Examples and Case studies by Essential Element: 

Essential Element 1: Addressing Relevant Question

Essential Element 2: Choice of Control and Standard of Care

Essential Element 3: Choice of Study Design

Essential Element 4: Choice of Participant Population

Essential Element 5: Potential Benefits and Harms

Essential Element 6: Informed Consent

Essential Element 7: Community Engagement

Essential Element 8: Return of Research Results and Management of Incidental Findings

Essential Element 9: Post Trial Access

Essential Element 10: Payment for Participation

Essential Element 11: Study Related Injury



Addressing Relevant Questions:




“Thorough scientific evaluation of any promising treatment before market authorization is an ethical requirement.  In the continuing search for medications with improved efficacy and safety profiles, it is necessary to fully investigate and understand new products before public exposure.”

“Drug X has a different mechanism of action compared with marketed drugs and may potentially be a valuable addition in this field.”


“This study is being conducted to determine the pharmacokinetics of drug X in subjects who are patients with disease Y.  The results of this study using healthy subjects will provide information on the pharmacokinetics and urinary recovery of drug X given at the current dosing regimen.  These study results will provide valuable information with regards to dosing drug X in patients.”

Pediatric pharmacokinetics

“This study is being conducted to evaluate the single-dose pharmacokinetics of drug X at two different doses given to pediatric subjects in need of pain management therapy.  These data are needed to assist in developing dosage adjustment guidance in children in need of pain management.”

“The purpose of this study is to collect concentration data across the pediatric age range in order to characterize the dose-exposure relationship in the pediatric population.  This relationship is critical in determining the dosage regimen that will deliver concentrations at or above the minimum inhibitory concentration for a sufficient duration of the dosing interval.  The information gathered from this study will guide dosing recommendations for drug X in children hospitalized for infections.”

Disease specific

Example 1: “This study is being conducted to determine: What is the frequency of adverse event Z for drug X?  The results of this study will influence the amount of safety information that will need to be collected in Phase 3 studies and will provide useful information for physicians treating patients with drug X.”

Example 2: "Current long-term treatment of disease Y is unsatisfactory.  Poor compliance with approved treatments frequently results in relapse and rehospitalization.  Although gains have been made in treatment of some symptoms, other symptoms are not as responsive to presently available medications.  Poorly tolerated side effects including ___ continue to be problematic in treatment of these subjects.  Drug X is an investigational anti-disease Y therapy which is longer acting and does not require refrigeration.  Drug X offers a number of potential advantages including more stable plasma concentrations, improved compliance and thus reduced rates of relapse, improved tolerability with improved personal and social functioning, and reduced healthcare resource utilization. This study is being conducted to determine: Do less frequent office visits facilitate treatment access and medication adherence among patients with irregular or sporadic access to treatment for disease Y?”

Example 3: “On the basis of data accumulated to date, the sequential combination of drug X and drug Y has the potential to become an important addition for a group of subjects with limited therapeutic options for treatment of cancer Z. This study will answer the question: Is the sequential combination of drug X and drug Y an effective first-line treatment strategy for subjects with cancer Z?”

Example 4: “Major depressive disorder is a common, severe, chronic and often life-threatening illness.  It is now the leading cause of disability worldwide.  There is a clear need to develop novel and improved therapeutics for major depression.  Drug X has shown rapid antidepressant effects in a small number of studies and has been well tolerated in these clinical studies. This study is being conducted to investigate: Is Drug X an effective, well tolerated treatment for major depressive


Choice of Control and Standard of Care

Obese/increased body mass index

“The main risks to subjects are exposure to a study drug whose safety profile is not yet well developed.  Subjects randomly assigned to the active drug may have some benefit from participation in this study as it expected that they may lose weight to a greater extent than placebo subjects although this cannot be guaranteed.  All study subjects will be offered a lifestyle modification program including moderate physical activity and dietary counseling and will receive an adequate diet to treat obesity which may benefit all subjects.  Available non-clinical safety and toxicology data, as well as high unmet medical need for the new treatments of obesity, justify from an ethical and safety perspective, administration of total daily doses of ___ in well controlled in-patient settings.”


