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Chapter 3: Ethics and Study Design
A. Introductory
Clinical research can be defined more or less broadly. For our purposes we
define it to be any study that requires IRB approval. These include:
a. Data from living individuals
b. Biological material from living individuals
c. Interaction or intervention with a living individual
d. Use of a non-FDA approved, drug, device or biological
Such research includes:
a. Physiological or behavioral studies of normal individuals or those
with a specific condition.
b. Review of data from large populations (Health Services Research)
or from selected populations (chart review)
c. Epidemiological studies of populations with or without an
intervention.
d. The study of human tissue either fresh or from repositories such as
Banks or Pathology departments
e. Interventional studies
Types of studies include
Phase 1: Toxicity (small number of individuals)
Phase 2: Efficacy, may include pharmacodynamics (small
number of individuals)
Many studies are mixed Phase 1 and 2.
Phase 3: Efficacy and safety of unapproved drug, device or
biological (tend to be large studies)
Phase 4: Efficacy and safety of approved drugs, devices or
biologicals, or a comparison between interventions.
Each of these types of study requires the appropriate design to reach
scientifically sound conclusions while protecting the participants and their
identifiable human information.
A. Ethical Design
In clinical research, ethical science requires quality science. Although this
may be morally obvious, it’s also important practically because of the huge
investments in money, effort, and personal risk and discomfort that the
sponsor, investigators and the participants make. But poorly designed and
executed studies are frequently reported and can even influence practice and
policy development. Among elements that make for poor and therefore
unethical science are excessive risks compared to benefits, inadequate power,
inappropriate allocation of dosages in comparison trials, poor selection and
misallocation of participants, midstream changes of protocol, and failure to
either monitor or record significant adverse events.
An important part of research integrity is the analysis of data. It’s critical to
recognize the importance of appropriate statistical analysis. Statistical
approaches should be developed as part of the study design. If possible,
hypotheses should be well defined in advance. Current statistical packages
permit the mining of entire databases to identify statistically significant
results that were not anticipated. The role of such findings continues to be
subject to debate. Post-hoc reasoning should be employed only to generate
new hypotheses and experiments, not to resurrect a failed investigation.
In therapeutic studies, both efficacy of the interventions and their safety are
generally studied simultaneously but the design may focus on one or the other.
C. Appropriate risk to benefit ratio
Risk is defined as the probability of physical, psychological, social, or economic
harm occurring as a result of participation in a research study. Both the
probability and magnitude of possible harm in human research may vary
from minimal to considerable.
The federal regulations define only “minimal risk.”
Minimal risk exists where the probability and magnitude of harm or
discomfort anticipated in the proposed 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.
[45 CFR 46.102(i)]
Risk above this standard is more than minimal (moderate, maximal) and
that imposes limitations on the conduct of the research and increases the
requirements for monitoring. It also requires more stringent approval
processes when studying children or otherwise vulnerable populations.
Increased risk should be accompanied by the probability of appropriately
increased benefits.
Benefit applies to the potential of the research treatment to ameliorate a
condition or treat a disease. This can apply to an individual participant or
to a population. In research as in clinical medicine, results cannot be
Blinding refers to a process whereby the participant does not know whether
he/she is receiving an active agent or a similar appearing inactive
substance or mock procedure. Blinding is also used in research to refer
to investigators who analyze components of a study such as X-rays or
EKGs without knowing the identity and treatment of the participant.
“The X-rays were read blind.”
Double blinding is a process whereby neither the investigator nor the
participant knows which agent the participant is receiving. Usually the
research pharmacy holds the master list in case there are complications.
Over the course of the last 30 years it became apparent that blinding
both participants and research teams reduced biases in the results of
studies where subjective elements were important. One result that is
almost invariably subjective is the adverse event profile. In the absence
of blinding very serious biases have occurred.
Sometimes the effects of the agent in question are so obvious that true
blinding is impossible. For example, if a weight loss drug were
immediately effective, then the results would be obvious to everyone.
Under those circumstances special attention has to be given to unbiased
evaluation of adverse events, and conflicts of interest (see below) must
be avoided.
