Not blogging, trying to get studies approved

Everyone agrees--IRB members, investigators, administrators: It is not satisfying to delay research. So why do we?

Investigators
Either lack of qualified research staff (high turnover or no money to hire/retain) or interest to learn what IRBs want and ask for. They can make significant life-saving scientific discoveries, but they do not know how to submit an IRB application, respond to questions from the IRB, or simply have a general irritation towards the IRB which is reflected in their effort. Sloppiness leads to delay.

IRB members
Like investigators, overworked and limited resources. High turnover, little training for members. Terrible questions. Poor reviews such that upon first or second review, significant issues aren't raised and after three years of approval, major questions are asked. The current IRB gets blamed for mistakes and sloppiness of the past IRB, which may now have different and/or better trained members.

Chief Executive
Despite the spin, money talks. Inadequate resources are allocated to administrative IRB infrastructure, including investigator support and training, IRB staffing, IRB member training, and technology. Listen to your advisers, investigators, IRB members! But instead they are ignored and the system suffers from lack of action and mismanagement. No recognition that an efficient IRB will result in improved recruitment of top faculty and increased research money into the institution.

Back to work!

I'm sorry, Dr. X

Dear Dr. X,

I am sorry it has taken over 5 weeks for you to receive your letter from the IRB. What's more, your response, whenever you actually respond to it--because investigators such as yourself take a long time to respond but like to blame the entire time it takes for your study to be reviewed on the IRB--will have to go back to the full IRB. Lucky you.

We needed a consultant for your study because it was so obscure and strange in design. You won't like to hear this either but federal regulations require us to seek out expertise when none are available on the Board for your line of research.

But I hope you take my advice and simply answer the questions, give in and agree with the IRB on the minor issues raised, and did I say answer the questions? Most investigators (often study coordinators) DO NOT answer the questions. The result? More delays.

These sorts of delays are easily but erroneously blamed on the IRB. Still, the IRB is such an easy target and the temptation so great that it is understandable. However, it's a shared blame and one which can be fixed given a re-prioritization of the powers-that-be to resourcing, education, and collaboration. In time, I believe this will occur.... It must, actually, for the sake of advancement of science in the long run.

This is a letter I could never write in real life. And so I write this make believe letter here on this make-believe blog.

Busy is as busy does

I have not been able to write recently for the simple reason that the IRB has been as busy as ever. We lost a number of high level staff in the last six months and while always a struggle, it represents an opportunity to bring new energy and personnel with expertise in both applied research and human subjects protection.

The learning curve for anyone coming into a new organization in this field is quite steep regardless of one's prior experience. The work we do can be nuanced and difficult. There are multiple agencies which oversee an IRB at an academic research institution and sorting, interpreting, and coordinating all of the laws, regulations, and guiding documents is a formidable task.

I share this because it is not just enough to have the right number of staff to enable an IRB to function. Trained staff is important. So for those who loathe the time it takes for studies to be reviewed and approved by your IRB, among the many questions which could be asked, "How many trained staff are there?" should be one of them.

IRB Tip: Genetic Anaylses

If genetic analyses will be performed, I suggest you address the following in the cover letter and clarify these issues in the revised IRB application:

1. Describe the analyses that will be conducted on the saliva samples, and the genetic markers that will be analyzed.

2. Clarify the purpose of the genetic testing in this study and revise the Protocol Summary.

3. Clarify in the application and consent form whether subjects will receive their results from the genetic testing.

a. If so, clarify whether the genetic tests to be conducted have been scientifically validated and whether the lab where the testing will take place is CLIA certified.

i. If not, provide an ethical justification for providing subjects with their results from the genetic testing.

b. If not, revise the consent form to indicate that subjects will not be provided with their results from the genetic testing.

4. Revise the application to include background information regarding the genetic testing to be conducted in this study.

5. Clarify in the application and consent form whether there are potential benefits to society as a result of the genetic testing to be conducted in this study.

Super busy

Understaffed and overworked...welcome to any IRB in the country.

IRB Tip: Deferral avoidance for recruitment

Deferred is a categorization which an IRB gives a study after it has been reviewed by the Board and found to have significantly unclear or missing study procedures and/or goals. Most deferrals, believe it or not, are avoidable. Unfortunately, few on the research-side know how to accomplish this.

From time to time I think (mistakenly) that I could make a lot of money by helping biopharma or some for-profit consulting group manipulate the IRB review system such that as an IRB consultant I could prevent all studies I touched avoid deferral. Such an attitude is really quite silly. Like individuals, IRBs develop tendencies--personalities if you will--which cannot be predicted with 100% accuracy.

But I do believe I think I know my IRB pretty well and with that, another IRB tip.

When describing how you will recruit subjects for your study, it should almost never be just one sentence.

You would be surprised how many studies come across my desk with just this weakness.

You need not describe every second of the recruitment process, but you should describe it such that a reader who is unfamiliar with your project could envision when and how you identify, approach, screen, and enlist a prospective subject up to her signing the consent form.

There are some areas of an IRB application that you could be lazy and get away with it. However, recruitment procedures are not one of them. It's okay to use bullets, paragraphs, or even comic strip depictions--but clearly describe recruitment.

Suppose you are recruiting subjects directly in the context of clinical (non-research) procedures This is pretty common in medical research: You'd like to enroll your own patients in your study. Coercion, however, is a real concern. In other words, are your patients feeling pressure (real or imagined) to participate in a study for which you are both treating health care provider and researcher?

I recommend the following when recruiting subjects who are also patients: (1) Provide a study flyer, (2) recommend your patient review the flyer at home and talk to family members and/or friends about participating, (3) call the study team at the number on the flyer if interested in the study.

