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Community Consent: A Debate in Research Ethics

When it comes to doing research in emergency medicine situations, it is often difficult or impossible to receive informed consent from a patient to be a part of a research study. This is especially true for situations when the patient is unconscious or in critical condition. When researchers want to conduct a study in an emergency medicine situation such as this, the most popular method of obtaining informed consent from the research subjects is instating an “opt-out” community consent model in which the community around the hospital is informed of the study that will be done in the hospital, and everyone in the community will be considered having given their informed consent to be a part of this study unless they opt out of the study and wear a wristband indicating that they do not consent to being a part of this study. As can be expected, successfully informing the entire community is a difficult task, and there are potentials for abuse if all research projects were allowed to use this informed consent model. The FDA has laid out its requirements for a study to be allowed to use this opt-out community consent model. The opt-out community consent model is not without its controversies despite the FDA requirements. Issues tend to focus around properly informing the community and ensuring that proven and satisfactory treatments are not withheld from these patients.

 

 

Exception from Informed Consent in Emergency Research ("opt-out")

FDA Exception from Informed Consent Requirements for Emergency Research

https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm249673.pdf

"All of the following conditions must be present:

  • The human subjects are in a life-threatening situation that necessitates urgent intervention;
  • Available treatments are unproven or unsatisfactory (See also Questions 23, 24, and 25);
  • Collection of valid scientific evidence is necessary to determine the safety and effectiveness of the intervention;
  • Obtaining informed consent is not feasible because the subjects are not able to give their informed consent as a result of their medical condition;
  • The intervention must be administered before consent can be obtained from the subject's legally authorized representative;
  • There is no reasonable way to identify prospectively individuals likely to become eligible for participation;
  • Participation in the research holds out the prospect of direct benefit to the subjects (See also Question 21); and
  • The clinical investigation could not practicably be carried out without the waiver (See also Question 29)."

Additionally, the FDA requires that for exception from informed consent to be used to enroll an entire community there needs to be significant community consultation and public disclosure of the details of the study. In the event that the patient is unconscious or unable to give their informed consent during the course of the treatment, researchers need to make a reasonable effort to track down the legally authorized representative for the patient and obtain a written consent if possible.

Holsti, M., Zemek, R., Baren, J., Stanley, R. M., Mahajan, P., Vance, C., ... & Shreve, K. (2015). Variation of community consultation and public disclosure for a pediatric multi-centered "Exception from Informed Consent" trial. Clinical Trials, 12(1), 67-76.

An examination of the methods of the different hospitals in a multi-centered emergency research study found that a great deal of variation of interpretations of the requirements for community consultation and public disclosure by the IRB at each institution, which led to different presentations to the different communities. This study also found that only 5% of the patients enrolled through the exception from informed consent had heard about the study from the community consultation and public disclosures activities.

Kutcher, M. E., Forsythe, R. M., & Tisherman, S. A. (2016). Emergency preservation and resuscitation for cardiac arrest from trauma. International Journal of Surgery, 33, 209-212.

Griggs, B. (2014, June 23). Cheating death through 'suspended animation' Retrieved from

http://www.cnn.com/2014/06/23/tech/innovation/suspended-animation-trials/index.html

Another exception from informed consent study is being conducted in an emergency medicine setting where patients with severe trauma could have hypothermia induced to give the surgeons extra time to operate before the patient dies. The community was informed they would be enrolled in the study if they did not opt out and wear a wristband, just like with the PolyHeme study. However, there does not seem to be as big of an issue raised by the community and lawmakers with this study perhaps because the study sponsors were forthcoming with the information. Additionally, the procedure would only be performed on patients with such severe trauma that the patient has a minimal chance (5-10%) of surviving if the normal techniques are used. Also, the study sponsors realized that the study protocol was too narrow and they were unable to receive a single patient in four years that met the requirements, so the sponsors are reapplying to do the study with broader requirements.

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Example of the PolyHeme study involving Community Consent

WASHINGTON, March 14, 2006 (UPI) -- U.S. Sen. Charles Grassley, R-Iowa, says the Food and Drug Administration has made patients into "potential guinea pigs" in a blood substitute study. Grassley says a patient-safety office within the Department of Health and Human Services has been expressing ethical concerns about the study to the FDA for nearly two years, The Wall Street Journal reported Tuesday. The concerns centered on the design and implementation of a study of the blood substitute PolyHeme, made by Northfield Laboratories Inc.

Summary & Timeline

Polyheme bagDecember 2003: Phase III Trial of Polyheme begins enrolling patients in a study investigating the “ Safety and Efficacy of PolyHeme ® in Hemorrhagic Shock Following Traumatic Injuries Beginning in the Pre-Hospital Setting.” The study starts at the injury scene and continues through ambulatory transport and up to 12 hours of inpatient hospital stay or 6 units of PolyHeme. Trauma victims are automatically enrolled unless they wear a blue bracelet that indicates their desire to “opt out” of the study.

As of March 2006, more than 600 patients at 31 trauma centers in 18 states have been enrolled. Northfield Laboratories has reported that a total of 2000 people have requested the blue bracelets, and 11 victims who initially received the blood substitute declined to continue participation once in the hospital.

An earlier non-randomized trial (October 2004) has been published in the Journal of the American College of Surgery.

  • What is PolyHeme?
    Created by Northfield Laboratories, this blood substitute is an oxygen-carrying resuscitative fluid. PolyHeme uses hemoglobin extracted from red blood cells and then modifies the hemoglobin into a polymerized from. This is a chemical reaction in which two or more small molecules combine to form larger molecules that contain repeating structural units. The polymerized hemoglobin is then put into solution in approximately the same concentration that hemoglobin is found in natural blood.