“Although subjects are not expected to receive any clinical benefit from a 2-week treatment period with XXX, this information will be useful in designing subsequent studies to evaluate the safety and efficacy of XXX in diabetic patients with nephropathy.  Subjects will continue to receive the medications prescribed by their physician during the course of this study.  Thus, it is anticipated that there will be no loss of clinical benefit from the ongoing treatments to any subject.”


Choice of Study Design

Concern about Scientific Bias

An example of a design which may not support claims of efficacy due to irreproducibility and potential bias is the open-label, single arm efficacy study. This design may be problematic, for example, in various psychiatric diseases.  

Example 1: Although validated endpoints are available (e.g., PANSS in schizophrenia), these are patient reported outcomes and subject to bias in an open-label, single arm study.  

Example 2: Although a measurable change from baseline (which is the only option as a control is not being used) might be demonstrable, placebo responses in many of these diseases can be substantial and can vary widely from region to region. A control arm for comparison is critical. Ethical justification: The design is scientifically biased and thus not ethically justified unless such concerns can be overcome in some way.

Use of Experimental Drug in a First-In-Human (FIH) Study or Whenever the Dose or Regimen is Untested

“The initial dose in this FIH study was calculated according to internationally accepted standards, and all assumptions and safety margins were conservatively estimated. Non-clinical toxicology findings do not indicate any severe toxicity within the range of doses and exposures anticipated in humans. Dose escalations to the next higher dose will only occur after all relevant safety, tolerability and pharmacokinetic data are available. To ensure optimal clinical judgment in cases where further advice on unblinded data is necessary, an internal Data Review Committee may be convened."

Ethical justification: It is critically important in a FIH study to justify the choice of dose given for the first time and the safety of any dose escalation scheme. International guidelines are available to help guide dose calculation and the details should be given in the body of the protocol.  An important aspect of the FIH design is the approach to escalating the dose, the rules for stopping, and the use of monitoring committees. Although the very first administration to a human subject is the most uncertain use of a drug, other circumstances such use of a new formulation or a supratherapeutic dose also can present additional risk.

Withdrawing a Demonstrated Effective Therapy from Some Subjects in a Randomized Withdrawal Study

In randomized withdrawal designs, subjects are treated initially with the experimental therapy and those who respond by predefined criteria are randomized to continued experimental therapy or to no (placebo) therapy. The subjects on no (placebo) therapy are allowed to decline over some time frame or to a certain level.

Ethical justification: Part of the justification might be that the withdrawal period is for a short time that does not cause permanent harm or that a rescue therapy will be given if there is a defined level of decline. Quantification of the amount of that rescue therapy could be predefined as a secondary objective.

Continuing Treatment with a Failed Therapy

A study of a new treatment for hepatitis was proposed in which subjects who had failed to respond to the currently available therapy were to be enrolled. The new therapy was to be used in combination with the currently available therapy. If randomized to the control group, subjects would be given only the currently available therapy, a regimen that they had already received and no longer responded to. 

Ethical justification: The protocol should explain that 1) although subjects had already failed to respond to the currently available therapy, using this regimen in the controlled setting of a clinical trial and with aggressive side effect management, there was an expected response rate of at least 10% which made it necessary and appropriate to have a control group, 2) there were early assessments of response, with opportunities for rapid discontinuation from the control group if no response was being seen to minimize side effects, and 3) control group subjects would have the opportunity to receive the new regimen if it was demonstrated to be effective.

Washout Periods for Subjects who Need Therapy

Washout periods are often needed to eliminate co-administered therapies that might interfere with the ability to detect the effect of the experimental therapy, might interact pharmacologically or pharmacokinetically with the experimental therapy, or might compromise the ability to define the safety profile of the experimental therapy. The therapies in question would in general be known to be effective in the disease.  

Ethical justification: One way to support this approach is to select subjects who still have active disease even after a prior adequate course of standard therapy. Thus, these potential subjects might already be candidates for a different therapy and a washout period of some sort might be initiated in any case. A statement that a pre-existing therapy will not be withdrawn strictly to allow enrollment in a study is often appropriate.

