Shades of Gray

The New England Journal of Medicine recently published an article of an OHRP determination and apparent backtrack with a mea culpa.

The article is slim on details, however, it appears a research protocol was being followed involving hand-washing using different sanitizing techniques and placement location in the insertion of central venous catheters to determine whether a protective effect exists based on the technique and/or placement strategy used.

Yet the authors suggest this study could have, and should have, been expedited under Category 4 and Category 5.

Expedited review can occur only when specific criteria are met. Category 4 states:

Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/approved for marketing. (Studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications.)

Examples: (a) physical sensors that are applied either to the surface of the body or at a distance and do not involve input of significant amounts of energy into the subject or an invasion of the subject=s privacy; (b) weighing or testing sensory acuity; (c) magnetic resonance imaging; (d) electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow, and echocardiography; (e) moderate exercise, muscular strength testing, body composition assessment, and flexibility testing where appropriate given the age, weight, and health of the individual.

Meanwhile, Category 5 reads:

Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for nonresearch purposes (such as medical treatment or diagnosis). (NOTE: Some research in this category may be exempt from the HHS regulations for the protection of human subjects. 45 CFR 46.101(b)(4). This listing refers only to research that is not exempt.)

Yet the protocol in question involving the placement of a catheter, appears to disqualify this study from Category 4 as a catheter placement is inherently invasive. In addition, the protocol also appears to vary placement of the catheter for comparison purposes in the hopes of acquiring generalizable conclusions (e.g., it is safer/better minimize the placement of the catheter at the femoral site).

45 CFR 46.102 defines research as:

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.

My sense is a reasonable person would concur this is research.

Therefore, if this is research, invasive, and data in part is collected for research purposes, it seems clear such a study would not qualify for expedited review.

How can so many people, including the federal body regulating IRBs come to so may different conclusions? One, someone at OHRP does not know what he is doing. Two, Johns Hopkins IRB/staff do not know what they're doing. Three, I don't know what I'm doing. Or four, in a world of "black and white" regulations, we live in an IRB world of frustrating grays.

Change is in the air

We have lost another senior staff person this week.

Such is the nature of IRBs around the country, actually.

Turnover comes is waves and it appears unavoidable. One person leaves and others follow. The effect is significant change--some good and some bad. With the changes in staff, institutional knowledge is unquestionably lost. But also with change comes new perspectives and new energy.

My hope is that the new energy can somehow make up for the significant loss when a co-worker and friend sets sail to another opportunity.

IRB Tip #2: HIPAA

Old school medical researchers (and social-behavioral, for that matter) find HIPAA the bane of their collective existences. Codified into federal law in 1996, HIPAA established national standards for health care insurance portability and patient privacy rights. From the researcher point of view, she could no longer simply open a medical record and review it for research purposes without written permission from the patient-subject or a waiver by a privacy board / IRB.

Patient advocates rejoiced. And despite being on the research side at the time, I celebrated too. How dare I, you ask? What self-respecting researcher likes HIPAA?

Frankly, I'm a big believer of individual rights. And this is a clear-as-day issue of individual rights.

Unfortunately, then states' rights ruled the day when it came to patient privacy. These rights were not consistent from state to state and depending on where you lived, someone could take a peak in your medical record without your permission. HIPAA ensures patient-subject rights to some degree. IRBs are often the entities which review requests to open medical records in a research setting.

Regardless of your feelings about HIPAA, I bet we'll agree on something HIPAA related: our HIPAA Research Application (HRA) is terrible. It is perhaps the worst form we have next to the Internal Adverse Event report form. More on that another time. Back to the HRA.

First the 4 page application is backwards. The first determination investigators must make is, "When will I look at the medical record?" If the answer is to enroll subjects, without first obtaining their permission, you will want to ask for a waiver of HIPAA and informed consent for research purposes. Respond to Section B (on Page 2 of the application), Section II.B (on page 1), Section I.A, I.B, I.C (also on page 1). Asking for a waiver of HIPAA will also lead you to complete section B.1-B.4 as appropriate.

If you will be reviewing the medical record only after obtaining signed informed consent, complete Section I.A, I.B, I.C (on page 1) and Section A (on page 2) by writing, "I assure the Board I will use the UCLA HIPAA authorization form and IRB approved informed consent form."

If at any time you add research information to the medical record, more often than not you must get HIPAA authorization and obtained signed informed consent to do so. This means complete Section I.A, I.B, I.C (on page 1) and Section A (on page 2) by writing, "I assure the Board I will use the UCLA HIPAA authorization form and IRB approved informed consent form."

10,000 emails

That's how many I have in my email inbox after one year in this office. Keep in mind, I delete items from my inbox regularly.

So now it's come to haunt me and I'm sorting and cleaning my inbox.

This is what I do in my "spare" time. Sad, I know. But over the last 3 days, I'm down to a mere 8,800. It's a party.

IRB Tip #1

One of the reasons for starting this blog was to help investigators and research assistants and coordinators in an unofficial way. Don't get me wrong, I think I'm a pretty helpful guy in real life, but there are limits to what is proper in an official setting.

However, this blog gives me a good opportunity to expose the "secrets" of IRB functionality. And they really aren't secrets at all. But my sense is that IRBs generally do a poor job of educating, and researchers do a poor job of passing on information from staff to staff due to high turnover. Let's be honest, some (many?) PIs know little to nothing about an IRB submission and they can't teach their staffs what they don't know.

