Tuesday, July 14, 2015

Waiver of Informed Consent - proposed changes in the 21st Century Cures Act

Adam Feuerstein points out - and expresses considerable alarm over - an overlooked clause in the 21st Century Cures Act:

In another tweet, he suggests that the act will "decimate" informed consent in drug trials. Subsequent responses and retweets  did nothing to clarify the situation, and if anything tended to spread, rather than address, Feuerstein's confusion.

Below is a quick recap of the current regulatory context and a real-life example of where the new wording may be helpful. In short, though, I think it's safe to say:

  1. Waiving informed consent is not new; it's already permitted under current regs
  2. The standards for obtaining a waiver of consent are stringent
  3. They may, in fact, be too stringent in a small number of situations
  4. The act may, in fact, be helpful in those situations
  5. Feuerstein may, in fact, need to chill out a little bit

(For the purposes of this discussion, I’m talking about drug trials, but I believe the device trial situation is parallel.)

Section 505(i) - the section this act proposes to amend - instructs the Secretary of Health and Human Services to propagate rules regarding clinical research. Subsection 4 addresses informed consent:

…the manufacturer, or the sponsor of the investigation, require[e] that experts using such drugs for investigational purposes certify to such manufacturer or sponsor that they will inform any human beings to whom such drugs, or any controls used in connection therewith, are being administered, or their representatives, that such drugs are being used for investigational purposes and will obtain the consent of such human beings or their representatives, except where it is not feasible or it is contrary to the best interests of such human beings.

[emphasis  mine]

Note that this section already recognizes situations where informed consent may be waived for practical or ethical reasons.

These rules were in fact promulgated under 45 CFR part 46, section 116. The relevant bit – as far as this conversation goes – regards circumstances under which informed consent might be fully or partially waived. Specifically, there are 4 criteria, all of which need to be met:

 (1) The research involves no more than minimal risk to the subjects;
 (2) The waiver or alteration will not adversely affect the rights and welfare of the subjects;
 (3) The research could not practicably be carried out without the waiver or alteration; and
 (4) Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

In practice, this is an especially difficult set of criteria to meet for most studies. Criterion (1) rules out most “conventional” clinical trials, because the hallmarks of those trials (use of an investigational medicine, randomization of treatment, blinding of treatment allocation) are all deemed to be more than “minimal risk”. That leaves observational studies – but even many of these cannot clear the bar of criterion (3).

That word “practicably” is a doozy.

Here’s an all-too-real example from recent personal experience. A drug manufacturer wants to understand physicians’ rationales for performing a certain procedure. It seems – but there is little hard data – that a lot of physicians do not strictly follow guidelines on when to perform the procedure. So we devise a study: whenever the procedure is performed, we ask the physician to complete a quick form categorizing why they made their decision. We also ask him or her to transcribe a few pieces of data from the patient chart.

Even though the patients aren’t personally identifiable, the collection of medical data qualifies this as a clinical trial.

It’s a minimal risk trial, definitely: the trial doesn’t dictate at all what the doctor should do, it just asks him or her to record what they did and why, and supply a bit of medical context for the decision. All told, we estimated 15 minutes of physician time to complete the form.

The IRB monitoring the trial, however, denied our request for a waiver of informed consent, since it was “practicable” (not easy, but possible) to obtain informed consent from the patient.  Informed consent – even with a slimmed-down form – was going to take a minimum of 30 minutes, so the length of the physician’s involvement tripled. In addition, many physicians opted out of the trial because they felt that the informed consent process added unnecessary anxiety and alarm for their patients, and provided no corresponding benefit.

The end result was not surprising: the budget for the trial more than doubled, and enrollment was far below expectations.

Which leads to two questions:

1.       Did the informed consent appreciably help a single patient in the trial? Very arguably, no. Consenting to being “in” the trial made zero difference in the patients’ care, added time to their stay in the clinic, and possibly added to their anxiety.
2.       Was less knowledge collected as a result? Absolutely, yes. The sponsor could have run two studies for the same cost. Instead, they ultimately reduced the power of the trial in order to cut losses.

Bottom line, it appears that the modifications proposed in the 21st Century Cures Act really only targets trials like the one in the example. The language clearly retains criteria 1 and 2 of the current HHS regs, which are the most important from a patient safety perspective, but cuts down the “practicability” requirement, potentially permitting high quality studies to be run with less time and cost.

Ultimately, it looks like a very small, but positive, change to the current rules.

The rest of the act appears to be a mash-up of some very good and some very bad (or at least not fully thought out) ideas. However, this clause should not be cause for alarm.