Clinical Trial Watch: Emergency Research With Waiver of Informed Consent (FDA Regulations at 21 CFR 50.24)
The Polyheme® Trial Pt. 1: What's Wrong with This Trial
The Polyheme® Trial Pt. 2: Community Consultation and Public Disclosure Information Submitted to FDA docket 1995s-0158 for Polyheme® Trial Sites
The Polyheme® Trial Pt. 3: Media Articles and Related Publications About the Polyheme® Trial
The Polyheme® Trial Pt. 4: Links to Articles on Polyheme® Published in Medical Journals
Clinical Trial Watch II: Studies Worth Keeping an Eye On
Institutional Review Board Meeting Minutes What information they're likely to contain, OHRP and FDA regulations and guidance, and some examples of publicly available IRB meeting minutes.
Resources for Understanding Informed Consent in Research Why informed consent is a process, not a pile of paper; how to evaluate informed consent, good and bad practices, elements required by federal regulation (where applicable), checklist of things you should know after reading but before signing, getting answers to your questions, red flags and why they're red, and additional reading.
Objectionable Practices in Clinical Trial Recruitment Advertising and recruitment is the beginning of the process of informed consent. We offer tips for understanding clinical trial recruitment.
Posted 2006-08-24 (comments forthcoming). MedlinePlus Interactive Tutorial: Clinical Trials. National Library of Medicine / National Institutes of Health. Available from http://www.nlm.nih.gov/medlineplus/tutorials/cancerclinicaltrials/htm/index.htm
Posted 2006-08-24 (comments forthcoming). An Introduction to Clinical Trials. National Library of Medicine / National Institutes of Health. Available from http://clinicaltrials.gov/ct/gui/c/a2r/screen/PrintURL?file=whatis.html&JServSessionIdcs_current=jug5rydgna
Below are five brochures that provide basic information about participating in research. Four brochures are published by U.S. government agencies and the fifth is published by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO). We provide our opinion of the pros and cons of each brochure. All brochures are free and available online.
1. National Institutes of Health (NIH) and National Institutes of Health Clinical Center. Are Clinical Studies for You? National Institutes of Health Clinical Center, National Institutes of Health. Available at: http://www.cc.nih.gov/participate/studies.shtml. 2005. Accessed 2005-10-01.
These comments are also applicable to a second NIH brochure reiterating much the same information: Partners in Research. National Institutes of Health Clinical Center, National Institutes of Health. Available at: http://www.cc.nih.gov/participate/_pdf/partners.pdf. 2005. Accessed 2005-10-01.
General Comment: NIH shoots itself in the foot by combining good intentions with misleading information. The Partners in Research
brochure reiterates and expands on the information (and misinformation) offered in the shorter brochure titled Are Clinical Studies for You?
The Partners in Research
brochure, however, provides useful information on how trials work with good definitions of randomization, study phases, and placebo controls. Text quoted below comes from Are Clinical Studies for You?
but comments are applicable to both brochures.
Caveat(s): Many. The following sections are objectionable as described in comments following quoted brochure text.
Quote: There are strict rules for clinical trials, which are monitored by the National Institutes of Health and the U.S. Food and Drug Administration.
Comment: This is inaccurate and misleading because FDA regulates drugs, devices and other products in interstate commerce. FDA does not monitor
clinical trials in any sense consumers would understand. Monitoring
conducted by FDA is intended to prevent sponsors from submitting false information to the agency in marketing applications. The safety of human subjects in research is secondary to data integrity, and the most of the limited monitoring
by FDA (more accurately called inspection) happens after trials are finished. Not all studies funded or conducted by the National Institutes of Health (NIH) come under FDA jurisdiction, and NIH has consistently asserted that it's a funding agency, and not a watchdog. The Office for Human Research Protections (OHRP) is the federal agency charged with the protection of human subjects in studies funded by NIH (and other federal agencies). OHRP doesn't monitor clinical trials either.
The sentence also suffers from careless grammar in use of the relative pronoun which
: as written its antecedent is the strict rules.
Perhaps NIH and FDA monitor the strict rules.
They don't monitor clinical subject safety in clinical trials.
Quote: Why Participate?
Patients taking part in NIH Clinical Center studies are seen by a team of expert doctors, dentists, nurses, technicians, and support staff.
