REGARDING WAIVERS OF INFORMED CONSENT

We occasionally find there is confusion about waivers of informed consent.  That may be because different regulations and guidances govern different situations.

Waiver requirements differ depending on whether or not FDA regulates the research.  Also, there are different requirements for waiving (or altering) informed consent overall, versus waiving the requirement to document written informed consent.

So, when applying for a consent waiver, determine first:  is the research FDA regulated, and is an overall waiver, or just a waiver of getting written consent, what is required?

Please note that any waivers or alteration of consent, or its documentation, are, in the end, the IRB’s decision, not the investigator’s or the sponsor’s.  Aspire will work with its clients to be sure that the decisions and their documentation are appropriate.

Most of the research submitted to Aspire is FDA-regulated, so let’s start there.

For waivers of informed consent overall, in FDA-regulated research:  FDA allows full-on waivers of informed consent only in limited situations.  A long list of requirements must be met, but the “gatekeeper” requirement is that the research must be emergency research for life-threatening situations.  See 21 CFR 50.24 for the applicable regulations.  If your research is FDA-regulated (that is, involving a drug, device, or other substance regulated by FDA), and it is not emergency research, you need to get informed consent, and follow the required elements of informed consent.

A significant exception to this is in vitro diagnostic device research that uses archived, leftover human specimens obtained during the course of other research or routine clinical care.  The regulations do not say that consent may be waived in such cases, but, in a 2006 guidance document, the FDA said it would use its “enforcement discretion” if seven specific criteria are met and the IRB documents that they are met.   The criteria, paraphrased here, are IRB review of the study, plus these six: a) the device must be IDE-exempt; b) the specimens must be leftover from routine care, analysis, or other research, and would have otherwise been discarded; c) the specimens are not individually identifiable by the investigators “or any other individuals associated with the investigation or the sponsor”; d) clinical information may accompany the specimens as long as it does not make the specimen source identifiable; e) the individuals caring for the patients supplying the specimens “are different from and do not share information about the patient with those conducting the investigation”; and f) the specimens are provided “without identifiers and the supplier of the specimens has established policies and procedures to prevent the release of personal information”  (emphasis by Aspire).  ALL of these must be met.  The last one, item f) bears particular emphasis:  there must be a process in place at the specimen source (e.g., tissue bank) to protect personal information, and the IRB must be satisfied that the process is in place.

Also, for research involving children (minors), FDA regulations provide, in 21 CFR 50.55, for waiver of assent under certain conditions:  a) the child is unable to provide assent, OR b) (paraphrasing here) the prospect of direct benefit is important and available only in the study, OR c) the research is minimal risk AND the waiver will not harm the children’s rights or welfare AND the study could not be “practicably” carried out without the waiver AND “whenever appropriate,” the subjects will be given pertinent information after participation in the study is over.  These criteria also apply to alteration of the assent process.

[Note that “practicably”:  Many have complained about the use of that word.  Interpreting it in the context of the regs involves a judgment call by the IRB.]

FDA does allow that the requirement to document informed consent may be waived (21 CFR 59.109) if EITHER the research is emergency research, OR “the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.”  At least, these are easier to remember, but if they apply, informed consent still must be obtained—you just don’t need an ICF.  In this case, the IRB will decide whether the exemption applies to all subjects in the study, or just some, and the IRB may require the investigator to provide subjects with a written statement about the research.

For research not regulated by FDA, the OHRP regulations in 45 CFR 46 are the most applicable.  In general, these apply to federally-funded research, but under the rubric of the Common Rule, Aspire considers them to apply to non-FDA-regulated human subject research in general when it comes to questions of waiving consent.  Here:

The requirement to obtain informed consent may be waived, or the elements altered, for non-FDA-regulated research, if ALL of the following are true (45 CFR 46.116(d)):  the research involves no more than minimal risk to subjects AND the waiver or alteration will not adversely affect the subjects’ rights or welfare AND the research could not be “practicably” [there’s that word again] carried out without the waiver or alteration AND subjects will be given pertinent information after participation “whenever appropriate.”  Sound familiar?  Note this overlaps with FDA’s requirements ONLY with regard to waiver of assent for children.

