What is Informed Consent for Research Subjects?

informed_consentAs I mentioned in my last post, the Institutional Review Board (or IRB) has a responsibility to review and monitor all human subject research to help ensure that the subjects are treated ethically.  But how does the patient know what they are getting into if they are interested in participating in  a research study?

One of the key parts of the Belmont Report (that report that sets the rule for human subject research) says that subjects must be treated with respect.  A huge part of this is to inform research subjects about the research, the risks, and the possible benefits. Because of the importance of informing the subject, most research studies involve providing the potential participant with an Informed Consent Form (ICF) that the they must read, understand, and sign before joining a clinical trial.  This informed consent form is reviewed by the IRB and usually much discussion goes into whether it is clear (ideally 6th-8th grade reading level), accurate, and informative.

So how do investigators or the IRB know what to inform the potential participant about in this informed consent? Well the government tells us – of course! The intuitively named Title 45 CFR 46 subparts A, B, C and D outline the rules and regulations for human subjects research.  Because this is the government’s stupid way of naming things, the easier name used for these rules is the Common Rule. This rule outlines what’s needed in an informed consent form (paraphrased directly from the Common Rule):

  1. A statement that the study involves research, an explanation of the purposes of the research and the expected length of the subject’s participation, a description of the procedures to be followed, and identification of any procedures which are experimental.
  2. A description of any reasonably foreseeable risks or discomforts.
  3. A description of any benefits to the subject or to others which may reasonably be expected from the research.
  4. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might benefit the subject.
  5. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records.
  6. For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained.
  7. An explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in the event of a research-related injury to the subject.
  8. A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

The intent of the informed consent is for the subject to actually be informed.  This means that the investigator needs to clearly and honestly explain the research to the subject.  For example, when we provide informed consent for patients to provide tissue samples for the biobank, we tell them that their tissue may be used for any type of future research, it may be used to create commercial products but won’t financially benefit them, and that we won’t be able to provide any research results back to them.  In this context, participating in the biobank may sound like a raw deal.  However, we also explain how the tissue they donate will be used by researchers to better understand diseases and develop new treatment. Therefore, even though they may not directly receive benefit, they may benefit others with their disease in the future.

The potential participant is also given the chance to ask all the questions that they have about the study.  They can ask to bring the consent home to read it.  They can ask their doctor about it. Then after they are fully informed, they decide if they want to sign it or not. If not, that is okay.  It’s up to the patient if they want to participate and the investigator cannot do anything to coerce the patient to sign or participate.  At the same time, if the patient does decide to participate, they may leave the research study at any time with no penalties. Their participation is entirely voluntary.

One other quick note about making sure the patients are fully informed…the Common Rule has added additional safeguards in the case “when some or all of the subjects are likely to be vulnerable to coercion or undue influence.” These vulnerable subjects include children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons. For example, you don’t want to force imprisoned people to participate in research just because they are in jail or poor people to participate just because you are paying them a lot of money to participate.

The US Office of Human Research Protection is working on changes to the Common Rule right now (it’s called a Notice of Proposed Rulemaking – these silly government names).  The original re-write was sent out to the public for review in 2011.  The updated version was made available in September of this year (look at that for the glacial swiftness of the government!) for even more review.  It has many proposed changes that will affect human subject research and research using human tissue samples. To learn more about what this means for clinical and other research, check out the recent story from NPR.

Overall, the purpose of informed consent is to make sure anyone volunteering to participate in a research study knows what they are getting into. If you are interested in a clinical research study, can you find more at clinicaltrials.gov or talk to you physician.

The difference between basic, translational and clinical research

When I started as a researcher, I had no idea that there were different types of research.  I don’t mean that some scientists study cancer and some scientists study Alzheimer’s disease.  I mean entirely different kinds of research that have fundamentally different methods, sources of funding, and purposes. Today’s post is going to outline three main types of research in the biological sciences: basic, translational and clinical research.

Basic Research:

science_image

By en:User:AllyUnion, User:Stannered (en:Image:Science-symbol2.png) [CC BY 3.0 or GFDL], via Wikimedia Commons

 Right off the bat, I need to be super clear that basic research is NOT research that’s easier to do or simpler than any other type of research.  It is just as complex and just as hypothesis-oriented as other types of research.  However, the goal of basic research is to  understand at a very basic level some aspect of biology.  Also called fundamental research, basic research doesn’t require that the outcome of the research can cure a disease or fix a problem.  That being said, basic research often does create the foundation that is required for other researchers to apply to solving a problem. I like how basic research is described on WIkipedia as “Basic research generates new ideas, principles, and theories, which may not be immediately utilized but nonetheless form the basis of progress and development in different fields”  This research can be in biology, physics, math, environmental sciences or any other scientific field. So what are some examples of basic research in biology?

