instituted EDC and other technologies for data collection/review, have not decreased on-site monitoring time they continue to rely on the “gold standard” of visits every 4 to 6 weeks and 100% SDV. FDA does advise that at least one on-site monitoring visit should be done to ensure processes and procedures are in place at the site to ensure data quality. FDA continues that to use centralized monitoring properly, Sponsors need to develop methods and standard operating procedures so that site records, data entry, and data reporting follow well-defined procedures.

FDA guidance on clinical trials monitoring

Risk-Based Approach

FDA recommends that the monitoring plan is developed based on a risk assessment of the study complexity, study endpoints, disease complexity, geography, Investigator experience, EDC capabilities, Investigational product safety, study stage and quantity of data. After risk assessment, the Sponsor prepares a tailored monitoring plan for each study that will address that risk and outlines the multi-faceted approach to the trial. The plan, that includes monitoring procedures, monitoring responsibilities, and trial requirements, should be in sufficient detail so monitors and others involved can carry out their respective tasks correctly.

The plan should also include: monitoring methods, communication of monitoring findings, resolution of issues, training topics, training evaluation, and monitoring plan amendments.
It will be interesting to read the comments sent to FDA in the next 90 days. Some Sponsors will say “it’s about time” monitoring will be optimizing 21st century technology. Others may struggle with the changing of the “gold standard” of monitoring. In any case, this guidance may be the catalyst the industry needs to optimize monitoring methods and effectiveness.

FDA Guidance for Industry: Oversight of Clinical Investigations– A Risk-Based Approach

Visit Lorraine’s Website

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How to comment: Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!

Location of Monitoring guidance FR

The Federal Register Docket Number is FDA-2011-D-0597

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You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives and the discussion on risk-based monitoring. I also encourage you to get an email subscription (on the sidebar to your right) or join the LinkedIn group (below).

Please take a short 3-question survey to help GxP Perspectives improve! Survey begins 22 SEP 2011

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On the Blogroll: Chromosome which features an excellent post on, “The Site’s Side,” by Jae Chung, founder of goBalto, Inc., located in San Francisco. The post discusses some of the problems clinical sites face with monitors.

On The Blogroll: On Biostatistics and Clinical Trials– Finally a blog on biostatistics that I can almost read:) It is written by Dr. Deng, 邓春勤 A Medical Doctor turned into Biostatistician in Clinical Trial and Drug Development Industry
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clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the draft guidance document. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

GxP Perspectives LinkedIn Group

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The FDA, Center for Drug Evaluation and Research (CDER) is announcing an industry workshop entitled ‘‘CDER Small Business Assistance – Clinical Trials and Electronic Submissions.” This two day event will be held in two California locations consecutively. The first workshop will be held in Los Angeles, CA, on September 26-27, 2011, followed by a second in San Francisco, CA, on September 28-29, 2011.
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This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)
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Informed Consent: Questions on New FDA Requirement

February 13, 2011

FDA Requirements Informed Consent Questions

FDA Has New Requirements for Informed Consent

FDA has implemented a new informed consent requirement by updating their informed consent regulations (21 CFR Part 50). The principle of informed consent has been a central ethical factor for efforts to protect participants in clinical trials since the aftermath of World War II. This Guest Commentary by Steven Steinbrueck discusses the new FDA requirement and asks some basic questions about informed consent. I think they are questions well worth asking. What works and what doesn’t work in the informed consent process? Are informed consent forms understandable? Do research participants understand the concepts of the research? Are the right questions being asked? The new FDA regulation is copied at the bottom of Steven’s commentary.

Guest Commentary by Steven Steinbrueck

I was prompted to write by two things—a nice invitation from Carl and the soon to be implemented change to the informed consent regulations. As most of us are aware, there will be a new element required for those clinical studies subject to 21 CFR 50.25; notification that results of the trial will be published in clinicaltrials.gov.

