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GetResearchSmart^SM

Decisions

GetResearchSmart^SM

1) What is GetResearchSmart LLC (GRS^SM) and how might it and its website benefit prospective research subjects (prospects)?

A: GRS offers a Code of Reasonable Expectations (GRS Code), information, self-help tools, information, and references to other resources for use by prospective subjects (prospects). The GRS Code and self-help tools serve as benchmarks against which prospects can compare an offer to participate in research (an offering). The principal means of access to these resources is through getresearchsmart.org.

2) Upon what information does GRS rely in preparing resources that it posts on its website?

A: Experience of GRS authorship and reviewing advisors, including prior knowledge of federal regulations (both strengths and weaknesses), and prior review of thousands of protocols, related consent documents, responses to thousands of inquiries, and/or deliberations concerning related federal policies.

Endorsements by organizations and adopters will be posted on the GRS website as they become available. In addition, as they occur, testimonials will be posted on the GRS website from either fellow research subjects or other interested parties.

3) Does the GRS website provide direct advice or assistance to individual subjects?

A: No. The GRS website posts information, provides self-help tools, and encourages more confident decisions by subjects about participation in research. The philosophy behind the site is to get prospective subjects more involved in their decisions. Decisions about participating in research are solely that of prospective subjects.

4) Are the contents of the GRS website available for copying?

A: Yes, GRS website contents may be copied for personal use or reproduced in bulk for noncommercial distribution, republication, and other forms of publicity, so long as the copied materials are (1) unaltered, (2) include full credit to the GRS website, and (3) provide the full GRS website address (URL). In all other respects, copyright law is considered applicable.

Contents of the GRS website may not be downloaded and used for rebranding in the name of other organizations unless written permission is granted by GRS. Such organizations are encouraged to contact GRS for partnering or sponsorship opportunities or discussion of suitable terms and conditions for customized use.

5) Who benefits from the information, features, and impact of the GRS website and how?

A: Besides prospective research subjects themselves, investigators may also benefit. Research is often hampered by difficulty in attracting prospects, low rates of consent, and the inability to retain subjects through an entire study. Loss of subjects during a study (sometimes called attrition) can occur because subjects belatedly become disillusioned. This can occur because of something that comes to be seen as not previously explained, understood, or expected. For example, an investigator may come to be seen as having downplayed risks, oversold benefits, or simply failed to adequately provide for pertinent protection of subjects.

A prepared prospect is an investigator's best subject. Why? A prepared prospect who consents is less likely to change his or her mind during participation. Not only is each prepared subject more attuned to his or her role, risks, and what to expect, but the investigator stands a lower risk of prepared subjects dropping out of the study before completion.

As a prospect, it's reasonable for me expect forthrightness and adherence to the highest standards of ethics in pursuit of scientific research. These expectations include looking out for my dignity, safety, and well-being, as well as that of others who may be affected. Unprepared prospects who consent may later question the events that unfold. This can even lead to a loss of trust in and support for science itself.

Ultimately, human research would cease without public trust. Therefore, everyone benefits from a well prepared prospect. Therefore, investigators, the enterprise of research, and the general public, are all potential beneficiaries of reliance on appropriate standards aimed at protecting subjects.

6) How can the GRS website's existence and its benefits be made known more widely?

A: Like any Web-based initiative, publicity is essential. Amongst other means of spreading awareness are word of mouth, media coverage, and promotion by third parties who have a stake in the ethical conduct of research. Third parties with a stake include sponsors of human research, institutions conducting human research, contract research organizations (entities that provide research support), ethical review boards (known as institutional or independent review boards [IRBs]), regulators of human research, and editors of research to be published.

The GRS website includes, among its materials, a standard brochure and press release. Either may be copied and used with credit without further approval. Distribution of these and other GRS website materials to individuals, local members of the press, and professional entities (with credit to GRS) are all of potential value. E-mail notice to GRS of such distributions would be appreciated, but is not essential. Such notices help GRS in understanding its website traffic. Suggestions are welcome about other means of spreading the word.

7) How does the GRS website pay its way?

A: The GRS website is offered as a free resource. It's creation, posting, and costs are primarily borne from within plus any income that may be generated from displayed advertisements.

The selection of advertisements for display is determined by algorithms of third party specialty firms. GRS does not screen or select such advertisements.

GRS cannot accept offers of financial or other support that may compromise or appear to compromise its objectivity and integrity. All unsolicited offers will be reviewed accordingly.