Duration of Exposure

In some studies, the proposed time on the experimental therapy is shorter than what is has been necessary for other drugs of the same class with the same disease to determine if there is a clinical effect. Alternatively, as clinical development proceeds, the duration of exposure may be longer than previously examined. Why is this safe?

Ethical justification: Convincing arguments need to be made that the duration of exposure will at least give an indication of effect or that other equally important objectives will be addressed. If the duration of the study is longer than previously examined, there should be adequate preclinical data available to support longer exposures or, in the prior studies of somewhat shorter duration, it should be clear that the therapy was well tolerated.  

Use of Unequal Randomization 

Unequal randomization (e.g., 2:1 or 3:1 experimental therapy to placebo) is sometimes used to reduce the number of subjects who will not receive the experimental therapy. This may improve recruitment as subjects would have a higher likelihood of receiving the experimental therapy.  This has also been used to help justify use of a placebo as fewer subjects would be denied the experimental therapy. However, withholding a potentially important therapy from even a small number of subjects has to be acceptable.  Does the benefit to others outweigh significant harm to even one individual?  This design element could also be challenged scientifically as this might make drawing inferences, for example, about the relative safety profile more difficult.  For uncommon events, a few events in the active treatment arm but none in the control arm could be due to the unequal randomization. (Halpern, et al.)

Ethical justification: This will be dependent on the specific protocol.  It should be statistically demonstrable that the sample sizes are adequate to demonstrate efficacy, that the control group size is adequate to detect Ethical justification: This will be dependent on the specific protocol.  It should be statistically demonstrable that the sample sizes are adequate to demonstrate efficacy, that the control group size is adequate to detect an important safety signal, and that the placebo subjects are not placed at undue harm from the lack of experimental therapy for the duration of the study.

Adaptive Trial Designs

Adaptive trial designs involve pre-planned modifications that take place while the study is ongoing based on analyses that incorporate data accumulated over time. The design elements “adapt” to the accumulating knowledge albeit in a pre-specified manner. As a result, substantial changes may occur such as alterations in dose (e.g., eliminating an ineffective or unsafe dose or regimen), a change in the number of study arms (and thus more or fewer subjects on placebo), or an adjustment to the overall sample size. The study may be stopped early for futility. The technical challenges are significant.  Adaptive designs may be more complex to carry out than fixed designs, the information that may be formally inferred from the data may differ or be more limited than what can be realized from a fixed design, and they may be hard to replicate (Van der Graaf et al.).  The rate of enrollment or the difficulty of getting timely and adequate interim analyses could prolong the study. The potential efficiency, the possibility that fewer subjects may be exposed overall to study risks or to an ineffective dose, and that a larger population may receive a possibly effective therapy are major advantages of this design.  In addition, as the sample size can be modified, adaptive designs help protect against a study being underpowered which in more traditional designs may not be known until the study is complete.  Nonetheless, at the level of the individual subject, it may be difficult to adequately explain the concepts of ongoing modification of what will happen to participants and that this cannot be defined at the outset of the study. 

Also, subjects who enroll later in the study may be more likely to receive a more effective (or a better tolerated) dosing regimen. Investigators might engage in differential selection of subjects by making assumptions about enrichment. Adequately informing subjects and feeling comfortable that informed consent has been obtained is a challenge.

Ethical justification: Adaptive designs can have real advantages in identifying better therapeutic regimens more rapidly and with fewer subjects. To support ethical justification, it is important that the specific adaptive design has addressed technical issues and can, in fact, be carried out and that the special challenges such as interim analyses and maintaining the blind are well thought out. A key issue is whether informed consent is adequate. The uncertainty of what a subject will undergo has to be conveyed and alternatives explained without overwhelming the subject.  A potential subject should understand that there are a broader range of options early in the study and a lesser likelihood of receiving the ultimately chosen optimal dose or regimen and that the options will change as the study progresses without those changes being made transparent. Consideration should be given to modifying consent as the study progresses if unblinded data become available.  The expectations of the subjects should be managed.