Although I have very little against this requirement, I do find it interesting that the first substantial change in informed consent regulations in quite some time, while logical and required by FDAAA 2007, adds little to help potential research subjects make an informed risk assessment regarding the advisability of participating in a clinical trial.

I think we should stop and think about what we believe, and what we know, about informed consent.

Fundamentally, we believe that human research requires voluntary consent by the participant and that this consent may only be legitimately sought following the provision of required information. Without such consent, human research is thought to be unethical. We can all point to multiple publicized instances where this widely accepted tenet has been ignored.

informed consent questions

The Nuremberg Code was Adopted After the World War II Nuremberg Trials

More than 60 years ago, the Nuremburg Code began with the exhortation that “…voluntary consent is absolutely essential;” the guilt of the physicians on trial began with consent issues. We find similar and more detailed guidance in Belmont, Helsinki and ICH. Most countries have codified their requirements in multiple laws and regulation. In the US, these requirements are primarily found in 21 CFR 50.25 and 45 CFR 46, the so-called Common Rule.

I doubt that we have much argument about the fundamental requirement for truly informed consent, or even its major topics. So, what am I even talking about?

But, what do we know? Essentially, that a large portion of research participants do not understand one or more important concepts about the research they are involved in. Many researchers have documented what has been called therapeutic misconception, therapeutic optimism, and even therapeutic nihilism on the part of both participants and researchers. Although percentages vary between 40 and 70+%, we are aware that we have not fulfilled the obligation to ensure that the information provided is not only complete, that it contains all elements required by regulation or guidance, but also that the volunteer comprehends the information provided—prior to their participation.

Although compliance is necessary, it is insufficient. We must do something about the incomprehensibility of many consent forms. They must be shorter and the time between presentation of the information and consent must be longer. Additional information, including HIPAA authorizations and lengthy explanations of alternative treatments and non-experimental procedures must be provided in separate documents. And finally, we must routinely assess understanding before and during the trial. For, to enroll someone who does not understand, is to enroll someone who has not truly been given the opportunity “to decide what shall o r shall not happen to them.” And that is simply against our collective beliefs.

Steven Steinbrueck, MPH
Stonebridge Consulting

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“Sec. 50.25 Elements of informed consent.

* * * * *
(c) When seeking informed consent for applicable clinical trials,
as defined in 42 U.S.C. 282(j)(1)(A), the following statement shall be
provided to each clinical trial subject in informed consent documents
and processes. This will notify the clinical trial subject that
clinical trial information has been or will be submitted for inclusion
in the clinical trial registry databank under paragraph (j) of section
402 of the Public Health Service Act. The statement is: “A description
of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

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MHRA and Clinical Trials– Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma
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GCP Training on Informed Consent: The Basics for Compliance

March 29, 2010

GCP Informed Consent Training

Informed Consent: Protecting Participants in Clinical Trials


The most serious GCP compliance concerns in a clinical trial are frequently regarding informed consent. FDA recently issued several Warning Letters about clinical sites failing to appropriately consent a clinical trial participant. Training that informed consent is a Process and not just a form to fill out is essential to a quality clinical trial. FDA looks closely at the Qualifications of research staff obtaining informed consent. In this guest commentary Mikki O’Neal discusses the importance of informed consent training from the perspective of a clinical site.

Guest Commentary:

By Mikki O’Neal, CCRP, CCRC
Regulatory Compliance Manager
Houston, Texas

Informed Consent Training: A Site Perspective

Lack of {adequate} training frequently seems to be a standard hot topic in research circles. What constitutes solid training? By what measures should a researcher be deemed qualified to obtain informed consent? While I feel that online training modules provide a good basic foundation, institutions are often relying on them as the sole requirement to satisfy the training process of a researcher. I like to refer to this as theory-based training. While online modules and classroom training do give a researcher a good grasp of how research evolved into what it is today, what is often missing from these training methods is application training. How do you take what you have learned in a module and apply it to every day research activity? Informed consent training is a perfect example. You can speak about informed consent theory until you are blue in the face, but until a researcher is able to see an actual consent process applied, how can they truly grasp the relevance of “it’s all in the details”? This is one of the first steps that foster the communication gap between a poor consenter and a well informed research subject.

