Continue reading »]]> Many different factors assist in determining if your project requires IRB review and approval prior to inititation.

Is the project “regulated research“?

Regulated by OHRP: Is the project, or any portion of it, being federally funded, or taking part in a university or hospital?  If yes, the project is regulated research subject to the Common Rule / OHRP regulations (45 CFR 46), and likely requires IRB review and approval if the project is research involving human subjects by the following definitions:

• Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains
• Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes. For example, some demonstration and service programs may include research activities.

Regulated by FDA: Does the project, regardless of funding, involve a clinical investigation intended to support applications for research or marketing permits of products regularted by FDA, including but not limited to, drugs intended for humans, medical devices, dietary supplements, biological products for human use, and/or electronic products?  If yes, the project is regulated research and it is subject to FDA regulations (21 CFR) if it involves human subjects using the following definitions:

• Human subject means an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient.
• Clinical investigation means any experiment that involves a test article and one or more human subjects and that either is subject to requirements for prior submission to the Food and Drug Administration under section 505(i) or520(g) of the act, or is not subject to requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be submitted later to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit. The term does not include experiments that are subject to the provisions of 21 CFR 58, regarding nonclinical laboratory studies.

Voluntary Review: Sometimes a privately funded non-regulated project, involving human subjects, will be designed to produce generalizable knowledge, which the investigator or sponsor may wish to publish, or build regulated research upon in the future.  In this scenario, sponsors and/or investigators may elect to undergo a “voluntary review” by an IRB to determine that the project, although not regulated research, met the same scrutiny of human subjects protections.

E&I offers assistance in determining whether or not your project requires IRB reivew and approval.

Continue reading »]]> This past June marked the 30^th anniversary of the recognition of the first cases of a strange new syndrome that became know as HIV and AIDs.  In the months that have followed much attention has been given to this landmark through symposiums, memorial services, ceremonies, blogs and numerous newspaper articles.  Although considerable scientific advances have been made towards the diagnosis and treatment of this heart-wrenching disease, the anniversary brings back some powerful memories of an much earlier time.

A member of our West Coast IRB, a health educator, shared her experience from a retrospective AIDs activity at San Francisco General Hospital which led to conversation including the usual hand-raising: Who treated patients in 1981?  Who remembers what the name of the disease was at first?  And, who wasn’t even born yet?   So here are three stories from members of the E&I West Coast IRB that illustrate, in their own words, exactly how small the world is and how very far we have come.

Story 1 – Erica Heath, CIP, Director of Regulatory Affairs, E&I

For many years, I have counted myself as being responsible for the first AIDS treatment protocol.  What a claim!

I was secretary (Administrator by today’s terms) to the UCSF IRB, called the Committee on Human Research or CHR..  One day I got a call from Dr. Connie Wofsy, a physician at San Francisco General Hospital, who said she was treating a young male patient with pneumocystis carinii, a rare form of pneumonia.  She knew of only one drug that might help.  Pentamadine was investigational and was available only from CDC.  Could she use it?  On my own, I said yes.

There is an exemption from the IRB review requirement.  It reads:

“§56.104 Exemptions from IRB requirements:  (c) Emergency use of a test article, provided that such emergency use is reported to the IRB within 5 working days.  Any subsequent use of the test article at the institution is subject to IRB review.”

Although such situations occurred rarely, each event was urgent so I had prepared a handout and short report form that could be sent through inter-office delivery (there was no e-mail and few faxes then).

I said yes (as if I had a clue what PCP was) and sent the hand-out.  A week later Dr. Peter Jensen called from Fort Miley VA (they also used the CHR) with exactly the same story.  So, different institution, I sent off the same paperwork.  A little later I got a call from someone at the newly opened Long Hospital and then Moffitt Hospital (which was really one unit but could maybe be considered two hospitals).  On the 7^th or 8^th call I finally picked up the phone and called Dr. Wofsy.   My message was … You must write a protocol. Any kind of protocol.  Some excuse for a protocol. Anything.  And do it quickly please.  She did.

Story 3 – Fern, IRB member

I was working as a communicable disease specialist for a very early incarnation of the State Office of AIDS circa-1983-1985 and while assigned to the Bay Area Field Office in Berkeley, I was tasked with visiting all the hospitals in the Bay Area, meeting with the Infection control nurses to identify how they were going to identify, track and report their AIDS cases.  Essentially we were setting up the active surveillance systems that would get cases reported.

No one wanted to report, it was like being a door-to-door salesman, I would come home each night and have a cocktail frustrated and defeated!  My motivational counseling included how this was going to mean $$$ for PWAs (People with AIDS) and for your hospital ultimately.