Equipoise
The concept behind equipoise is that in order for a therapeutic trial to
be ethical there has to be genuine uncertainty as to the relative efficacy
or safety of the treatment arms. Is this new drug better than placebo? Is
drug A more efficacious or safer than drug B? In theory, if we knew the
answer, there would be no reason to do the trial. In order for a clinical
trial to be ethical, then either
1. The individual investigator has genuine uncertainty regarding the
comparative therapeutic merits of each arm, or
2. The medical community has genuine uncertainty regarding the
comparative therapeutic merits of each arm.
Arguments have been made that true equipoise rarely exists because
previous research, whether it be in cells or animals or in small groups of
humans, usually suggests that the proposed treatment has a better than 50%
chance of being effective. In fact, those sponsoring clinical trials have to
invest so much money and effort that they would hardly take the risk of such
an undertaking unless they felt that the evidence supporting the efficacy of
the intervention was reasonably strong. The FDA would not permit a Phase 3
trial unless the preliminary evidence was promising.
Use of Placebos
A placebo is an inactive version of a treatment identical in appearance to the
real thing. Sometimes part of the treatment consists of active medications
and part is placebo.
Once you recognize the need for controls then the question of whether
placebo controls are desirable or acceptable must be answered. This has
become a major issue because of international research (see below), in which
it became apparent that placebos were being used when, in the developed
world standard therapies were available and routinely utilized. The most
recent version of the Declaration of Helsinki states:
The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists. See footnote: Footnote: The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:
- Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or
- Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.
All other provisions of the Declaration of Helsinki must be adhered to, especially the need for appropriate ethical and scientific review.
The issue of placebo controls also applies to studies in developed countries
where the cost of studies using standard therapy in the controls is much
greater and the end points much less definitive than in the use of placebo
controls.
Standard of Care:
This term applies to the expected care in the medical community as a whole.
Often, standard of care can be defined on the basis of practice guidelines,
which are being developed by all medical specialties, element by element. The
issue of standard of care becomes problematic when a study is to be
performed in a developing country where it is impossible to provide medical
care at anywhere near the level available in the developed world. The current
expectation is that controls will be treated at the level of the Western
standard of care, not the indigenous standard.
B. Selection of subject populations
Justice
Justice relates to access to research of all relevant populations specifically
including age, ethnicity, gender and preexisting conditions. The federal
government has made it clear that studies should try to include ethnic groups
and women in proportion to the population in the community unless there is
a good scientific reason not to (for example studying hypertension in African
Americans). Issues that must be considered in justice determinations include:
Socioeconomic Status
Gender,
Race,
Age,
Existing medical conditions
Vulnerable populations (as noted above)
Determining ability to consent
Ensuring understanding of protocol
Appropriate surrogate for consent
Coercive nature of relationship (prisoners)
The need to use such populations must be justified
Cases:Chapter 3
Case: Depression
Jones agreed to join an ongoing sponsored clinical trial of an investigational
new agent for treatment of severe unipolar depression, directed toward persons over
age 55, to include at least 40% above age 70. Previous clinical trials with this agent
have studied younger persons. This drug differs from others in that it is supposed to
increase limbic serotonin levels and receptors markedly and rapidly, thus relieving
an entire depressive episode in two days. The drug, when administered long-term,
has been shown to increase limbic system serotonin receptors as demonstrated by
PET scanning.
Jones was invited to participate because of her interest in clinical
investigation, expertise in depression, and patient base as director of the hospital’s
in-patient depression unit, where she cares for the most severe cases including
numerous suicide attempt survivors.
The study requires that patients be severely depressed and not suffer from a
chronic medical condition. The acute study will compare the new agent with
established drug therapy over a three-day period. Progress will be measured using
depression instruments, serotonin and serotonin metabolite measurements, as well
as PET scans on day zero and three. Following the acute trial, the participants will
be treated for depression free of charge for 1 year either with the new agent or a
standard regimen and will have quarterly clinic follow-ups.
Participants will receive a payment of $200 at the end of hospitalization, and
$50 plus transportation for each of the quarterly follow-ups.
Informed consent will be obtained on admission.
The anticipated adverse events from studies in other subjects are limited to
nausea, dizziness and thirst, never serious in the younger populations previously
treated.
A corporate Data and Safety Monitoring Board will monitor the study. The
study will be carried out under the auspices of the GCRC but within the locked
psychiatric ward, mainly on patients admitted under a 72-hour hold.
A. Critique this study as though you are an IRB member, assessing the
various review elements.