Protections

8) Why can't prospects simply rely on procedures required by existing federal regulations? Why do they need to bother with self-help tools? After all, aren't there requirements for ethical review of research and prior consent of subjects? Like patients who rely on the their physicians, why can't decisions be left to ethical reviewers and investigators?

A: There are four general reasons why the existing process of protections for subjects may be necessary but still insufficient to protect your interests as a prospect or the interests of those you legally represent.

First, federal regulations (including details concerning ethical review and prior consent) are only required for federally supported or regulated research.

When applicable, minimum federal requirements provide for a thorough and time-tested process of ethical review. Ethical review includes attention to scientific issues. Amongst other things, review is designed to ensure that (1) risks have been minimized, (2) benefits (if any) to subjects or others are maximized, and (3) only ethically worthy offerings (called research plans or protocols) are presented to prospects for consideration. There is no guarantee of benefit. Approved offerings normally include the need for prior consent. Consent may not be required under some circumstances. Consent requires that subjects are informed in understandable terms and under circumstances that minimize avoidable pressures of circumstance.

Second, even if review and consent regulations do apply (either because federally supported or regulated research is involved or because the investigator or his or her institution has chosen to comply), these federal regulations are only minimum requirements.

Some research can qualify for automatic exemption from these requirements. Exemption, in the opinion of some, might not always be in the best interest of individual subjects. In addition, there are three points that either are not mandatory or included in the federal requirements: (1) mandatory protection of subject confidentiality unless waived, (2) disclosure by investigators and/or their institutions about important conflicts of interest, and (3) compensation to subjects for research-related injuries cannot be assumed.

Third, current practices often do not involve input from the community of interest (e.g., all persons with a history of the condition under study - like heart patients).

As a result, significant issues, needs, and interests of prospects chosen from the target community may go unknown. This might result in either shortsighted consent or flat refusals to participate. Ethical review does draw upon varied reviewers (including some from the general ranks of everyday people). However, effective involvement of and contributions by everyday people in the review process are often limited.

Fourth, otherwise trusted sources of advice may not be appropriate (e.g., your doctor is now an investigator) or is no better prepared to evaluate participation than the prospect. As a result, prospects can be left at a disadvantage.

When your doctor becomes an investigator his or her decisions become determined by a protocol and not by clinical judgment (e.g., which medication to prescribe). Your doctor turned investigator may have something to lose if your consent is not granted which might influence his or her impartiality. Although not a certainty, you should be aware that such influences may be at work. Just be sure that sufficient consultation has been sought to compensate for these possibilities (e.g., an opinion from another doctor not involved in an offered study).

Research can be complex, hard to understand, high risk, and, in some cases, offered under circumstances that may make things difficult on those invited to participate. In short, prospects may be caught off guard, find it difficult to get up to speed on short notice, and not know how best to protect their personal interests. Satisfy yourself that adequate precautions and safeguards are in place and that any specified benefits are real not imagined. As an example, monetary inducement to participate should not be considered a "benefit" of research. It may actually constitute an unethical influence on the otherwise objective decision-making of a wary prospect.

9) What should I as a prospect understand before deciding about participation in a clinical trial?

A: Participation in research is an option, not an obligation. In clinical research, for example, an offer from my personal doctor may make me feel uneasy about saying no. As a patient I may feel obligated to say yes to avoid threatening an existing trust relationship. However, a decision to decline is my right and should have no bearing on existing relationships. Any indication to the contrary is reason to rethink an offering.

Clinical trials are not all the same. For a number of reasons, participation in such studies does not ensure even a reasonable chance of benefit. Some studies are designed for reasons unrelated to clinical benefit (e.g., those focused on safety and toxicity). These are known as Phase 1 trials. Some trials are limited to discovery of clinical effect at what dose. These are called Phase 2 trials. Phase two trials, like Phase 1 trials, involve small numbers of subjects. The probability of being a subject who positively responds and at a clinically significant dose is low. Those who get too high a dose may suffer more harm than benefit. Even later stage large scale studies that are designed to demonstrate benefit do not ensure that any one person will be assigned to receive the article under study. These Phase 3 trials are late stage trials that look for effectiveness at dose levels or circumstances of intervention thought to be of therapeutic benefit. However, these trials may include a group to which I might be assigned that either consists of what I could get without being in the trial or, in some cases, a fake drug or procedure. Even if received, the test article may prove to be of no value or worse.

10) What should I as a prospect understand about confidentiality before deciding about participation in research?

A: With the exception of certain protected health information that can be linked to me, there are some types of research where there is no legal requirement to ensure that private information about me (either existing or to be collected) will necessarily be kept in confidence and released only with my prior permission.

