Institutional Review Board (IRB) – Keeping Research Subjects Safe

Xmas

I was working over the holiday weekend, but at least I was working in my decorated living room with a fire going (the high in Arizona was only 66 today!!)

Hope you had a fabulous Thanksgiving weekend! Four day weekends are great, and even I took some time off to enjoy the holiday with my husband and the puppies.  And then I got back to work because I have an Institutional Review Board (shortened usually to the acronym IRB) meeting in two weeks and the committee has eight new protocols to review. This likely means very little to you, but the IRB is what ensures that the rights and welfare of humans participating as subjects in a research study are adequately protected. And here’s why that’s important…

In a previous post, I explained clinical research.  Clinical research studies new drugs or devices to determine if they are safe or effective. As you can imagine, at a world-class hospital, we have hundreds of clinical trials. You can check out information about these clinical trials by following the links for the Barrow Neurological Institute, St Joseph’s Hospital and Medical Center and the University of Arizona Cancer Center at Dignity Health.  Physicians and surgeons are studying new treatments for many different cancers, devices like the NovoTFF for glioblastoma, and comparing new drugs or combinations of drugs to current treatments to see if the new regime works better.

Now if a  company wants to test a new drug, they can’t just pick up the phone and ask their physician buddy if they could just use a few of their patients to test some stuff out. But why not?  Honestly, it’s because at one point researchers did some pretty crappy things in the name of science.  Thins like Nazis studying prisoners against their will and in the US and scientists who studied the untreated progression of syphilis in black patients in Tuskegee, Alabama from the 1930s-1970s. In these and other cases, the welfare of the patient (who is called a subject once they are part of a research study) wasn’t considered AT ALL and what the subjects had to endure was truly awful.

To avoid this from happening in the future, in 1974 the government passed the National Research Act, which resulted in the Belmont Report. From this, three ethical principles were developed in the treatment of research subjects:

  • Respect for persons.  This respect includes allowing them to make their own informed decisions about participating in the research.  This also means that the researcher conducting the study needs to be honest and not try to deceive or coerce patients into participating in the study. For example, the researcher can’t tell the patient that the research will be painless and cure their disease if they know it won’t.
  • Beneficence: Basically this ensures that the researchers do no harm to the research participants – for example, like the harm done during WWII or in untreated syphilis patients.
  • Justice:This is to avoid taking advantage of the patient or a vulnerable patient population.  For example, there are special rules to prevent taking advantage of prisoners or children. This principle also tries to make sure that all research participants receive benefit equally.

protocol for IRB reviewThese ethical principles have been developed into processes that are regulated by the Food and Drug Administration (FDA) and Department of Health and Human Services (specifically Office for Human Research Protections). How does the government make sure these regulations are followed?  Any institution that is performing human subject research has to obtain a Federalwide Assurance, which essentially registers the hospital or university with the government and assures the government that the hospital will follow the ethical rules and guidelines to conduct this research.

For each project or clinical trial involving human subjects, the investigator needs to put together a proposal – what we call a protocol.  This protocol includes information about exactly what is going to be done to the subjects, what the risks are, what the alternatives are for treatment, and how the subject’s safety and confidentiality will be safeguarded. This protocol is the sent to the IRB along with LOTS of other documents about how the patient will be informed about the research (in Informed Consent Form), whether or not the investigators have been trained to perform the research, and information about the drug or device being used.

The IRB is responsible at individual institutions for making sure that patients who become subjects in human subjects research are treated with respect, beneficence and justice while also decreasing the potential risks and letting the patient know what these risks are. The IRB reviews each new protocol (which is exactly what I am doing this weekend!) and at the IRB meeting (which is once a month from 7-9AM), the investigators present their protocol.  The IRB members then ask questions to the investigator and discuss the research after the investigators leave the room.  What do we discuss? It’s confidential for individual studies, but we may talk about how the study is being performed and identify possible problems with the study. We may also talk about the informed consent (what the patient reads to learn about the study – more on that in the next post) and if it accurately explains the research and the risks. We then can vote to approve the study, to send the protocol back to the investigator to answer questions or modify the protocol or to reject the study.