Finally, the requirement to document informed consent may be waived for non-FDA-regulated research (45 CFR 46.117(c)) if EITHER “the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context” [consonant with FDA on this point] OR the consent form would be the only record linking the subject and the research, and the principal risk would be harm from a breach of confidentiality.  Note that, in the latter case, “each subject will be asked (emphasis ours) whether the subject wants” such documentation, “and the subjects (sic) wishes will govern.”

It’s not TOO complicated, but it can get confused.  When requesting a waiver of some sorts regarding consent, walk through this process.  Ask Aspire for help if you need.

Oh, and note:  the above doesn’t have anything to do with HIPAA waivers.  That’s a different topic, for another time.

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INTO THE BRAVE NEW WORLD OF INTERNET RESEARCH

We at Aspire are just beginning to see submissions for research done via the internet.  It’s an area we are still learning ourselves, and for which some of our processes are in development.  At this juncture, we would make only a few comments about internet-based research.  From our vantage point, the most salient concerns so far appear to be over consent and confidentiality.

Regarding consent, the existing regulations still apply (at least, pending any relevant revisions to the Common Rule, which will not be in place for at least a little while yet).  Absent the appropriate waivers, consent processes and documents (provided online) still must include all the required elements of informed consent.  Depending on the case, obtaining documentation—especially, an appropriate signature—of informed consent may pose a challenge.

Regarding confidentiality, we are reminded that the internet is not a secure medium.  Transmission of data may be vulnerable, and precautions must be in place to protect from hackers and other workers of maleficence, spyware, and the like.  Aspire will need to see a description of the processes in place to protect confidentiality.  As part of our review, we envision routinely asking our in-house IT professional to review and assess these processes.

A recent PRIM&R webinar on the subject suggested the following practices for describing confidentiality protections; anticipate that Aspire will ask for these with any submission for internet-based research:

·       Explain how data are transmitted.  Is a survey host used?  Will the host retain identifiable data, and will they be encrypted?

·       Explain how data are maintained—in individually identifiable form, aggregate form, anonymized, etc?  These points become especially critical if data sharing is involved.

·       Explain the data security plan.  The webinar cited the Harvard security plan (security.harvard.edu) as an example.

·       Do not guarantee absolute confidentiality—in fact, point out to subjects that such a guarantee cannot be made.

·       If aggregated anonymized data will be made publicly available, consider whether subjects could be (re)identified.  In general, keeping data de-identified or anonymized is a concern for any internet-based human subject research.

Also, as for any human subject research it reviews, Aspire will want to understand who has access to what data and how that access is protected or restricted (passwords and the like).

We are always committed to service, and for any internet-based research we review, we will work with our clients to be sure that we have and understand the appropriate information.  We will remain responsive and, to the degree permitted by law and regulation, flexible as we handle these requests.  Please don’t hesitate to call us to discuss.

A BRIEF UPDATE ON CONFLICT OF INTEREST

One of Aspire’s tasks is to assess—for every investigator we review—whether that investigator has a conflict of interest (COI), and if so, what must be done about it.

The process begins with questions on our standard submission forms, and continues with a request for the investigator to submit a “conflict of interest management plan.”    Aspire wants to work with investigators to identify COI and make sure that it is appropriately managed, and to facilitate the documentation process.

Conflict of interest (COI) has been defined as “a set of circumstances that creates a risk that professional judgment or actions regarding a primary interest will be unduly influenced by a secondary interest” (Steinbrook NEJM 360:2160-2163, 2009).  Examples of primary interests are welfare of patients (subjects), research integrity, and advancement of medical education.  Examples of secondary interests are financial gain, professional advancement, and favors to others.

COI is usually, but not exclusively, financial. Federal regulation defines financial COI as "...a significant financial interest that could directly and significantly affect the design, conduct, or reporting of...research" (42 CFR 50, revised March 2011).  (Investigator might, of course, have non-financial COIs.  These can be harder to identify, but are also often properly addressed by a strong informed consent process and document.)