Choice of Participant Population

Ensuring there is a clear justification for excluding or including population groups:

Overprotection of women

During the 1970s and 80s extensive research on heart disease was conducted on mostly male participants. As a result misleading information was generated that heart disease occurred primarily in men and symptoms of the disease in women were not well understood.

Ensuring there is a clear justification for excluding or including population groups:

Under-representation of elderly

Most breast cancer research conducted in the 20th century was done in women under the age of 65 despite the fact that almost half of all breast cancer is diagnosed in women over age 65.

Ensuring there is a clear justification for excluding or including population groups:

Research on overburdened populations

Researchers at the Kennedy Kreiger Institute designed a study to test the effectiveness of less expensive lead abatement processes by measuring the lead levels of children living in low income housing units.

Ensuring there is a clear justification for excluding or including population groups:

Research involving only black patients

The A-HEFT trial was designed to evaluate whether a particular drug provided additional benefits in black patients. A subgroup previously noted to have a favourable response to the therapy.

Enrolment of Healthy Subjects

How to justify enrolment of healthy subjects who are exposed to risk and inconvenience without any possibility of benefit. “The primary ethical concerns of this study are that this study will be performed in healthy subjects who will receive no benefit from participation in the study, except for financial compensation for the time and inconveniences that may arise from participation in the study. Potential subjects will be fully informed of the risks and requirements of the study and, during the study, subjects will be given any new information that may affect their decision to continue participation. They will be told that their consent to participate in the study may be withdrawn at any time with no reason given and without penalty or loss of benefits to which they would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and potential adverse events of the study, and provide their consent voluntarily will be enrolled.  No undue incentives will be provided. 

Ethical justification - This reflects the principles outlined in the Belmont Report that competent subjects may make a choice to participate for their own reasons (respect for persons (Belmont Report). 

Enrolment of Healthy Subjects

“Subjects with medical conditions that might benefit from drug X are likely to have underlying conditions and be receiving numerous concomitant medications.  As a result, any potential effects that are a result of drug X rather than a result of some underlying condition or concomitant medication may be difficult to differentiate.  Therefore, the subjects enrolled in this study will be healthy subjects. As the disposition and elimination profile of drug X is considered uncomplicated, the pharmacokinetics in healthy subjects should translate to the target patient population.  Drug X in both healthy subjects and patients as subjects has been well tolerated.” 

Ethical justification: The lack of co-morbidity, absence of concomitant medication use, and the more homogeneous nature of healthy subjects may be critical to answering the question and should be pointed out.  This example makes the key point that the data will be relevant to the target patient population. A critical part of the justification that should be added is that the safety risks are not excessive and are limited.  Also, no undue compensation will be provided.

Enrolment of Healthy Subjects

“Determination that a new drug mechanism may offer therapeutic benefit to patients with disease Y is very challenging.  Clinical disorders of disease Y are syndromes that arise from multiple causes, wax and wane in severity, and have very high placebo rates.  As a consequence, before going into large clinical trials, it is worthwhile to assess the effects on cerebral function in a limited number of healthy subjects using this technology.” 

Ethical justification: This helps explain why use of healthy subjects at this stage of development is more appropriate than the target population by indicating that this will generate important and relevant information, but an explanation that the technology as well as the drug do not present significant risk in this population needs to be added.

First-in-Human (FIH) Studies - How to justify exposing any subject whether healthy subjects, subjects with stable medical conditions, or subjects with life-threatening conditions to a drug or therapy that has never been given to humans.

“This is the first-in-human study with drug X, an investigational drug being developed for the treatment of disease Y. The preclinical data have provided sufficient evidence of potential beneficial pharmacodynamic effects in the target disease population, and toxicology studies have established a sufficient safety margin to justify cautious and well-controlled human studies, initially in healthy subjects. Although the healthy male subjects that will be enrolled will receive no benefit from study participation, the data generated in this study will provide critical scientific information regarding the safety, tolerability, and pharmacokinetic profile of drug X.”

Ethical justification - In FIH trials, the preclinical data including relevant animal models and in vitro work, and the toxicology studies should indicate that there is good reason to move into human studies and that the anticipated exposure has been well thought out.