B. Provide constructive suggestions as to how it may be improved to be
more acceptable as a human subjects study.
After discussion and a number of revisions the IRB finally approves the
protocol.
Jones undertakes the study and finds that recruitment is slow, with only 30%
of eligible patients willing to participate. While the trial coordinator doesn’t
mention it, the Research Subject Advocate for the GCRC finds that those
participants who improve clinically become progressively more reluctant to
participate and have to be cajoled to continue. A subset of the subjects become
Blood pressure Hypertension
MRI of brain Tumors Anomalies Atrophy Multiple sclerosis
DEXA scan of spine and hip Osteoporosis
Serum Lipids (APO E 4 ) Hypercholesterolemia Risk for Alzheimer’s Coeliad disease
Carotid artery ultrasound Degree of atherosclerosis
Genotype Many risks over time
Many of these studies will be analyzed and reported long after the encounter with the participant.
How should the study deal with abnormalities in these results and how should the issue be presented to the participants? A significant number of the participants have no personal physician. How should that situation be handled?
Case: Hepatitis Vaccine and the Military
Hepatitis E is a relatively uncommon for of hepatitis that is usually transmitted by exposure to the blood of persons with conditions like hepatitis B and C. Hepatitis E is not tested for in blood donations. There is reason to be concerned that military personnel, at time of war when injuries requiring transfusions are being suffered daily, that hepatitis E could result in substantial long term morbidity (illness).
A vaccine was recently developed for hepatitis E that required testing. When it was mentioned at an international military training program that this new vaccine was imminent and a clinical trial needed to be done, a senior office in the Nepalese army volunteered the entire army in exchange for a donation of military supplies. The US Army was delighted to follow up on this.
As the director of this research program for the US Army, you are designated to arrange and perform this trial.
Questions:
- What ethical considerations are paramount to you in designing this study?
- Is there additional information you would like to have before you agree to this study?
Case: Prepubertal Girls
An investigator proposes to study the effects of dietary restriction and feeding on hormones related to metabolism and reproduction to learn more about the conditions conducive to the onset of menstrual periods in girls.
The proposed subjects are healthy girls between 8 and 12 years of age who have not had menarche but who are beginning pubertal development by Tanner Score.
The participants would be volunteers with parental consent admitted to the GCRC for 15 days full time during their summer vacation. They would have a 50 cc phlebotomy, be put on an optimal diet for three days, have another 50 cc of blood drawn, be switched to a diet with the same amount of protein but ½ the calories for six days have a third blood draw and then be returned to the optimal diet for six days and have a fourth 50 cc phlebotomy at completion.
The children would be given a gift certificate for $100.00 at Borders at completion of the study.
You are the IRB member assigned to this protocol. You are very supportive of clinical research.
Questions:
- Is this an appropriate experimental design?
- Is there a problem with consent?
- Is there an issue with blood?
- Is there an issue with the gift certificate?
- Is there an issue with HIPAA?
Case: Teenage subject
Narrator: Dr. Smith, a pediatric diabetologist conceived of an amino acid infusion to accelerate recovery in diabetic ketoacidosis DKA, the most serious emergency associated with childhood diabetes. She got the sterile solutions produced and an IND (investigational new drug) permission to try it from the FDA as well as approval from her local IRB. To show results, the amino acid infusion must begin within four hours of starting the insulin infusion and Dr. Smith makes arrangements for the Pediatric Intensive Care Unit nurses to call her whenever a patient is admitted with DKA. Dr. Smith has a lot at stake in this study. If it works, a company is ready to prepare and market the amino acid solution, giving her and her institution a substantial financial shot in the arm.
Scene 1: Dr. Smith’s bedroom. She and her husband are sound asleep. Her pager goes off when the clock reads 2:20 AM. She rouses, turns it off and hears a disgusted groan from her husband. Again!, he complains. She picks up the phone and dials. It’s the head nurse in the PICU.
PICU nurse: We just admitted Janey again in flagrant DKA. Do you know her, the fifteen-year-old who is always getting into trouble with her diabetes? She resents the condition, her family, and about everything else. You might want to ask her and her mother about participating in your study. In fact, I can get them to sign up and give the infusion so you won’t have to come in.