After the study has been approved, the IRB is also responsible for monitoring active research projects.  For example, we receive annual reports that let us know how many people have decided to participate in the study. We also monitor “adverse events.” Adverse events (or AEs) are any event that isn’t anticipated.  This can be anything from nausea to a broken leg to a rash to a missed appointment to death (death is considered a serious adverse event). Whenever an AE happens, the IRB is informed so that if it seems like there are too many of one type of AE, we can take measures to avoid them or tell the subject about an additional risk or shut the research project down.

My participation on the IRB is a responsibility I take seriously because I want any patient who comes to the facilities I work at to understand the research that may be made available to them.  And this understanding includes knowing what the research is all about and what risks the research entails. This is why I’m spending my holiday weekend reviewing research protocols for the IRB.

How scientists “cured” melanoma

When talking about Personalized Medicine, one of the recent shining examples of this concept in practice is in the treatment of melanoma. Melanoma is a cancer of the pigment cells called melanocytes and is most commonly diagnosed as a skin cancer. The prognosis for melanoma is dismal when caught at later stages where the cancer cells have spread into lower layer of the skin or throughout the body (see the stats in the image below). Treatment typically involves surgery to remove the cancer cells, followed by chemotherapy and/or radiation therapy, but the response to these treatments is low.

melanoma

There are two interesting personalized medicine examples for melanoma.  The first is in determining whether a low stage (I or II) melanoma has a likelihood of spreading.  Once a low stage melanoma has been removed by surgery, there is still a 14% chance that these patients will develop metastatic (melanoma that spreads) disease. To determine which patients are more at risk, a biotech company developed DecisionDx-Melanoma. This test looks at the expression of 31 genes and separates the patients into two groups based on the gene expression profiles.  One group only has a 3% risk of developing invasive melanoma within 5 years whereas the other group has a 69% chance.

However, whether the cancer progresses or not, treatment is still an issue. That is, it was until a few years ago when scientists found that  50-60% of all melanoma patients have a mutation in the gene called “BRAF.” This mutation tells the cancer cells to grow faster, so you can imagine that if you stop this signal telling the cancer cells to GROW, then they might stop growing and die. This is exactly what the drug PLX4032 (vemurafenib) does – it inhibits this mutated BRAF and stops the cancer cells from growing in 81% of the patients with this mutation (see the photo at the bottom of the post to see how dramatic this effect is).  On the other hand, in patients without this mutation, the drug has severe adverse effects and shouldn’t be used.  Because of this, doctors don’t want to prescribe this treatment to patients without the mutation.  Therefore, scientists created a companion diagnostic.  These are tests that are used to identify specific mutations before treatment to help decide what treatment to give (see image below). In the case of melanoma, this companion diagnostic tests if the patient has the BRAF mutation, and the patient is only treated with vemurafenib if they have this mutation.

This treatment was revolutionary with an incredible ability to cure melanoma. It was like melanoma was previously being treated with the destruction of a nuclear bomb, and now it is being treated with the precision of a sniper rifle – targeting the exact source of the cancer. So why is the word “cure” so obviously in quotes? Unfortunately, after continued therapy, the cancer relapses (see the image below). Imagine treating cancer cells being like closing a road- it’ll block up traffic (kill the cancer cells), but then you’ll be able to find back roads that get you to the same place.  In the case of cancer, the drug is targeting mutations in BRAF, and BRAF finds ways to evade the drug by mutating again (effectively removing the roadblock).  Or the cancer cells themselves may have other routes besides mutated BRAF making the cancer grow. So although this drug is a life extender, scientists have been working to combine it with other targeted drugs (blocking off alternative routes) to make it a long-term life saver.

melanoma_relapse

From the Journal of Clinical Oncology