The most memorable encounter was the day I visited a catholic Hospital in San Mateo Co. and while speaking with the Intensive Care Nurse who was also a nun, I was delicately informed that I was “wasting my time because they were NEVER going to have an AIDS case at their hospital – those types of patients would not be receiving care at this hospital”.

___________________________________________________________________________

I want to thank these valuable members for their very relevant contributions to the research community, as well as to our board and for sharing their experiences related to this dark period in medical development.

As an aside, I would also like to thank Paul Volberding.  In 1984 I left UCSF on maternity leave and had some spare time.  I got a call from Paul.  His coordinator, Debbie Hahn had left for industry and would I come in just to prepare his now numerous studies for submission to the IRB… the same one I had just left.  Every IRB administrator should be required to submit an application to their IRB just to learn how hard it is to walk in the other guy’s shoes.  Thank you Paul for that great education.

Erica

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Who is responsible for determining if a medical doctor, who has lost their license twice in the past year for personally abusing drugs, is qualified to act as the principal investigator in a clinical trial involving a schedule II narcotic?

Defining “Qualified Investigator”

Historically, when the majority of research took place in hospitals and universities, defining the term “qualified investigator” was a relatively straightforward task.  Regulation found at 21CFR 312.53(a), 21CFR812.43 and guidance at ICH GCP 5.6.1 made it clear investigators should be qualified through training and experience.

In an integrated setting such as a medical center, approval of the specific investigator, who was typically part of the institution where the research would take place, and likely known by the other physicians and administrators, was assumed as part of the approval of the research activity itself.  The local institutional review board (IRB) could rely upon other committees, such as Promotions and Tenure or License and Privileges, for verification of the investigator’s credentials, allowing the IRB to focus on other factors of qualification, such as specific research experience.

In the 1980’s and 90’s the research paradigm shifted to involve a larger number of community based physicians bringing with it an introduction to IRBs that were independent from the institution. These “real world” doctors, although often experts in their field, present significant challenges when it comes to determining whether or not they are “qualified” to act as investigators.  The independent IRBs didn’t have access to the internal support system available at the local level where responsibilities were shared. Times have changed but has the delegation of responsibilities been clarified?  This leads to the question, “who is responsible for investigating the investigator?”

Changing Landscapes

As the landscape of research changes, it is clear that the traditional methods used to define and verify a “qualified investigator” also require revision.   With more research occurring in a private setting, the traditional “local” IRB, whose Human Research Protection Program (HRPP) likely included multiple departments, committees and local knowledge all working within their institution, is often replaced by an independent “central” IRB.  The central IRB is part of a “non local” program of protection, utilizing a virtual partnership with the sponsor or Contract Research Organization (CRO), and accessing public databases or medical board records to learn about the applicant investigator.

What these databases are revealing is cause for concern.  A brief glance through the public records available on most individual state medical board sites will disclose an entire world of unsavory behavior, including but not limited to, doctors who have been disciplined for practicing without a license, sexually deviant behavior, misdirecting drugs for personal use, drug addiction and repeated rehabilitation.  Include public legal records in your search and you will find doctors who have criminal convictions for activities such as physical assault of their spouses, embezzlement and even terrorism.

Additional Risks

Even when the applicant investigator has a clean medical and legal history, the terrain remains challenging as these practicing investigators present additional risks that raise questions when determining qualification.  Concern that a lack of research and regulatory experience makes them less likely to understand the expectations of regulatory authorities.  Apprehension over the risk of financial conflict created by the payments made to doctors for their participation as investigators, or for speaking engagements on behalf of the sponsor have lead some to question if the investigator can truly remain unbiased.

Additionally, the risk of therapeutic misconception increases in this environment.  Despite their best attempts, are doctors truly able to clearly convey to their patients when they take off their “physician hat” and put on their “investigator hat?”  Or, as suggested in an article in PLoS Medicine Clinical Trials and Medical Care: Defining the Therapeutic Misconception, do trial participants really fail to grasp the difference between treatment and research?

Not Just Clinical

It must be noted that not all researchers are working in clinical trials.  Although this article focuses on multi-center clinical studies, a tremendous amount of important research involving human subjects is social in nature, involving interviews, questionnaires, and focus groups.  Some research takes place in schools and targets increased knowledge of behavior. Should the standards for these researchers be the same as those imposed on clinical trial investigators?  Most would agree that a researcher wishing to use a questionnaire to study quality-of-life issues but who falsely presents himself to the IRB as having a PhD should not be granted approval, but what if he is a highly experienced researcher with multiple drunk driving convictions?  Is there a need for concern of his ability to interpret and manage the data?  Or does that step outside the limits of the board’s authority?