Comment: With all due respect to the clinicians and staff at the NIH Clinical Center, medical care, like financial compensation, is a recruitment inducement. This seems to suggest medical care is a benefit of research participation instead.
Quote: Clinical Center patients often are first to receive promising new treatments before they become available in the community.
Comment: People enrolled in research are not patients: they are research subjects. The source of this problem seems to be FDA regulation where the term patient
refers to subjects with a disease, disorder, or medical condition as opposed to healthy subjects. Calling research subjects patients
fosters the therapeutic misconception. If the experimental intervention turns out to be safe and effective, and if the experimental intervention is offered to all the subjects in the study, this is all well and good. It's also rare. A number of promising new treatments
turn out to be ineffective, and randomized controlled trials may provide placebos to some subjects. The purpose of a study is to test whether the experimental intervention is safe and effective. It's important to remember an experimental intervention is not the same as a treatment.
In research the term treatment
is best avoided altogether or should be qualified as experimental treatment.
Quote: Risks and Benefits
It is important to understand that some risks are involved in clinical research, just as in routine medical care and activities of daily living.
Comment: Risk in clinical research is not just as
in routine medical care or activities of daily living because most if not all of these risks are unavoidable or justified by benefit, whereas risk in research is voluntarily assumed and unknown. This one reason why the standard of disclosure in research is more rigorous than in routine medical care.
Quote: In thinking about the risks of research, it is helpful to focus on two things: the degree of harm that could result from taking part in the study, and the chance of any harm occurring.
Comment: This very useful explanation is introduced only to be left unexplored. Risk
can be a source of confusion for consumers when they think of risk
as approximately the same as How likely am I to get hurt?
Quote: Most clinical studies pose risks of minor discomfort, lasting only a short time.
Comment: This is misleading and tends to undermine the authority and credibility of NIH. When research subjects have questions about risk
the last thing we should do is confuse them with an answer in which we use risk
to mean two different things. It may or may not be true that most studies
involve minor transient discomforts. Frankly few research subjects are likely to be surprised or frightened by a needle stick or terribly concerned by the fact that half of them will probably get a rash that will disappear in a week. A phase I or II trial of a new cancer drug is all but certain to pose risks of minor discomfort if given intravenously (e.g., the needle stick hurts briefly, the drug might sting), but it may also pose risks of harm from serious adverse drug reactions (if the study drug causes heart block, for example). In early phase studies the incidence and duration of harm from serious adverse drug reactions may be (relatively) unknown. In addition to risk of direct harm from serious adverse drug reactions, there may be risk
of harm to research subjects if they don't receive treatment: placebo controlled trials can expose subjects to harm if disease progresses when treatment is withheld. In clinical trials comparing two treatments (or more) there may be risk
of harm if the study drug turns out to be inferior.
The statement is misleading to the extent that nobody knows precisely how many studies are conducted each year or what's being tested on whom, let alone the rate of adverse events / adverse drug reactions or their severity.
Quote: Dealing with Fears
Many protections and safeguards for volunteer patients are built into the Clinical Research process. It may help alleviate some of your fears about participating in a clinical study to know what some of these are:
The Patient Bill of Rights. All patients who take part in studies at the Clinical Center are protected by the Patient Bill of Rights, developed by the American Hospital Association for use in hospitals across the country. The Patients' Bill of Rights contains guidelines to ensure privacy and confidentiality of patients and their medical records.
Comment: This is misleading because the Patient Bill of Rights applies to privacy in medical care rendered in hospitals. In research, subjects are told (ideally) that confidential information about their medical condition may be disclosed to FDA, OHRP, the IRB, and the sponsor.
Quote: Hospital Accreditation. As in any medical research facility, an institutional review board (IRB) must review and approve every new study at NIH before the study can begin. The IRB is made up of medical specialists, statisticians,nurses, social workers, medical ethicists, and members of the community. The IRB reviews protocols to ensure patient safety. In addition, The Joint Commission on Accreditation of Healthcare Organizations (JCAHO), periodically reviews the Clinical Center hospital to see if stringent standards, leading to JCAHO accreditation, have been met.
Comment: This is misleading and just plain wrong because it conflates JCAHO approval of hospitals with IRB review and approval of research. The two are unrelated.
Quote: Who Participates?