It is clearly a conflict for a researcher to have a financial interest sufficiently large to affect his or her participation in research.  Just how much financial interest is too much is not universally agreed upon; Aspire’s practice is to adopt certain thresholds that are stated on our submission forms.  If those thresholds are exceeded, then a COI exists by definition, and it is not correct to claim, for example, “I sit on this company’s board of directors but I do not have a COI for this study.”  

If a COI exists, it must be "managed" by whatever steps are necessary to remove the risks to human subject protection or avoidance of bias or frank fraud in research.  These steps may include measures like requiring the investigator to divest her financial interest or asking her to withdraw from or change the nature of her participation in the study.  Depending on the specific study or financial interest, steps short of that may be sufficient.

Other appropriate steps to manage COI may include modification of the research plan, monitoring of the research by independent reviewers, using independent consultants and/or “unconflicted” personnel in the research, or others. 

Disclosure in the informed consent process and document is a COI management step that should virtually always be taken when conflict exists.  Please note, however, to identify that COI is present is a great start but insufficient by itself to manage it.

What it the “best” COI management plan?  It depends on the study.  There is not a “one size fits all.”   It is Aspire’s  policy to ask the investigator to propose a plan.   Upon review of this plan, Aspire IRB will make a determination as to whether the plan is sufficient to manage the conflict. 

Like everything we do here at Aspire, we aim to be as efficient as possible.  That means you may expect us to work with you to resolve issues quickly and judiciously to permit a prompt review.

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INFORMED CONSENT—FOCUS ON THE DOCUMENT

Last month, we commented on the need for personal, ongoing contact in the overall informed consent process.  This month, we return to the informed consent form (ICF) itself.

Of course, every ICF must explicitly contain or cover certain basic required elements of informed consent (21 CFR 50.25 and 45 CFR 46.116).  Other elements are required if applicable, while still others have the status of recommendations or best practices.  Aspire reviews every consent form to ensure that it includes what is required. 

On a client’s request, we (actually, I, the Medical Director) will draft the ICF for a small fee.  In that case, we will use a client’s preferred template, if requested, or we are happy to use a lovely template, complete and written in plain language, that was developed by my predecessor, Dr. Currien McDonald. 

I like that template because it is simple.  Anyone who has spent any time around clinical research knows well the ideal that ICF’s be written at an 8^th-grade reading level—and also knows well how elusive that ideal is.  To anyone in that group, I recommend our template.  (I can’t say we’ll just send it to you—you probably need to be using our services first.)

We see many ICFs from experienced investigators or well-honed industry clinical trial departments.  They are typically complete—or almost—and usually complex.  Despite that, many appear to be made as readable as possible.  But we still see too many ICFs that read as if they had been written by one of three groups—lawyers, bureaucrats in Brussels, or the Solenoid Robots.  (The Solenoid Robots were the nerdy villains on the old Roger Ramjet cartoons when I was a kid.  They were kind of like a bunch of malevolent Sheldons.) 

As I mentioned in last month’s post, leaders of one session at the December 2011 meeting of Public Responsibility in Medicine and Research (PRIM&R) commented that most adults understand and follow medical instructions poorly, if at all.   ICFs often look like intimidating legal contracts.  Some 40 million Americans cannot read complex texts and, in one study, 60% did not understand a “standard consent form.”  Media tools, “teach back” techniques, and just proceeding slowly and in simple language can help a subject navigate an ICF.

Moreover, it was said at PRIM&R that subjects want the following from consent documents:

·       An up-front explanation of their role in research and their rights as a subject;

·       Simple language and format; and

·       Separation of the important from the unimportant.  (Emphases mine in these bullets.)

We at Aspire appreciate that an ICF has already been labored over extensively before it is sent to us for review—and, in industry, that labor includes several rounds of review and efforts to comply with internal SOPs.  Therefore, we do our best to avoid unnecessary editing or rewriting.   But we do plead with clients to use simple organization and sentences in their ICFs, and focus on the most important things.  In particular, we will ask for revisions in two cases:

1.     An over-reliance on technical, medical terms (e.g., without defining or replacing them with everyday terms); and

2.     A “data dump” approach to listing risks, that does not clearly identify the risks that are expected to be a) most likely and b) most serious.  Believe it or not, we see some risk sections that look like unedited SAS outputs from a safety database.