Dr. Smith: Janey’s my clinic patient and I know all about her. She is one of those teenagers who need to grow up, but at the rate she’s going she might not live to be an adult.
infusion to what you’re already receiving but it won't add to your time here. It may possibly shorten it. However, we don’t know all the possible effects of the infusion because it is research.
Here is a copy of the consent form for you to assent to, so why don’t you look at it and see whether you want to participate. You don’t have to do it at all. It won’t affect your care from me whatever you decide.
[Janey takes the papers and begins to read.]
Mrs. Granger: [points to the papers she has been reading] It says here that you stand to make a lot of money if this works and that none of the subjects will get any part of it. Is that fair? [Somewhat irritated].
Dr. Smith: Well that’s the way it has been done. We don’t want people to join research programs and take risks because they think that they might win some kind of lottery. Besides, don’t you think that the people who thought of the idea and developed it should get the benefits.
Mrs. Granger: [annoyed but somewhat mollified] Well, not all the benefits. Since I trust you and am grateful to you I will sign.
Janey: It doesn’t look like this stuff will hurt me and maybe it will get me out of here a little sooner. That sounds fair [giggles] and it’s better if Mom is reluctant. I’ll sign because I love you Doc and you’re never on my case. She signs the forms.
Dr. Smith: Thanks. [Gives Janey a hug]
Case: Appropriateness of placebo controls
Matrix Pharmaceuticals developed a new drug that increased bone density in mice by facilitatinging osteoblast function without stimulating osteoclasts nearly as much, thus increasing bone density. Phase I and II trials were conducted with no significant morbidity at an effective dose.
A number of international experts in the field were asked to consult on the design of the hopefully definitive Phase III clinical trial that was going to be carried out at 100 sites in 15 countries.
Matrix’s vice president for research proposed a placebo-controlled trial of 8,000 women over one year, with a direct measure of bone density, DEXA scanning, as the principal end point.
A European investigator indicated that they follow the latest version of the Helsinki Accord that indicated that placebo controls should not be used if there are effective standard therapies. In the case of osteoporosis, bisphosphonate were effective and relatively safe standard therapies.
An American representative pointed out that the FDA prefers placebo-controlled trials if there is no serious safety issue. Furthermore, he pointed out, comparison with an effective agent to demonstrate “non inferiority” or “superiority” would require a study of 30,000 women rather than 8,000, would take much longer, by vastly more expensive, and would require a greater number of adverse endpoints in both treatment categories to reach a conclusion, thus making it less safe over all for the research participants.
Company representatives agreed whole heartedly and suggested that the study be designed so that it focused on early findings, diminished bone density by DEXA and appropriate chemistries. The key to
a successful outcome and limited fracture morbidity would lie in the selection criteria for participants.
Another team member argued that an intermediate end-point like change in bone density by DEXA scan will not answer the question about preventing fractures. Bisphosphonates have been shown to reduce fractures already so that a new agent will have to be equal to or superior to them in protecting against fractures. In that case they will have to recruit women at high risk for osteoporotic fractures, for whom a placebo control is not benign at all.
Another team member added that with the availability of bisphosphonates, very few women with osteoporosis will be found in developed countries that are not taking an effective agent. Therefore most of the study will have to be done in developing countries.
There are plenty of untreated Americans if you look to underserved populations, stated one of the team.
Questions: Put yourself in the position of an ethics consultant to this meeting. What would you recommend as the most appropriate ethical randomized clinical trial for this new agent and give your reasons for the choice?
Case: Asthma Comparison
Asthma is a serious chronic problem in pediatrics. New drugs being developed for asthma need to be tested in children.
This study (an actual study) compared Beclomethasone (established therapy) with a new steroid that we will call NUSTER and placebo. Subjects were recruited from ages 12-16 and were required to have had asthma for at least 6 months and to have used steroids in the last 30 days, signifying serious shortness of breath.
The subjects were randomized to 4 groups and treated for 12 weeks: Beclomethasone bid, NUSTER 100 μ g bid, NUSTER 200 μ g bid, and placebo. Subjects would use albuterol, another standard agent, as needed. The main outcome measure was FEV 1 , a measure of ability to take deep breaths. The study showed that all of the steroid doses were statistically equal and better than placebo, where FEV 1 deteriorated. Ten percent of the active treatment subjects and 44% of the placebo subjects had to discontinue the study because of shortness of breath.