First-in-Human (FIH) Studies –How to justify exposing any subject whether healthy subjects, subjects with stable medical conditions, or subjects with life-threatening conditions to a drug or therapy that has never been given to humans.

“The initial dose was calculated according to internationally accepted standards, and all assumptions and safety margins were conservatively estimated. Non-clinical toxicology findings do not indicate any severe toxicity within the range of doses and exposures anticipated in humans. Dose escalations to the next higher dose will only occur after all relevant safety, tolerability and pharmacokinetic data are available. To ensure optimal clinical judgment in cases where further advice on unblinded data is necessary, an internal Data Review Committee may be convened.”

Ethical justification - It is critically important in a FIH study to justify the choice of dose given for the first time and the safety of any dose escalation scheme. International guidelines are available to help guide dose calculation and the details should be given in the body of the protocol. An important aspect of the FIH design is the approach to escalating the dose, the rules for stopping, and the use of monitoring committees. The ethical section should acknowledge and refer to those considerations.

First-in-Human (FIH) Studies – How to justify exposing any subject whether healthy subjects, subjects with stable medical conditions, or subjects with life-threatening conditions to a drug or therapy that has never been given to humans.

“Dose escalations in patients with disease Y will occur only after review of safety data from the previous dose level. The target concentrations for investigations in subjects with disease Y will not exceed those concentrations that have been achieved and found to be well tolerated in healthy subjects.”

Ethical justification - One approach to allowing subjects with the target disease to participate in FIH studies is to show adequate tolerability in healthy subjects first.

First Time in Women - For most drugs women will be part of the target population and, from the perspective of fair distribution (NIH Guidelines), they should be adequately studied to identify any issues specific to women.

Example 1: “No gender differences were observed in nonclinical studies of drug X. The reproductive toxicology studies revealed no relevant fetal malformations with the anticipated plasma exposure levels for this trial. As a safety precaution, during the trial all women of childbearing potential will need to utilize the double-barrier method of birth control from screening, and throughout the study until the follow-up visit.” 

Example 2: “The previous first-in-human study was conducted entirely in men. Since disease Y affects both men and women, evaluating the pharmacokinetics, pharmacodynamics, safety and tolerability of drug X in women is desirable for further development of this new agent. In the present study, it is planned to include post-menopausal or surgically sterile women. Based on the first-in-human study in healthy male subjects, it is justified to include women in this study at the planned doses.”

Ethical justification (for both examples) - Women must be studied in the development of new drugs.  However, the possibility of pregnancy and the potential risk to the unborn child always has to be considered. Possible approaches include the initial use of women who are surgically sterile or postmenopausal. In fertile women, it is important to have reproductive toxicology studies completed and any risks of the particular class of drug reviewed.   

Other Populations that May Need Specific Justification


Example 1: Renal impairment: “The main ethical consideration for this study concerns the risks associated with the use of study drug in healthy subjects and in subjects with end stage renal disease (ESRD) who are otherwise medically stable, and for whom there will be no direct therapeutic benefit.  The results of this study will provide useful information on the effect of ESRD on study drug pharmacokinetics in order to develop safe and effective dosing recommendations in these subjects.”

Example 2: Hepatic impairment: “The main ethical consideration for this study concerns the risk associated with the use of study drug in subjects, both healthy subjects without hepatic impairment and subjects with mild or moderate hepatic impairment who are otherwise healthy, for whom there will be no direct therapeutic benefit. The potential risks to subjects include exposure to study drug which may have increased exposure in subjects with hepatic impairment and the risk of side effects. An additional concern may be the capacity to consent if subjects develop severe hepatic impairment with an element of encephalopathy.”

Ethical justification (for both examples) - The details for protection of both healthy subjects and subjects with significant medical problems should have been provided in the protocol.  However, in the ethical section it is important to recognize the potential risks and indicate why it is important and acceptable for these subjects to be studied.