Although the idea here is for most tips to be specific to the IRB I know best, other IRBs follow similar policies. These policies, after all, have basis in federal regulations. Still, it's remarkable even to me--a "professional"--how varying IRBs work from institution from institution. Nevertheless, I will try to provide helpful tips to readers of this blog as best as I am able. Contact your own IRB for specific consideration. And feel free to let me know if their handling/processing is different from what I've described.

And with that, my first IRB Tip of GTMR:

IRB Tip #1
When your IRB takes forever to review and approve a new study, and you just want "administrative approval," you can get it pretty easily but only if you haven't submitted the full IRB application already.

Federal regulations (45 CFR 46.118) permit approval of a study prior to review by the IRB when "lacking definitive plans for involvement of human subjects."

This is a particularly good option when you can't access your grant money until IRB approval is obtained or if you're applying for a Certificate of Confidentiality from the NIH. Sometimes the NIH accepts it, other times they don't. But when it takes 3 months to get a CoC, it's worth trying to apply early, isn't it?

Frankly, I think many investigators should request administrative approval under 45 CFR 46.118, especially if your IRB is notorious for being slow or "picky."

Here's how you do it: In a simple letter, explain that you've been awarded X grant and wish to prepare the IRB application but cannot until you get IRB approval to release those funds. Provide your assurance that you will not initiate research involving human subjects until you obtain prospective IRB approval. State the title of the grant, the title of the study, and include a copy of the grant application (the protocol is sufficient). Complete the first 2 pages of the IRB application. Turn it in. That's it. Really. IRB approval is on its way. You can thank me another time.

What good are we? (and by "we", I mean IRBs)

Perhaps the most sweeping, bitter criticism comes from those who say IRBs are worthless and/or pointless. We are just a bunch of bureaucrats with nothing better to do except legitimize our existence by unrolling more red tape. A form of this criticism comes from the author of Scientific Misconduct Blog. (I am taking a bit of a liberty putting harsher words in his mouth but I wanted to reference his page in this post with a little emotion and this seems just as good as a way as any.) Although it was a short email, I think I understand his point. IRBs just don't cut it like they, perhaps, at one time did.

There are times I question whether the process itself is meaningful. In the end, I come to the definitive--and I mean definitive--conclusion that IRBs are important and necessary even if their responsibilities weren't codified in law.

However, I do believe IRBs are losing their way a bit. And I hope to be part of a movement that puts them on track and adapts to the modern times of research, compliance, and human subjects protections.

Specifically, this renaissance of human subjects protections begins with the acceptance that researchers are motivated by good and are well intentioned. Once that is agreed upon, the IRB's next goal is to promote and take active roles in ensuring the proposed and approved protocols are conducted ethically. This takes major form in Post Approval Monitoring. Most IRB's lack a strong PAM program. PAM is a terrific opportunity to ensure the research is being carried out as intended, study procedures are being followed, subjects are in fact being consented, and so on. I feel so strongly about this responsibility that I believe half of the resources of an IRB should be dedicated to this endeavor. It is that important.

I have little doubt this will be a common discussion item on this blog. But let's start here.

Phillip Morris

Are you guilty by association?

This is a question posed to Edthye London by skeptics of her work. London is a researcher from my alma mater. She has been targeted on two fronts in recent days. The first from animal rights extremists: her home has been both flooded and later fire bombed. The other side is going at her for taking tobacco industry money to pay for her research on addiction--specifically nicotine and children.

In the LA Times, state senator Leland Yee suggests it is inevitable that London's research is biased and flawed because of the financial relationship:

"It is absolutely outrageous to see this kind of funding and this type of
research within the UC system," said Yee, a psychologist. "The fact that a piece
of research is funded by the tobacco industry, and their singular issue is how
to sell cigarettes, taints the results of whatever the findings might be."

Surely Yee has accepted political donations for his numerous campaigns for office. His comments suggest that he is beholden to them since he has accepted their money, no?

A review of his fundraising through the CA Secretary of State indicates he has accepted donations from casinos, alcohol distributors, and the like. Holding himself to London's standard, Yee implies every piece of legislation he sponsors in those industries will serve those financial backers' ends. Of course, this is a ridiculous notion.

And yet, London is indicted for accepting money from big tobacco.

Is an insurance company an worse? Blue Shield has given money to both Yee and the University of California for research purposes. His money is clean, but the University's is dirty?

And watch out! Xerox has begun to sponsor medical research. The horror. The horror....

The ethics of being a drug manufacturer

"Drug trials under pressure" is a strange title from USA Today for an article suggesting pharma is struggling to prove their drugs work.

Drug cos. solution recently, and perhaps since the beginning, is selectively choosing which data to use from their studies conducted in collaboration with universities nationwide. Naturally, drug cos. encourage the use of data which shows benefit from the use of their drugs while concealing/ignoring data showing no effectiveness.

The evidence in the form of a smoking gun for this ethically questionable practice is not out yet. But I foresee Congressional investigations in the next two years and hopefully serious reform in the next five years.

I'm not against drug manufacturing. Indeed, we need better drugs. However, I want to see them developed safely and the data presented openly and with transparency.