The reality is, investigators are human.  They are vulnerable to the same difficulties and failures that exist in the rest of the population.  It would be easy to say that only investigators who are impervious to such behaviors should be allowed to assume responsibility for research involving human subjects, but is that realistic? Who should decide what the limits of acceptable failure, or shortcomings are for an investigator responsible for ethical research? And who is responsible for enforcing them?

Delegation of Roles

These real questions create a demand for important discussions about the roles and responsibilities of the IRB and their non-local HRPP. Already in a “gate-keeping” position, most independent IRBs have established policies to ensure verification of required licensure, set limits on allowed financial earnings from the sponsor or even require human subjects training as a condition of approval.  Additionally, if the study involves a schedule II narcotic, they may seek verification of a valid DEA license.

What they may not have clearly defined among their HRPP partners is how to address review of an applicant investigator whose background is not ideal.  In our example, an investigator was asking to participate in the study of a marketed schedule II narcotic.  The IRB found a history of diverting drug for personal use resulting in the loss of his license twice in the past year; the license is now reinstated with unrestricted prescribing privileges.   Should this applicant be denied participation? If yes, then by whom?  If the medical board believes the investigator to be rehabilitated, who has the right to say otherwise?

If the IRB establishes levels of investigator eligibility for a given study, do they expose themselves to claims of discrimination or even slander by refusing approval to a licensed physician over actions the medical board has determined resolved?  Will their increased scrutiny be interpreted as a benefit to the protection of human subjects, or as another example of the IRB overextending their authority?

Should the responsibility, particularly in a multi-center trial, be the sponsor’s?  They hold the regulatory obligation and are the ones selecting the doctors before submitting them to the IRB for review. If the sponsor was paying the investigators for their service, they would have the option to set the expectation as high as they choose for a given study.

Perhaps the best solution encompasses both the sponsor and the IRB, as partners under the shared program of protection.  If the IRB already has a procedure in place to ensure the applicant investigator meets a minimum requirement for training and experience, is legally licensed and has an acceptable research track record with the FDA, perhaps the establishment of any additional requirements should belong to the sponsor or CRO specifically. Through communication in the “study set-up” phase of the trial, the IRB as a team member in the protection program could even assist in vetting the sponsor’s additional criteria.

At a minimum, if not in the public forum, this is a discussion that needs to occur between the research sponsor and the IRB as they establish the specific needs and requirements for a given study.  The risk of not having this discussion is the potential for another bad investigator to cause harm to subjects through unethical behavior, tainting research outcomes and reputations.

Continue reading »]]> IRBs speak a variety of languages.  For nearly 30 years our IRBs have been fluent in the language of biomedical reviews.  We have specialized in all phases of drug and device research and the evaluation of risk that is associated with each.  Our IRBs speak more than biomedical, however. Our service languages also include:

• Outcomes Research
• Educational-based Research
• Clinical Effectiveness Research
• Biological Specimens
• Registry Studies
• Grant Reviews
• Focus Groups
• REMS / KABs

Not all research is the same, and neither are the requirements for their review.  If your research involves these types of languages we can help you determine when IRB review is required, when voluntary review might be beneficial, and how to decide if your project is exempt or simply not human subjects research.  We can help because we speak your language and understand how to administer and review non-invasive research. E&I has learned to apply a “tiered” approach to the studies we review, distinguishing between identifiable-data collections, interaction studies and intervention studies.  This method benefits our clients through more appropriate, and often shorter, application forms and review times.

Give us a call to discuss your type of project further…we speak your language.

For more information please contact us.

Continue reading »]]> PRESS / NEWS RELEASE

Independent Review Consulting (IRC) and the Ethical Review Committee (ERC), both Independent Institutional Review Boards (IRB) representing nearly 50 years of combined service to the research industry are pleased to announce the finalization of their merger agreement.

While the individual boards of each company will continue their review of existing projects respectively, all new submissions of business will be accepted and managed by Ethical and Independent Review Services, LLC (E&I). E&I will offer review of research by an AAHRPP accredited board in California.  A second board in the Midwest anticipates receipt of accreditation in the coming months.

Services offered through E&I will include reviews of both private and federally funded research, training and consulting services, and the development of more specialized review boards. Both companies are excited by this opportunity to provide a larger spectrum of review services and a greater base of experience from which they can support their human subject protection program.

Both companies have experience in the review of late-stage, multi-center trials.  While IRC specializes in medical devices and federally funded studies, ERC has developed processes specializing in efficient turn-around of large, late-stage multi-center trials.