In this way, a prospective subject's real or perceived pressure to join your study is minimized. Of course, some patients will want to participate in your study straight away. And that is okay. Simply describe in the IRB application that if a patient asks to join the study during her clinical appointment, this will be clearly documented in her medical record.

Last but not least, include the following language (or something similar) on the first page of your consent form:

Disclosure Statement
Your health care provider may be an investigator of this research protocol, and as an investigator, is interested in both your clinical welfare and in the conduct of this study. Before entering this study or at any time during the research, you may ask for a second opinion about your care from another doctor who is in no way associated with this project. You are not under any obligation to participate in any research project offered by your physician.

Choose the name-brand placebo over the generic placebo

The New York Times is reporting that placebos which cost $2.50 are more effective than the $0.10 version. Yes, this is ridiculous but important at the same time.

Especially in psychiatric studies, the placebo effect shows her head time and time again.

What does this mean for research studies? We should never discredit, or over credit, the role of a placebo. Is it appropriate? It is harmful when proven treatments exist?

I will write more about this topic later and please do not mistake the length of this post as indicative of the complexity of the issue. I could never write enough about placebos in research.

Data Suppression

I'm curious to know what researchers think about data suppression and whether they consider it a human subjects issue, academic ethics issue, or something else.

Howard Brody writes about recent new evidence of pharmaceutical companies practicing data suppression for financial gain. But if pharma can do it, surely an individual investigator could.

Without a doubt, data suppression is difficult to detect from the outside. Big pharma collects data from all of their research sites and analyze, clean, and process data without transparency. To manipulate data is frankly too easy and financially tempting.

As you might imagine, I see this as both a human subjects protections issue and an academic/business ethics issue. Let us not fool ourselves, the University is a business center as much as an educational one.

But before we begin to catch data suppression, we as a research community must agree it is a priority for science and the health care industry, and then we can address who should be responsible for investigation and enforcement.

FDA & suicide

I haven't decided whether it's good or bad (I lean to the latter) that the FDA recently announced "findings" in studies involving antiepileptic drugs an increased report of suicidal ideation.

An FDA analysis of suicidality reports from placebo-controlled studies of 11 antiepileptic drugs shows that patients taking these drugs have about twice the risk of suicidal thoughts and behaviors (0.43 percent), compared with patients receiving placebo (0.22 percent). This risk corresponds to an estimated 2.1 per 1,000 more patients in the drug treatment groups who experienced suicidality than in the placebo groups.

Keep in mind, these are not big numbers. But when it comes to risk ratios, for researchers, it's the comparison that matters (0.43 vs. 0.22). It translates to twice the risk!

Scary! Fear! Boogeyman!

It would not be surprising--given FDA is inherently political despite their best intentions--that soon research studies involving any antiepileptics will require procedures for addressing situations in which subjects exhibit suicidal thoughts. Again, I'm not convinced this is bad necessarily, but it is yet another issue researchers will need to be aware of when preparing their research applications and another item to be added to the consent form.

As far as suicide procedures, this is what IRBs like to see:

- A qualified individual should evaluate all subjects whose responses indicate that they may be suicidal.

- Potentially suicidal subjects should be referred for appropriate clinical care. Please outline your procedures for ensuring that all potentially suicidal subjects are provided with referrals for appropriate clinical care.

- If a subject is acutely suicidal, they should be transported to the emergency room by trained personnel and a trained member of the study staff should remain with the subject until they have been transferred.

And then, in the consent form, languages something like this:

In the event that you tell the research staff that you are thinking about killing yourself or you answer “yes” to a question about having thoughts about suicide, the investigator will ask you more questions about the thoughts. Depending on how intense your thoughts are or how much you feel like hurting yourself, the research staff may provide you with referrals for treatment, work with you to contact your personal physician, trusted family member, or therapist to discuss your thoughts of harming yourself; or work with you on a plan that may include getting you to a hospital for safety.

Don't hate me me for this. If and when the time comes, complain to the FDA.

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.

What is an IRB?

I'm a bit bothered that I found a good definition of an IRB at a private IRB like Quorum Review. But I did, and I'm not about to steal their explanation of what an IRB is or does without crediting them. It would be quite unethical after all.

An institutional review board ("IRB"; known in Canada as a research ethics board, or "REB") is a group of individuals who are responsible for reviewing a study to make sure that the research participant's rights and welfare are protected. Most clinical research studies cannot begin without a review board’s approval. Board members generally include health care personnel such as doctors, nurses, and pharmacists. The Board also includes other members of the scientific community, non-scientists such as clergy or social workers, and community members (For Canadian research, a majority of REB members must be Canadian citizens).

Ethics Boards carries out their responsibilities to protect the rights and welfare of research participants by reviewing the protocol to make sure that risks to participants are minimized, that risks are acceptable in light of the possible benefits, that the informed consent document is accurate and complete in describing the study and its risks and benefits, and that the clinical research study is conducted in an ethical manner. If the Board believes that these conditions have been met, it may approve the study and allow it to begin.

Once the clinical research study begins, the Board is responsible for periodically reviewing the approved study to assure that the rights and welfare of research participants continue to be appropriately protected. Usually, the informed consent document will provide the research participant with a phone number to contact the clinical investigator or the IRB/REB if the participant has a question or concern about how the study is being conducted.

And there you have it. This is pretty much my world.

What is Greater than Minimal Risk?

Greater than minimal risk is a term commonly uttered in the Institutional Review Board (IRB)world.

45 CFR 46.102(i):

Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

The tricky part of this definition is what is considered "routine." What is routine for one person--a cancer patient, for example--may not be the same as a healthy individual with no illnesses. Or suppose someone is bipolar or schizophrenic. Her routine tests may be quite unroutine for others even if they are the same exact procedure.

What appears to be a simple definition can actually be something quite complicated.

And so it begins

The first entry.