People who take part in Clinical Center studies include:
Children and adults wishing to improve their own health. They may be patients with newly diagnosed medical problems. They may have had the problems over a period of time, or they may have a family history of a certain disease.
Comment: This is misleading because it fosters the therapeutic misconception. Yet again. The purpose of research is to answer a question or add to general knowledge. People who enroll in research because they wish to improve their own health
are under the misconception that research aims to provide them with direct medical benefit. It doesn't. NIH of all institutions should not foster this misconception.
Forthcoming: Program for Healthy Volunteers. National Institutes of Health Clinical Center, National Institutes of Health. Available at: http://www.cc.nih.gov/participate/studies/healthy_vol_prg.shtml. Undated. Accessed 2006-02-02.
2. Office for Human Research Protections. Becoming a Research Volunteer: It's Your Choice. Office for Human Research Protections, Department of Health and Human Services. Available at: http://www.hhs.gov/ohrp/outreach/documents/3panelfinal.pdf. Undated. Accessed 2005-10-01.
Comment: Highest marks for straightforward explanations and readability.
Caveat: The statement that Scientists do research because they don't know for sure what works best to help you
is unfortunate because it encourages people to confuse research with medical treatment. Confusing research with medical treatment is called the therapeutic misconception.
It's impossible to evaluate whether or not research participation is in your best interest if you think you're being offered medical treatment. The statement is also misleading because not all research tests medical treatment, and not all research testing treatments provide them to every subject. You might get a placebo in some studies. The purpose of research is to extend general knowledge, not to provide you with direct medical benefit. This brochure is the best bet for people just beginning to learn about research.
3. U.S. Food and Drug Administration (FDA). Why Volunteer? Clinical Trials of Medical Treatments. Food and Drug Administration, Department of Health and Human Services. Available at: http://www.fda.gov/opacom/lowlit/cltr.html. Undated. Accessed 2005-10-01.
Comment: High marks for straightforward explanations and lots of relatively detailed information on FDA-regulated research.
Caveat: (1) The information doesn't apply to all research testing medical treatments (drugs, devices, and dietary supplements). Practically speaking it applies to research conducted under an Investigational New Drug application (IND), Investigational Device Exemption (IDE, full or abbreviated), and bioequivalency studies (ANDA applications for generic drugs). (2) It doesn't mention non-therapeutic research regulated by FDA. Early research, often called Phase I
studies, offers no direct medical benefit because it involves healthy subjects in safety and dose-ranging studies. Other kinds of research without direct medical benefit include pharmacological studies of drug absorption and metabolism, drug-drug and drug-food interactions, and drug safety and efficacy tests in subjects with impaired kidney and liver function. FDA might reconsider using file names like lowlit
(=low literacy
). Some people who find reading difficult are sufficiently literate to be offended by this file name. In CIRCARE's experience, people have difficulty understanding information about research because the information is poorly written and unedited, false, misleading, and often deliberately recondite, either because the people providing the information don't care or because they would prefer that potential research subjects not understand the actual conditions of research participation.
4. Department of Veterans Affairs. I'm a Veteran. Should I Participate in Research? Department of Veterans Affairs. Available at: http://www1.va.gov/resdev/programs/PRIDE/veterans/vet-brochure.pdf. Undated. Accessed 2005-10-01.
Comment: Very good overall with quality information including a description of the Institutional Review Board, what it does and why.
Caveat: Research and treatment are not the same. Some veterans will be approached by their health care providers to participate in research, but because you're used to receiving medical care from him or her, it's easy to forget there is a difference between research and treatment. It's important to keep this in mind when deciding whether or not to participate in research.
5. Joint Commission on Accreditation of Healthcare Organizations (JCAHO). (Formerly Partnership for Human Research Protection Inc.) What You Should Know About Research Studies. Joint Commission on Accreditation of Healthcare Organizations. Available at: http://www.jcaho.org/NR/rdonlyres/6DCE201D-78BC-4E36-A673-BC46F42A77F2/0/speakup_research.pdf. 2005-10-05. Accessed 2006-02-01. (1)
Comment: Well written high quality information.
Caveat(s): Virtually none.