Example 3: AHEFT study: A retrospective analysis of data from a clinical database indicated that response to ACE inhibitors tended to be less efficacious in blacks. This data was the basis for the A-HeFT (African-American Heart Failure Trial sponsored by NIH), which involved only African Americans and excluded all other racial groups with a low ejection fraction and a dilated left ventricle. 


Potential Benefits and Harms

Risks inherent to the experimental drug or therapy: safety profile

In every research study in which participants receive an experimental drug, there is a potential for harm that the subject would not face outside the study.  If the safety profile is well described for the dose and regimen, there may not be particular ethical issues that need to be brought up in the ethical section.  However, any special concern and the mitigations planned to deal with the concern should be acknowledged in the ethics section.  Examples would be an unusual pre-clinical finding or a serious problem seen with other members of the drug class.  Adverse events of special interest should be highlighted.  Administration of an experimental therapy to individuals for the first time such as women, children, the elderly, or a sensitive population such as poor metabolizers or renal/hepatic impaired should be justified.  Even if the drug is well-tolerated, a new formulation or supratherapeutic dose may need discussion.  Radiation exposure from a radioactively labelled drug needs to be minimal such as no more than background exposure. 

Risks inherent to the experimental drug or therapy: risks to others

In some studies, there may be risks to health workers, family members, or others in close contact with the subject. Examples would be the risks of radiation exposure, any risks associated with gene transfer studies, or the risks in vaccine studies.

Risks from study procedures

The procedures in many studies will involve only minimal risks such as drawing blood. Taking large volumes of blood or blood sampling in children will need justification in the protocol and mention of why this is acceptable in the ethics section. Other procedures may be more invasive such as tissue biopsies, lumbar punctures, or excessive exposure to multiple x-rays or CAT scans. These should be appropriate and acceptable.

Non-physical harm

Risks can also involve non-physical harm, such as breach of confidentiality and privacy, damage to reputation, monetary harm, legal risk, loss of insurance coverage, emotional stress, genetics issues such as paternity, and discrimination.  Information might be published that could stigmatize a group or expose its members to discrimination. For example, the information gained from a study could indicate, rightly or wrongly, that the group has a higher than average prevalence of alcoholism, mental illness or sexually transmitted disease, or is particularly susceptible to certain genetic disorders. There may be risks to family members from knowledge gained in genetics studies.

Potential benefits to the individual subject

Ethically, considerations for the well-being of the subject should take precedence over the interests of science and society (CIOMS 2002, Declaration of Helsinki 2000, para 5). If there is lack of potential benefit, this should be stated. Benefits to subjects might include positive response to the study intervention (both products and procedures), additional medical care and oversight, possibility of life-style modifications (e.g., programs for diabetes or obesity), coverage of costs of additional medical care, payment for participation, or post-study continued access to study interventions.

Potential benefits to others including the community and society: Knowledge 

The knowledge that results from a study and the application of that knowledge may benefit society.  The kinds of knowledge may be the resolution of a safety issue or the proof that a new mechanism of action is relevant in a hard-to-treat disease.  In spite of societal benefit, there may be some risks to the individual that are too great to support conducting the study, so how the balance is achieved is properly discussed in the ethical section.  

Potential benefits to others including the community and society: Community building 

Community benefit might include capacity building for local sites, increased medical and scientific capabilities and training of local investigators and study staff, or brick and mortar facilities such as clinics or laboratory equipment.  


Informed Consent

Informed consent: participant population

If the participant population is likely to speak languages other than English, the informed consent disclosures should be translated, in advance, and be available to the investigators for the study (i.e. in the local language(s) understood by the target population(s)). In addition, special care needs to be taken with regard to the processes for informed consent, whenever studies will target young children, adults with severe mental or behavioral disorders, or persons who would be unfamiliar with medical concepts and technology.

Informed consent: biological specimens

Investigators may want to use records or biological specimens that another investigator has used or collected for use, in another institution in the same or another country. If informed consent or permission was required to authorize the original collection or use of such records or specimens for research purposes, secondary uses are generally constrained by the conditions specified in the original consent. The process of seeking informed consent should describe whether there will or could be any secondary use, how broad such future uses might be, and any protections to be afforded to the subject’s data or specimens.