The study was done in doctors’ offices using a commercial IRB.
This study was published and used to support the introduction of NUSTER.
- Was this an ethical study?
- Was a placebo control justified a. If the subjects were children? b. If the subjects were adults?
- Seven ethical requirements for clinical research as delineated by Emanuel et al are: a. scientific value b. scientific validity c. fair subject selection d. favorable risk/benefit ratio e. independent review f. informed consent g. respect for enrolled subjects
Questions:
- Would the IRB and the University-Industry Conflict of Interest Committee of your institution
have a problem with this study?
- How will you determine whether participants can consent for themselves? What should you do if
some cannot?
- How will you present the studies to the subjects and to their surrogates?
- This category of patients experiences a lot of “sundowning.” Will this likely affect your study?
Expecting the Phase I and II trials to be highly successful from the basic mechanism and the
animal experiments, you are planning a phase 3 clinical trial that will involve 300-400 participants.
- What ethical issues must you consider in this large trial?
Chapter 3: Bibliography
Experimental Design
Adrian, S. (2005). "Placebo effects in developmental disabilities: Implications for research and practice." Mental Retardation and Developmental Disabilities Research Reviews 11 (2): 164-170. The author discusses the importance of a placebo in the trial of secretin injections in autism research. She then elaborates on the "Hawthorne effect" and elaborates on the physiological consequences of placebos. A very worthwhile read.
Carpenter, W. T., Jr., P. S. Appelbaum, et al. (2003). "The Declaration of Helsinki and Clinical Trials: A Focus on Placebo-Controlled Trials in Schizophrenia." Am J Psychiatry 160(2): 356-362. This provides an excellent analysis of the placebo-control problem generated by the 2000 version of the Declaration of Helsinki as modified in 2001 and formally appeared in October 2002. It argues for the proper use of placebos and the benefits of having them in studies where numbers are important, failure to respond to current meds is widespread and in cases where the availability of standard Rx is problematic.
Tishler, C. L. and S. Bartholomae (2003). "Repeat participation among normal healthy research volunteers: professional guinea pigs in clinical trials?" Perspectives in Biology and Medicine 46 (4): 508-20. The authors try to determine the amount of repeat volunteerism, motivation (altruism, money, obligation), ethical, and methodological problems and some suggestions.
Richardson, L. (2005). "The ethics of research without consent in emergency situations." Mt Sinai J Med 72 (4): 242-9. This is an excellent review of the federal rule that permits research without consent in emergency situations. The detail about the limitations and the arguments about whether personal therapeutic benefit must be part of the process are discussed. http://www.mssm.edu/msjournal/72/724242.shtml
Whitehead, J. (2004). "STOPPING CLINICAL TRIALS BY DESIGN." Nature Reviews Drug Discovery 3 (11): 973. This paper discusses the DSMB stopping rules which, he says, should be built into the design, before efficacy, lack of safety, or inevitably no evidence of benefit. If you belong to a DSMB or have one on your study this is very worthwhile reading. http://www.nature.com/nrd/journal/v3/n11/abs/nrd1553_fs.html
Weijer, C. and P. B. Miller (2004). "When are research risks reasonable in relation to anticipated benefits?" Nat Med 10 (6): 570. The authors propose to use "component analysis" to assess risk vs. benefit in clinical research. The therapeutic components are assessed differently from the non-therapeutic. They use equipoise to justify the therapeutic component. http://www.nature.com/nm/journal/v10/n6/abs/nm0604- 570.html;jsessionid=00E29673439DE2E30C826750460B6D
Morris, M. C., V. M. Nadkarni, et al. (2004). "Exception From Informed Consent for Pediatric Resuscitation Research: Community Consultation for a Trial of Brain Cooling After In-Hospital Cardiac Arrest." Pediatrics 114(3): 776-781. Hypothermia may help treat cardiac arrest in children, but it must be applied quickly. A research project studying their potential benefit without prior consent was proposed to the community and substantial support was obtained but the results were far from unanimous. This study requires Federal approval as well. They concluded that making sure that prospective cardiac arrest parents be notified and allowed to decide whether to participate in advance but that timely consent was no feasible. http://pediatrics.aappublications.org/cgi/content/full/114/3/