More and more you see non-research clinical staff being burdened with the additional responsibility of consenting a subject for a trial while they are performing their basic job functions. Not only does it add extra responsibility to their plate, but obtaining proper research informed consent is typically not even a topic that gets entertained because they don’t understand the reasons, importance, or implications.

GCP Training

GCP Training for Informed Consent Compliance

What is more surprising is that very often these observations occur with “experienced” research personnel, which begs to question the methods in which they were trained. One of the largest mistakes that I think a site manager can make is to hire a researcher based on experience listed on paper and then assume that because of said experience, training will not have to occur (or that very minimal training will suffice). Taking it “back to the basics”, in my opinion, is a critical factor with this topic. It is very easy to start cutting corners and minimizing the importance of a true informed consent process when a study seems simple or the researcher is rushed.

Food for thought: Should researchers be required to demonstrate informed consent ability with an annual practical assessment? Would it be beneficial for sites to implement random “audit” shadowing of researchers during an informed consent process? Is there a “one size fits all” solution to solving informed consent issues? A vital piece of the puzzle is oversight. Know what is going on at your site. Assess the capability of your research personnel. Standardize your training so that all personnel are trained in the same manner regardless of experience. Require continued education. And most of all, never assume that someone is adequately trained just because they have worked in the field of research for an extended amount of time.

Please read other Guest Commentary on the page at the top of the Blog.

UPDATE 6 January 2011: Two Important New GCP Documents:

There is a Draft Guidance on Electronic Source Documentation in Clinical Investigations. The comment period is for 90 day (April 4, 2011 ?)

There is a new Final Rule on required elements of Informed Consent. You can read the Federal Register Announcement here that includes FDA comments in the preamble. The exact change in 21 CFR Part 50 is:

“Sec. 50.25 Elements of informed consent.

* * * * *
(c) When seeking informed consent for applicable clinical trials,
as defined in 42 U.S.C. 282(j)(1)(A), the following statement shall be
provided to each clinical trial subject in informed consent documents
and processes. This will notify the clinical trial subject that
clinical trial information has been or will be submitted for inclusion
in the clinical trial registry databank under paragraph (j) of section
402 of the Public Health Service Act. The statement is: “A description
of this clinical trial will be available on
http:[sol][sol]www.ClinicalTrials.gov, as required by U.S. Law. This
Web site will not include information that can identify you. At most,
the Web site will include a summary of the results. You can search this
Web site at any time.”

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FDA Warning Letter on Informed Consent

February 12, 2010

A new FDA Warning Letter shows the concern regarding the informed consent process that FDA has, along with most of us involved with clinical trials. This is a top FDA enforcement issue. However, are standard operating procedures (SOPs) the way to ensure GCP regulatory compliance at clinical trial sites?

informed consent

Informed Consent of Research

In a letter dated 28 January 2010 to a clinical investigator at the Women’s Hospital, affiliated with the University of Michigan Health System, FDA’s Division of Scientific Investigations (DSI) at the Center for Drug Evaluation & Research raise some serious concerns regarding the informed consent process in several clinical trials for Cystic Fibrosis (CF).

CF is a devastating inherited disease with a juvenile onset that attacks the lungs and digestive systems of about 30,000 juveniles and adults in the United States. The impact on families who have a child with CF is dramatic with the lives of the entire family changed forever as they take steps to care for their children. CF patients and their families meet my personal definition of a “vulnerable population.”

I believe that clinical trials studying CF need special protections for the young participants and their families.

That is why this FDA Warning Letter is so disturbing. These are not studies for male pattern baldness or another minor indication. They are for very sick children and young adults. Although the FDA citations seem a bit “technical” at first, it is very important that full disclosure of research is included in the informed consent process.