Community Engagement  

Successful Community Engagement Efforts

  1. Community Action for Child Health Equity (CACHÉ)

  2. Health-e-AME

  3. Project SuGAR

  4. The Community Health Improvement Collaborative (CHIC)

  5. Healing of the Canoe

  6. Formando Nuestro Futuro/Shaping Our Future

  7. Improving American Indian Cancer Surveillance and Data Reporting in Wisconsin

  8. Children And Neighbors Defeat Obesity/La Comunidad Ayudando A Los Niños A Derrotar La Obesidad (CAN DO Houston)

  9. The Dental Practice-Based Research Network

  10. Diabetes Education & Prevention with a Lifestyle Intervention Offered at the

  11. YMCA (DEPLOY) Pilot Study

  12. Project Dulce

  13. Determinants of Brushing Young Children’s Teeth


Return of Research Results and Management of Incidental Findings 

Challenging issues related to the return of IRRs include

Example 1: The research results indicate a significant health concern for a research participant; however, the results are de-linked from participants’ identity and, although technically possible, re-linking them would violate the terms of the informed consent, which promised individuals that their confidentiality would be preserved through total anonymization and a promise not to re-identify research samples.

Example 2: The research aims intend to focus on a specific genetic variant; however, the proposed research methods call for WGS because it is a more efficient approach, notwithstanding the fact that researchers have no intention of analyzing the data gathered on other genetic markers (and such data may include information that would be relevant to participants’ health care decision-making).

Example 3: The research results will be processed in a non-CLIA approved laboratory because there is no CLIA-laboratory that performs the research test at issue; however, the researchers anticipate that the results will uncover information that would be relevant to a participants’ health care decision-making.

Examples of Incidental Findings include

Example 1: A spinal tumor detected through a research MRI where the protocol calls for the analysis of the image of an unrelated part of the body. 

Example 2: A genetic variant indicating a high risk of a certain type of cancer found during a WGS protocol where the focus of the research is limited to a different portion of the genome.

Example 3: Genetic variants uncovered in the analysis of banked specimens and data under circumstances where the significance of the variant may have been unknown at the time the materials were banked, and the retrospective research is not targeting such variants.


Post Trial Access

Cost to the sponsor and determining the long term safety and effectiveness of trial interventions

Example 1: A drug approved for diabetes is found to be safe and effective for the treatment of a water-borne parasite in Sub-Saharan Africa. After the research ends, the sponsor agrees to continue to provide the study drug as needed for the former subjects.

Example 2: An HIV vaccine study is conducted in a small community. After the trial ends, the sponsor leaves an HIV testing equipment at the clinic and allows continued testing of prior study subjects. 


Payment for Participation 

Warranted approach to compensation

In a Phase 2 trial, participants were required to come to the clinic every two weeks over a 3-month duration for blood draws. Participants were compensated for transportation and parking for these visits as well as a $100 gift card to compensate them for the inconvenience of frequent visits. 


Study Related Injury

Study Related Injury

Example 1: In the context of phase 2-3 trials, pursuant to the UK’s ABPI guidelines, compensation should be paid when, on balance of probabilities, the injury can be attributed to the intervention or procedures under the protocol. Generally, the assessment of attribution is made by the investigator. (APBI)

Example 2: In the context of phase 1 trials, under the UK’s ABPI guidelines, compensation should be paid, irrespective of fault, in the case of injuries to participants; a minimum of £2.5 million in insurance coverage is recommended for each phase I protocol. (APBI)

Example 3: There are a number of possible approaches to study-related injury or impairment, ranging from full compensation of loss and coverage of necessary care and treatment, to the provision of care charged at the usual rate without additional compensation, to providing compensation only in the event that the injured subject is successful in litigation. As indicated below, a policy that leaves injured participants to bear the costs of necessary medical care on their own will call for substantial ethical justification, even if it is legally sufficient. Please see Points to Consider and related Details sections for more information.

Example 4: Clinical trial claims are rare, with an EU government assessment showing claim rates of about 5 in 10,000 participants. In this regard, the cost of trial insurance is roughly E50/year/patient. (EU)