Roberts, L. W., T. D. Warner, et al. (2004). "Schizophrenia research participants' responses to protocol safeguards: recruitment, consent, and debriefing." Schizophrenia Research 67 (2-3): 283. This report describes interview of patients with schizophrenia who were currently involved in a research program. They indicate that the participants understood that they were involved in research and that they had agreed voluntarily to participate although some degree of coercion was noted. This is a worthwhile report for anyone considering research with vulnerable populations. http://www.sciencedirect.com/science/article/B6TC2-48Y0DV3-3/2/eaa1fedba809650b94c8231b368ecded
Markman, M. (2004). "Ethical Conflict in Providing Informed Consent for Clinical Trials: A Problematic Example from the Gynecologic Cancer Research Community." Oncologist 9 (1): 3-7. This thoughtful article raises a series of ethical dilemmas regarding a study of "consolidation" therapy for women who achieve a complete clinical remission of ovarian carcinoma. They use the actual conduct of the experiment as the basis for discussion and also introduce the special responsibilities of the initial major study to be as complete as possible. http://theoncologist.alphamedpress.org/cgi/content/full/9/1/
Ross, L. F. (2003). "Responding to the Challenge of the Children's Health Act: An Introduction to Children in Research." Theoretical Medicine and Bioethics 24 (2): 101. This article summarizes the arguments in this issue of theoretical medicine regarding the challenge of the Children's Health Act of 2001 that provided both funding and the opportunity to loosen restrictions on research with children. it clearly summarizes sophisticated arguments and could introduce the field to a novice. http://www.springerlink.com/openurl.asp?genre=article&id=doi:10.1023/A:
Rothmier, J. D., M. V. Lasley, et al. (2003). "Factors Influencing Parental Consent in Pediatric Clinical Research." Pediatrics 111 (5): 1037-1041. In research with small children one might ask why are parents consenting. This study queries 44 parents or guardians regarding volunteering their children and found that the leading reason was neither altruism nor free medications, but rather to learn more about the disease. Nicely done. http://pediatrics.aappublications.org/cgi/content/full/111/5/
Miller, F. G. and H. Brody (2003). "A critique of clinical equipoise. Therapeutic misconception in the ethics of clinical trials." Hasting Center Report 33 (3): 19-28. This sophisticated article argues that research differs from clinical medicine and that the concept of equipoise contains within it a "therapeutic misconception." Very worthwhile arguments are made in the context of an excellent review.
Steinbrook, R. (2005). "Gag Clauses in Clinical-Trial Agreements." N Engl J Med 352 (21): 2160-2162. This report discusses the evils of contracts with clinical research sponsors in which the investigator doesn't see all of the data before agreeing to publication. http://content.nejm.org/cgi/content/extract/352/21/
Friedrich, M. J. (2005). "Neuroscience Becomes Image Conscious as Brain Scans Raise Ethical Issues." JAMA 294 (7): 781-783. http://jama.ama-assn.org/cgi/content/full/294/7/ This brief perspective points to ethical dilemmas generated by FMRI in practice but especially in research. Findings can be interpreted to violate privacy by revealing emotions that one would normally hide. Furthermore, the very act of doing FMRI would reveal unexpected findings of variable clinical significance in 2-8% of scans. How to deal with these raises additional ethical dilemmas the handling of which is very variable.
Franck, L. (2005). "Research with newborn participants: doing the right research and doing it right." J Perinatal and Neonatal Nursing 19 (2): 177-86. This paper discusses the role of the neonatal nursing team in determining what research is ethical in the NICU and how the rights of the infants need to be protected.
Miller, F. G. and D. Wendler (2004). "Assessing the ethics of ethics research: a case study." IRB Ethics and Human Research 26 (1): 9-12. These authors analyze research into clinical research ethics that employs deception. The argument is made that deception causes harm and thus risk vs. benefit arguments are relevant. They also deal with an informed consent that is a lie.
Weijer, C. (2003). "The ethics of placebo-controlled trials." J Bone Miner Res 18 (6): 1150-3. This bioethicist challenges the concepts of Ellenberg and Temple regarding placebo controlled trials by elaborating on the concepts of risk. He argues that there are no good definitions or assessments of risk and that the case for a "sensitivity problem" is weak. He has no solution. Worth reading.