The brochure suggests people considering research ask for a copy of the study protocol to better understand the potential risks or adverse events they might experience if they decide to enroll. This is a fantastic idea in principle but in practice there are problems with this suggestion. The biggest problem is that investigators (and sponsors) are unlikely to agree because it's most often the case that the study protocol is considered proprietary information. Industry sponsors, like drug, device, and dietary supplement manufacturers are more likely to refuse on the grounds that the protocol is proprietary. This practice seems to be changing thankfully. In NIH–sponsored research, on the other hand, there is no similar basis for objection, and people are more likely to obtain the study protocol. In the event of refusal in the case of an NIH-funded study, the protocol can be retrieved by making a request under the Freedom of Information Act. The drawback is NIH FOIA requests take months to complete and so this may be of limited utility.
CIRCARE offers tips and information for making FOIA requests at: http://www.circare.org/FOIA/foia1.htm.
The other problem with this otherwise excellent suggestion is that many people will be unable to read or make sense of the study protocol. Protocols are written by scientists and intended to be read by scientists. While some protocols may be models of lucid prose, protocols are of necessity written in medical and technical jargon. What's more, it's not uncommon for study protocols to run to several hundred pages including bibliography. If you decide to tackle the protocol, you're likely to get the best result by reading selectively. Virtually every protocol has a table of contents, and you should use this to locate sections of interest. You can locate journal articles cited (footnoted) in the protocol bibliography through the PubMed search engine at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DB=pubmed.
The brochure correctly points out that Many studies are reviewed by an Institutional Review Board (IRB)
.
The corollary is that some studies are not reviewed by an IRB. If there is no indication of IRB review in the consent form, ask for clarification. If the study has not been reviewed and approved by an IRB CIRCARE strongly urges you to select a different study if at all possible. Put less politely, run like the wind.
Failure to obtain IRB review and approval of proposed research is unethical and indefensible. There is no excuse for failing to obtain IRB review and approval: investigators on staff at or affiliated with medical institutions and hospitals have access to institutional IRBs, and investigators without such affiliation can use one of a number of commercial IRBs. In the unlikely event an investigator or sponsor pleads lack of funding, you should be extremely skeptical. Commercial IRBs charge between $800 and $1500 for initial study review. If sponsors or investigators are genuinely unable to afford IRB review, they probably shouldn't conduct the study since it's possible they may not have adequate funds to complete it.
Several states have laws requiring IRB review and approval of research. For more information follow this link to CIRCARE's collected information about state laws for the protection of human research subjects: http://www.circare.org/statelegis.htm.
Finally, keep in mind that a study conducted without IRB review and approval will be rejected for publication (ideally). Sponsors and investigators who conduct research without IRB oversight do so with the knowledge that they can't publish their results. While it's true that some studies aren't published for a variety of reasons, some of which are beyond the control of the investigators or sponsors, deliberately conducting research that won't be published is unethical.
Parent's Guide to Medical Research. Children's Hospital Boston. Available at: http://www.bostonchild.vitalconsent.com/bstnchld/index.html. 2004. Accessed 2005-10-01.
Comment: Highest marks for tackling difficult issues head-on especially Common Misunderstandings About Research
in the Medical Research Basics section.
Caveat: (1) The site is a rich source of information but the sections appear shorter than they are because of the web page design. This might frazzle readers who don't realize how much they've read. (2) Comments pertain to text sections only (because the video file is allergic to my web browser). (3) The corporate logo and web link to ClinAero seem out of place. It's difficult to believe that many (or any) parents considering research participation for their child would also be in the market for the services of a human subject recruitment company. It may, however, remind parents that commercial interests exist in research. I was surprised to find ClinAero
is the third term in the HTML Keyword metatag.
National Institute on Aging, National Institutes of Health
Understanding Risk: What Do Those Headlines Really Mean? National Institute on Aging, National Institutes of Health. Word on Health. April 2004. Accessed on 2007-02-19 at: http://www.nih.gov/news/WordonHealth/apr2004/risk.htm
Notes
1. Updated 2006-02-01: Although Partnership for Human Research Protection Inc. (PHRP) is no longer offering IRB accreditation, their parent organization, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) adopted the brochure as part of its Speak Up™ safety initiative. The PHRP brochure was posted at http://www.phrp.org/media/pubs/phrp/PHRP%20brochure%204-22-05.pdf.
Last Updated: 2007-10-10
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