  • Understanding the proteins and pathways that result in cells dying by apoptosis
  • Developing technology to better determine the 3D structure of proteins.
  • Creating mathematical models representing population growth in cities over time
  • Studying how leaf litter affects the ecosystem (an actual active funded grant at TGen here in Arizona)

This research is often funded by the government, specifically the National Institutes of Health, which funds 50,000 grants to more than 300,000 researchers at more than 2,500 institutions around the world, and the National Science Foundation, which funds 24% of all federally-funded basic science research in the United States.

Translational Research:

mouse_for_research

By Maggie Bartlett, NHGRI. [Public domain], via Wikimedia Commons

Translational research is how basic research and biological knowledge is translated into the clinic.  Often called “bench-to-bedside” or research (referring to the research bench and the patient’s bedside) or “applied” research (of applying basic research to solve a real-world problem), this research is needed to show that a drug or device works in some living system before it is used on humans. This is the research that happens after the results from basic research are obtained and before clinical research.

For example, if a drug is found in the lab that targets a protein that is thought to cause a disease like cancer, the drug will first be tested on animal models.  The animal model may be a mouse that has been genetically altered so that it develops that specific kind of cancer or a mouse that has human cancer cells injected into it (like the patient derived xenografts I described in a previous post). The drug will then be used on the animal to see if it is safe or if low doses are so toxic that the animal dies. Whether or not the drug hits the targeted protein or cell type can also be tested in mice.  For example, if the drug is supposed to kill brain tumor cells, researchers would want to make sure the drug was able to pass the blood brain barrier of the mouse.  Finally, if the drug is supposed to kill tumor cells, researchers would want to check that the tumor shrinks, the cells die, and/or that the survival of the mouse is extended from using this treatment. Often, drugs are “weeded out” at the translational research stage saving millions of dollars and years worth of time and effort in clinical trials.

Translational research isn’t just for drug development.  It is also useful for devices. For example, to develop a device that can diagnose diseases in third world countries, where access to electricity and high tech labs is more difficult.

Clinical Research:

blood_tube_for_research

By Tannim101 [CC BY 3.0, GFDL or CC BY 3.0], via Wikimedia Commons

Clinical research is what is performed in a healthcare environment to test the safety and effectiveness of drugs, diagnostic tests, and devices that could be used in the detection, treatment, prevention or tracking of a disease.  The cornerstone of clinical research is the clinical trial.  There are 4 basic phases to a clinical trial.  Each phase is performed sequentially to systematically study the drug or device.

  • Phase I: This is the first time the drug or device has been in humans and it is used on a small number of patients in low doses to see whether or not it is safe and what the side-effects may be. At this point, the clinicians are not trying to determine if the treatment works or not.
  • Phase II: In this phase, more patients are treated with the device or drug to test safety (because more side effects may be identified in a larger, more diverse population) and whether the drug or device is effective (in other words, does it work?).
  • Phase III: This is the phase that focuses on whether the drug or device is effective compared to what is typically already used to treat patients.  It’s used on a large group of people and “end points” like increase in survival or decrease in tumor size are used to evaluate its effectiveness.
  • Phase IV: These trials are done after the drug has gone to market to see if it works in various populations .

There are several different types of clinical trials depending on who is funding them. Some clinical trials can be initiated by a doctor or group of doctors.  These are call “physician-initiated” or “investigator -initiated”  studies and are often used to determine which type of treatment works better in patient care.  For example, there may be two treatments that are commonly used to treat a disease. Investigators may initiate a study to figure out what treatment works better in what patient population.

The kind of clinical research you may be more familiar with are drug companies who are working to develop a drug or device.  These companies will “sponsor” (aka “pay for”) a clinical trial.  They work with clinicians at one or more medical institutes to use their drug or device in a particular way (depending on the phase of the trial) and the clinicians report back the results, including whether there were any side effects to the treatment. At the end of the clinical trial, if the treatment or device was a success, the drug company can apply to the Food and Drug Administration (FDA) for approval to use the drug in the general population.  Bringing a drug to market is a timely and extremely expensive process estimated at over 10 years and $1.3 Billion dollars per drug. Much of this time and cost is due to high cost of conducting the clinical trials.

If you are interested in what clinical trials are currently available in the United States, all clinical trials are registered on ClinicalTrials.gov.  Anyone can search this database to see if trials are available for them to participate in.

Overall, each type of research needs to understand the other, and researchers need to work together to successfully understand our world and to come up with solutions to prevent, diagnose and cure disease.