I should ask to ensure that appropriate precautions are in place to hold such information in confidence, satisfactory safeguards exist to deal with the consequences of any released private information, and there are remedies that compensate me if my information is inappropriately used. The importance of protecting confidentiality will vary, depending upon the nature of private information that can be linked to me.

Additional information is available from the Office of Civil Rights about protected health information about me that is intended for use in research (please see http://privacyruleandresearch.nih.gov/).

11) What should I as a prospect understand about conflicts of interest before deciding about participation in research?

A: Conflicts of interest can be thought of as investigator and/or research institution motivations that compete with objective pursuit of protections for prospects.

It is valuable for me to know about financial or other rewards of value to investigators or research institutions tied to the performance and/or outcome or a proposed study. For example, an investigator may hold stock options in a company that's developing a drug to be tested. Although the landscape is changing, there may be no requirement for disclosure of this information to me. I must ask. It's an illustration of how not being prepared with useful information can lead to a decision that I might wish to rethink later on.

12) What should I as a prospect understand about compensation for research-related injury before deciding about participation in research?

A: Compensation for research-related injury is not required by minimum federal regulations for protection of research subjects. Injury can take many forms. Amongst others are physical harm, loss of insurability, loss of employability, social harm (e.g., being "marked" and discriminated against by society), or personal harm (e.g., diminished dignity, diminished self-worth, aggravation of preexisting self-doubts, or other mental burdens). I must ask about plans for compensation. What would be compensated? I should compare that information with the nature and likelihood of serious harm to me and judge the value of the compensation to me, if any.

13) What should I know about taking money or other things of value if offered to me along with an invitation for participation?

A: Offers of material gain in some way (e.g., make money) from participation are inconsistent with what's generally considered to be an ethically designed and conducted study.

Why? Inducements (i.e., lures) can be an unfair influence on my ability to make an objective decision. Everyone has a "price." If offered that price, it may result in my disregard of other considerations, such as risk of harm which I might later regret. Offers to participate that promote material advantage (not just reimbursement for expenses and lost income) should be thoughtfully analyzed to subtract out their distracting influence before making a decision about participation. If the true intent of such offers is to say "thank you" from the investigator, that can be accomplished at the conclusion of the study without prior announcement.

Decisions

14) Does a visual roadmap exist to help prospective subjects decide about participation?

A: Yes. The GRS website has posted a Flowchart that illustrates some of the more important considerations in making decisions about participation.

15) Where can I go to learn more about words or concepts that are found in the GRS website or used by investigators?

A: The federal Office for Human Research Protections (OHRP) posts a useful reference entitled “IRB Guidebook.” The Guidebook contains a glossary of terms. The National Library of Medicine has posted two reference sources, one a dictionary and the other a glossary. These resources are available by clicking on the GRS website Glossaries tab.

OHRP has also posted public outreach materials. The federal Centers for Disease Control and Prevention has posted a useful list of questions to ask about research. These resources and more can be accessed by clicking on the GRS website Links tab.

In addition, the federal National Cancer Institute posts information about the specialty topic of cancer clinical trials (http://www.cancer.gov/clinicaltrials/learning/). The Veterans Administration has also authored a brochure for veterans but which may be equally helpful to the general population. The brochure must be mailed. A related film clip is available for download at http://www.research.va.gov/programs/pride/resources/materials.cfm.

16) What if a prospective research subject is a child?

A: Special federal research regulations have existed for more than twenty years that apply to children. These Department of Health and Human Services (DHHS) regulations are found at 45 CFR 46, Subpart D. The Food and Drug Administration (FDA) has adopted equivalent regulations.

These regulations even apply to certain kinds of research when they would not apply to adults. However, research that does not fall under the jurisdiction of either the DHHS or FDA may or may not be reviewed in compliance with these regulations. Most universities do elect to comply, even when not required. As always, assume nothing. Ask to know for sure.

Review of proposed research by an institutional or independent review board (called an IRB) under these special regulations includes attention to: (1) degree of risk, (2) directness of benefit (if any), (3) ability to and provision for assent by child-subjects, and (4) permission by parent(s) or guardian(s). In addition, appointment of a child advocate may be required if prospective child-subjects are wards of the state. Certain research may require additional special expert review.

These regulations define children as those persons "who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted." Please note that the definition does not rely on legal age alone.

Assent is the voluntary expression by children of their willingness to participate. In general, seeking assent of children is expected when they are judged to be capable. Normally, the expressed wishes of children (for or against participation) are to be honored.