The Belmont Report

It is of particular concern that these studies took place at a very prominent health system; the Women’s Hospital is affiliated with the University of Michigan, Ann Arbor. The informed consent forms were IRB approved (the Warning Letter does not state which IRB). However, the informed consent of research study participants is a cornerstone of ethical research in the United States and much of the world. In 1979 the

Informed consent FDA

Informed consent is a process

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issued the Belmont Report, the key document published by the United States Government on research ethics. The report states:

“Respect for persons incorporates at least two ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection. The principle of respect for persons thus divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.”

The violations documented by FDA include the failure to use language the sponsor requested to indicate a clear statement of research, a required element of informed consent (the sponsor requested changing the wording from “new drug” to “investigational or experimental drug”). In addition, the original approved informed consent form did not correctly state the purpose of the study originally stating the purpose was to see if the drug could “stop PA” (Pseudomonas aeruginosa). The wording should have been to “assess the safety and efficacy of a 28-day treatment… (to treat CF)” This is not a minor difference and there are more violations.

Standard Operating Procedures (SOPs)?

FDA warning letter informed consent

Shoud we require SOPs?

First, we need to clear: There are no regulatory requirements for SOPs at clinical sites. None. The clinical investigator offered some corrective actions that included writing SOPs about the informed consent process. FDA seemed to believe that SOP changes could be a satisfactory corrective action. They say:

“Your corrective actions to this finding included the development of new standard operating procedures (SOPs) including: ‘Completing the eResearch Application’ to ensure that a member of the study team reviewed the consistency of the information in the protocol, investigator’s brochure, consent document and the eResearch submission; ‘Responding to Monitoring Reports’ which required prompt response to any observations and a formal report to the IRB for further consideration; and ‘Obtaining Informed Consent’ which will prohibit handwritten statements on the informed consent form.”

FDA stated that the response was inadequate but later in the Warning Letter they say that another SOP would, “serve as corrective actions to prevent the recurrence of this finding” (to ensure that the investigations were conducted according to the investigational plans).

A Question of Training.

I have a different perspective. I think that the informed consent violations raise a genuine concern on how well the informed consent process and the principles of the Belmont Report are being taught to clinical investigators and IRB members involved in biomedical research at UM and the Women’s Hospital. To me, this

informed consent

GCP Training

is a question of being “qualified by training and experience,” and can’t be fixed with an SOP. For example, the primary method of training researchers at the University of Michigan, and a lot of other institutions, is through web-based training initiated by NIH. Web-based training is OK as a supplement to other training but ultimately a researcher needs to interact with others and have the opportunity to ask questions and be involved in problem solving discussions. Any reasonably bright individual is going to be able to breeze through a web-based training module and will retain very little.

We are placing a lot of administrative burdens and demands on both IRBs and clinical investigators. These demands take time and resources away from Good Clinical Practice. Investigators are being asked to sign and date reams of paper that could be delegated to the appropriate staff member. IRBs are asking for more and more documentation in an effort to comply with the requirements of FDA’s Bioresearch Monitoring program and other federal requirements. In fact, the University of Michigan had a simple checklist study halted because of bureaucratic interference. See this op/ed piece authored by the American Enterprise Institute, which accurately highlights some of the problems. I don’t agree very often with AEI but in this case they make a good point:

http://www.aei.org/article/100868

I would suggest that it is far more important to get “Back to Basics.” This includes research protocols that make sense and are practical in a clinical setting. It means emphasizing what is significant in protecting the rights, safety, and welfare of clinical trial participants (not the trivial). Finally it means ensuring that the data generated by a clinical trial can “stand alone” and be verified by regulatory authorities. Good, solid recordkeeping. I am not convinced that instituting SOPs at clinical research sites is the way to do this.

Here is a link to the Warning Letter:

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm199751.htm

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