Rosenblatt, M. (2003). "Is it ethical to conduct placebo-controlled clinical trials in the development of new agents for Osteoporosis? An industry perspective." J Bone Miner Res 18 (6): 1142-5. This industry wide discussion of the appropriate research design for drug trials in osteoporosis is very specific and responsive to concerns about the use of placebos. They suggest low-risk subjects, bone densities rather than fracture end points, extrapolation to and study of high risk subjects in a second trial, a reduced duration of study and an indication for prevention first. This interesting industrial response is well thought out and persuasive.
Ellenberg, S. (2003). "Scientific and ethical issues in the use of placebo and active controls in clinical trials." J Bone Miner Res 18 (6): 1121-4. This discussion by a member of the FDA office of biostatistics and epidemiology confronts the difficulties of equivalence or non-inferiority studies in comparison to placebo-controlled randomized clinical trials. Although not an official document, it provides the FDA rationale for greatly preferring placebo controls. A very good paper.
Heaney, R. (2003). "Ethical issues in the design of osteoprosis clinical trials: the state of the question." J Bone Miner Res 18 (6): 1117-20.
This discussion of study design in osteoporosis work, clearly and thoroughly discusses the issues regarding randomized control trials, placebo controls, and surrogate markers by an expert in osteoporosis research. Very worthwhile.
Cummings, S., K. Giacomini, et al. (2002). A Strategic Plan for Clinical Research at UCSF: 2-. The authors propose that UCSF develop an integrated, interdisciplinary and interschool Clinical Research Program. They think it needs a home of 150-200,000 square feet where those involved in the field could be housed, near each other and their subjects. They also suggest the creation of hubs for clinical research to provide the infrastructure. All of this would be connected via an electronic network for research. They also propose funding start-up clinical research through internal grants. This is a very far- seeing and expensive proposal, but if you don’t think big, you will never accomplish anything big.
DeAngelis, C., J. M. Drazen, et al. (2004). "Clinical trial registration: a statement from the International Committee of Medical Journal Editors." CMAJ 171(6): 606-607. This development, which is incomplete and applies only to a limited but extremely important group of journals simply states that clinical trial registration must take place before initiation of subject registration to be considered for publication. The registers must be transparent, independent and include the key information about the trial.
Marshall, E. (2004). "ANTIDEPRESSANTS AND CHILDREN: Buried Data Can Be Hazardous to a Company's Health." Science 304(5677): 1576-1577. This news article summarizes the Paxil in adolescents controversy. It raises questions about the right of drug companies to sequester data that theyown and paid for, in the face of society’s need to know. This question has littered the courts with respect to asbestos, silica, tobacco, cell phone radiation, etc.
Abboud, L. (2004). Drug Makers Seek to Bar "Placebo Responders" From Trials. The Wall Street Journal: B1, B5. June 18, 2004. An interesting article that brings to light controversial topic in clinical trial design. Should pharmaceutical companies be allowed to manipulate subjects participating in their study?
Agrawal, M. and E. J. Emanuel (2003). "Ethics of Phase 1 Oncology Studies: Reexamining the Arguments and Data." JAMA 290(8): 1075-1082. This is an important review of the literature evaluating Phase 1 clinical oncology trials to see whether the claims that the risk-benefit ratio is poor, the degree of understanding of the procedures is deficient and that coercion is routine are correct. They show that on balance, patients do a little bit better than expected, so benefits occur, that they understand what they are getting in to and finally that people with advanced cancer are willing to take risks for a possibility of improvement or cure. The lessons are to avoid underestimating the research participant. They may not know everything but they have a pretty good idea of what’s important to them.
Antman, K., S. Lagakos, et al. (2001). "Designing and Funding Clinical Trials of Novel Therapies." N Engl J Med 344(10): 762-763. This well-written article discusses the difficulties and importance of funding large-scale studies. Because larger trials have a greater chance of proving statistical significance, lack of subjects is a hindrance to study design. They suggest using a small percentage of health insurance premiums to fund the NIH and increase the scope of all studies.
Bailar, J. C., III (2001). "The Powerful Placebo and the Wizard of Oz." N Engl J Med 344(21): 1630-1632. The placebo is an unchallenged staple of study design necessary to determine efficacy. While it contrasts a treated group of subjects, it does not distinguish between the natural course of disease and the “placebo effect.” This article shows that a placebo has no benefit over nontreatment and may actually harm the doctor-patient by exposing patients to deception.