However, proceeding without seeking assent may be permitted by an IRB if (1) sufficient capability to assent does not exist (considering age, maturity, and psychological state) or (2) possible direct and important benefit is available only in the proposed research.

Permission refers to agreement by parents for their child or guardian for their ward to participate in proposed research (i.e., concurrence with expressed assent under most but not all circumstances).

Please consult OHRP's related posting, IRB Guidebook, and/or other posted resources, if desired, for additional information about participation of children in research.

17) What if a prospective subject is or may become insufficiently capable to make his or her own research-related decisions?

A: Federal regulations do not currently exist that specifically apply to persons with diminished capacity (sometimes referred to as those who are decisionally impaired) to make research decisions. Therefore, special alertness is warranted in connection with such decisions and participation. In addition, there may be state laws that offer some, but not complete protections.

Existing federal regulations do mention the need for additional safeguards to protect the interests of varied vulnerable populations. Specifically included, by example, are "mentally disabled persons" (i.e., 45 CFR 46.111[b]). Therefore, IRBs are expected to ensure that study plans adequate account for issues of diminished capacity. However, the lack of specific regulations results in the absence of a uniform approach upon which investigators and IRBs may confidently rely. This absence makes it all the more important to pay particular attention to matters of personal self-interest.

Valid consent requires sufficient information, the ability to comprehend, willingness, and freedom from coercion and/or undue influence. Some IRBs may hold that participation in research by persons with diminished capacity: (1) is not justified when persons of normal capacity will suffice, (2) is not justified when they would be exposed to more than minimal risk without the possibility of direct benefit, (3) requires capacity testing, and (4) should be preceded by designation of a surrogate (i.e., substitute decision-maker) to monitor participation if capacity is lost during participation. Other IRBs may be more or less exacting. Asking questions may offer valuable insight.

Prospective subjects, and/or their surrogates (i.e., substitute decision-makers), may wish to ask their investigator some or all of the following questions (the importance rising with the degree of risk):

• What standards will be followed to protect those with diminished capacity?
• Why are persons with diminished capacity indispensable for the proposed study?
• What has been done to minimize risk?
• What is the nature of the remaining risk?
• What will be in place to manage unexpected consequences of the remaining risk?
• Who will benefit, how, when, and from what?
• How will diminished capacity be determined, by whom, and when (initially only or more)?
• What assistance will be offered to advise on prospective authorization (prior consent and designation of a surrogate while capable) to encourage surrogate availability and function?
• Will objections of persons with diminished capacity be honored by investigators, even if beforehand they personally consented or permission was granted on their behalf by a legally designated surrogate (i.e., a legally authorized representative)?

Some prospective subjects may already fade in and out of normal capacity and/or may eventually become permanently diminished while participating in research. Research on conditions such as Alzheimer's can involve observation, interaction, and/or intervention with subjects while their ability to understand and express themselves changes from normal to diminished. Therefore, if not already done, it would be timely for such persons to plan ahead. Acting now could avoid a tragedy later.

Appropriate family, friends, family doctor, clergy, and/or legal counsel can help identify a suitable plan for future research decisions. For example, consider an advance health directive (i.e., living will and either a health care surrogate designation or durable power of attorney for health care) that clearly includes reference to participation in research. The named surrogate would be available to decide on and monitor recruitment, participation, and withdrawal. The existence of a Prospective Authorization (previously prepared by the subject when capable) would specify matters about which the surrogate would decide.

You may wish to consult a posted Department of Veterans Affairs (DVA) publication for related general information and tools. The overall discussion of issues and helpful checklists are of broad and universal value that extend beyond veterans and research to include broader life-planning choices.

Much has been discussed and proposed on the topic of participation in research by those of diminished capacity. Some information on this topic is included in the OHRP Guidebook (see below). Discussion of other classes of particularly vulnerable subjects is also available within the same source.

More recent thinking on the topic of diminished capacity is posted on the Web (e.g., see detail from posted proceedings of the National Bioethics Advisory Commission [NBAC] located at http://bioethics.georgetown.edu/nbac). If desired, you can review a brief digest of selected recommendations of the former NBAC. The brief digest is for your convenience. It takes the liberty of presenting the recommendations in terms of relevance to prospective subjects (see more).

18) How applicable is the GRS website guidance to other special subject populations (e.g., other than children and the decisionally impaired) or circumstances (e.g., Internet research)?

A: Posted information is currently aimed at the basics. The GRS^SM Code and Checklist are an appropriate starting point to sensitize and orient prospective adult subjects or their legally authorized representative. They are not necessarily sufficient in specialized situations.