Finally, there are a few edits that we will habitually make, either because they are required or they have become routine for Aspire IRB:

1.     Subjects will receive a “signed and dated” copy of the ICF.

2.     For FDA-regulated research, in the section listing parties with access to confidential information, the letters “FDA” or the words “Food and Drug Administration” will be in the final IRB-approved ICF.

3.     We routinely edit risk-related generalizations like “As with any drug…” [e.g., allergic reaction may occur].  The issue is not ANY drug, but the STUDY drug.

4.     We delete “yet” from statements like the following: “[The study drug] has not yet been approved by the FDA.”

5.     We revise phrases that sound like the subject is responsible for his or her own safety, e.g., “ you may harm yourself,” e.g., if study instructions are not followed. We prefer something like, “you may be at increased risk” for adverse effects.

6.     We look carefully at statements that imply or mandate subject “understanding,” preferring statements to the effect that the subject has received the information and has had sufficient opportunity to ask questions, and is aware of the voluntary nature of consent.  “I understand the study” is too tall an order.

7.     If a required clinicaltrials.gov statement is missing, we’ll insert the prescribed wording.

8.     PLEASE don’t just cut and paste a bunch of study procedures, in third-person language, from the protocol document (“subjects will ….”).  That’s not sufficient, and we’ll edit it.  Speak to the subject.

Informed Consent

INFORMED CONSENT—FOCUS ON THE PROCESS

Not quite a year ago, we posted an entry on this blog addressing consent forms. Informed consent is, of course, in the front of our minds every day at Aspire, and we’d like to revisit it. This month, we focus on the process of informed consent. Next month, we will speak again about the consent form itself.

It is Aspire IRB’s policy that each trial site provides its process for obtaining informed consent. Aspire must be able to determine that the process conforms to federal regulations found in 21 CFR 50, Subpart B and 45 CFR 46. Informed consent must be obtained from each subject or the subject’s legally authorized representative, and be properly documented, unless a waiver of some elements has been approved by the IRB.

Some descriptions we see of an informed consent process are, to put it bluntly, too sparse to be sufficient. Some descriptions amount to, “We give the subject the consent form, place him (or her) in a private room, and when they come out, they sign it.” We’d like to hear more, to be sure that each site is paying attention to the process of consent.

The informed consent begins when a prospective subject is first approached about a trial, continuing throughout that subject’s participation. Personal, face-to-face, ongoing contact between the study subject and the investigators or study staff, continuing throughout the study, are essential to ensure that each subject has sufficient information and understanding to provide voluntary consent to participate in the study. The process must cover the required elements of informed consent (21 CFR 50.25 and 45 CFR 46.116), which must also be embodied in the consent form, but simply handing a written list to the subject is not a complete process.

Sessions on informed consent at the December, 2011 Public Responsibility in Medicine and Research (PRIM&R) conference yielded a few points of note, including:
• Longer, more complex consent forms do not enhance the subject’s decision-making process and may in fact impair it (about which more next month);
• Multimedia approaches (e.g., using DVDs) do not necessarily improve subject understanding;
• 7 out of 8 American adults cannot correctly interpret and act on even basic medical information;
• Attempts to measure subject understanding, such as quizzes about the form, may measure test-taking ability but not understanding;
• Long consent forms look like legal contracts, making them, among other things, intimidating.

In other words, subjects need more handholding. In fact, the moderators of one session at PRIM&R said that subjects want pre-consent information, a peer mentor, tools to understand the study, a mid-study chance to revisit information and ask new questions, and an exit interview. Clearly, not all of these will apply in the same way for all studies, but it’s equally clear that a comprehensive consent form does not a consent process make.

Aspire will soon make available a “template” consent process, that it finds minimally acceptable, to sites that do not have a consent SOP or detailed process in place. If you do have one, send it with your application and we will review it. If you don’t, we can help you—you won’t have to try to guess what we are thinking.