Although the basics are of universal value, additional particulars are appropriate for various special populations and circumstances. Further searching and contact with other people who have prior experience or professional expertise is encouraged. Links are currently provided to other sources of information that may be helpful (e.g., the IRB Guidebook and the proceedings of the National Bioethics Advisory Commission located at http://bioethics.georgetown.edu/nbac).

19) How should I as a prospect decide if an offering is in my best interest?

A: First, what motivates my consideration of the offering? Is it the desire to please someone else, get a unique personal benefit thought not otherwise available, earn income (or other personal gain), or simply to help out by volunteering time and effort for the benefit of others, now or in the future? My motivation should be consistent with my best interests.

Second, apply the GRS website's self-help tools. After determining the offering's real pros and cons, compare the result with the original motivation? Is there a mismatch?

For example, if my initial motivation is to get a unique personal benefit (e.g., clinical improvement), and I discover that similar benefits are available without participation, it's time to rethink my basis for proceeding. If a clinical trial (clinical investigations are often called trials) is not designed for the purpose of clinical benefit, it's time to rethink the matter. Some studies are limited to safety and toxicity. Even if the offering is consistent with my initial motivation, has the investigator been forthcoming in response to my questions? If not, it's time to rethink. Last, if I find excessive risks in comparison with my original motivation, it's time to rethink. As an example, if I'm a healthy person who just wants to help out but am faced with the possibility of serious injury or death from my participation, I should think twice.

Has my investigator's institution and IRB filed papers with the government? Institutions are not prohibited from making a commitment to existing standards, even if technically not required. A written commitment by an institution that it assures compliance with certain government regulations is called a Federalwide Assurance (FWA). FWAs are filed with the Office for Human Research Protection (OHRP), an office within the federal Department of Health and Human Services (DHHS). OHRP will also accept registration of IRBs even when not otherwise required.

Third is the value of consultation with significant others (e.g., family, friends, clergy or others), my own doctor (if the research is clinical in nature), and/or those with prior appropriate experience or professional expertise (e.g., by links through the GRS website, Internet search, research institution IRBs and Ombudspersons, or otherwise).

The value of such consultations goes up with the risk of harm. Research that is formally considered to be more than minimal risk should move me to seek at least some consultation.

20) What if an offering compares favorably with most but not all reasonable expectations for protection?

A: Even the best designed and conducted research study may lack adequate attention to one or more expectations. The nature of any failing must be weighed against the risk of harm from participation, given expected research benefits, if any. Low risk research that fails to cover all the bases may not pose as much concern. Yet, even here, where little or no research benefit is expected, every negative can take on relatively more weight. The least amount of tolerance is appropriate for research with the potential for greater risk. If in doubt, I should consult with others at the research institution, such as the IRB and/or knowledgable ombudspersons, or consult other potentially useful resources (e.g. see Links).

21) What is available to me to check the background and commitments of research institutions, IRBs, and investigators?

A: The GRS website provides convenient links to government sources of information with which to determine if my research institution has filed an assurance to comply with existing federal requirements and its reviewing IRB has registered indicating intent, at the very least. Personal commitments by investigators are not necessarily required by the government.

22) Who can I go to if I consent and later suspect that things are not going as I had understood they should?

A: If I feel that I have sustained a research-related injury, I should report it to the investigator so that valuable information is not lost to the research study and I can be evaluated for corrective action.

If I feel that promises made to me, the course of unfolding events, and/or the manner with which my concerns are managed are questionable, then I can also contact some or all of the following: (1) the investigator, (2) an ombudsperson (an institutionally based subject advocate, if available) or (3) other persons who are not associated with the research study (either identified prior to consent or otherwise known to me, such as my doctor).

My research institution may have given written assurance to comply with certain protective regulations (45 CFR 46). If so, that assurance should be on file with the Office for Human Research Protections (OHRP). I can contact OHRP at 1-866-447-4777 for information related to human protections and appropriate referral to report complaints about research that is under the jurisdiction of OHRP. If OHRP cannot help in my specific situation, and the study is regulated by the Food and Drug Administration, I can contact the FDA Office of Special Health Issues at 1-301-827-4460 for information related to human protections and appropriate referral to report complaints about FDA-regulated clinical trials. I might also contact the office of my state's Attorney General to see if any protective state laws or regulations apply.

It is important to remember that my signature on a consent document does not prevent me from withdrawal from research. My signature only documents that I received at least the summary information contained in the consent document prior to my consent to participate. It does not hold me to continue participation. Withdrawal from some research could place me at risk. I should consult with my investigator beforehand to be sure.