    Polymerization

 

Official Study Title “A Phase III, Randomized, Controlled, Open-Label, Multicenter, Parallel Group Study Using Provisions for Exception From Informed Consent Requirements Designed to Evaluate the Safety and Efficacy of Poly SFH-P Injection [Polymerized Human Hemoglobin (Pyridoxylated), PolyHeme ® ] When Used to Treat Patients in Hemorrhagic Shock Following Traumatic Injuries Beginning in the Prehospital Setting.”

Learn more about this FDA-approved clinical trial.

This study has not been required to obtain the informed consent of trauma victims under FDA regulation 21 CFR 50.24 – the emergency research exception. This exception allows a waiver of informed consent requirements under emergency therapy conditions in which it is not possible to obtain standard consent.

polyheme transfusion bagMarch – June 2004: The Office of Human Research Protections (OHRP) raises concerns to the FDA regarding the PolyHeme study based on a complaint that alleging inappropriate use of the emergency informed consent waiver once subjects arrive as the hospital. In order for the waiver to be applicable, other available treatments must be unproven or unsatisfactory (21 CFR 50.24a, 1). Yet once in the hospital, trauma victims are usually able to receive matched blood within 45 minutes – 1 hour.

A discussion of the ethics of this type of artificial blood experiment took place on NPR in March 2004.

It is among the duties of the OHRP director to advise the Secretary of Health and Human Services on issues of human subject protections. Both the FDA and the OHRP fall within the purview of the Department of Health and Human Services.

July – November 2004: The Director of the OHRP makes multiple requests to meet with the various FDA officials to discuss concerns over the PolyHeme trial. In August, a meeting took place between OHRP and FDA officials, but this did not resolve the concerns over the PolyHeme study. The Director ultimately writes to the acting commissioner of the FDA, Dr. Lester Crawford, to urge that a review of the PolyHeme study (and other uses of the emergency waiver) be conducted.

March 2005: The FDA finally replies to concerns raised by the OHRP, claiming that FDA had requested more information from Northfield Laboratories on details of the PolyHeme study. They also agreed on the need for a clearer description whenever the PolyHeme study was added to a new community.

May 2005: OHRP again requests a joint review with the FDA to investigate implementation of use of the emergency waiver.

December 2005: OHRP finally receives a response to their requests for a review – the FDA conducts an internal review of the use of the emergency waiver in studies submitted to it.  PolyHeme bags

February 2006: (2-22-06) The Wall Street Journal publishes a story on a previous PolyHeme study from 2000 which is no longer in progress. The WSJ questioned whether Northfield Laboratories were secretive about negative side effects such as heart attack in patients exposed to PolyHeme. In response, Northfield Laboratories' stock plunges by as much as 27 percent.  

Northfield Laboratories issues a statement contradicting the claims in the WSJ story.

  March 2006: The March-April issue of the journal IRB: Ethics and Human Research will publish an article entitled “ Trials and Errors: Barriers to Oversight of Research Conducted under the Emergency Research Consent Waiver” in which criticism is made of the PolyHeme trial's use of emergency consent waivers.

Also, these same authors have written an open letter to IRBs concerning the Northfield PolyHeme. This letter is forthcoming in the American Journal of Bioethics .

Sen. Grassley

(3-13-06) Senator Charles Grassley (R, Iowa; Chair of the Senate Finance Committee) writes a letter to Secretary of Health and Human Services Michael Leavitt indicating his disapproval of the PolyHeme study and requesting attention to “problems that continue to plague the FDA” and a particular intervention into the PolyHeme study to address concerns of informed consent. He also requests that clear information about this study be made public by the FDA.

Northfield Laboratories has dedicated a large portion of their website to addressing concerns over the Phase III PolyHeme trial. This includes a fact sheet, and also a Question and Answer section. [Note: Northfield Labs filed for bankruptcy; it's website and FAQs on PolyHeme are no longer online. See: Northfield Laboratories to liquidate under Chapter 11, June 2, 2009.]

Where does the debate stand today on PolyHeme?

There has not been too much literature written about the PolyHeme study since Northfield Laboratories filed for bankruptcy in 2009. For the time being, there will not be any further PolyHeme studies, which might have contributed to the decreased interest in continuing the debate. Additionally, the majority of the literature is critical of the methods used during the PolyHeme study. A more recent article in support of PolyHeme does not necessarily condone the research methods of the PolyHeme study, but the article believes that PolyHeme showed at least some promise, and the potential use of the blood substitute should not be rule out just yet. It is important that lessons are taken from the ethical faults of this study most notably obtaining truly informed consent and providing patients with a proven and satisfactory treatment once that treatment is available, but there is some concern that increased regulation on research in emergency medical situations will make it too financially burdensome and require too much time for further research to be successful because Northfield laboratories invested well over a decade and hundreds of millions of dollars into PolyHeme. It is certain that this concern for informed consent will arise each time a new study is proposed in an emergency medical situation such as the one where trauma surgeons will test inducing hypothermia during surgery on patients with a minimal chance of survival. The debate will also center on whether opting out of consent and wearing a wristband to notify the emergency health care team is the best method for handling community consent.

Apte, S. S. (2008). Blood substitutes- the polyheme trials. McGill Journal of Medicine : MJM, 11(1), 59–65.

Apte takes issue with Northfield Laboratories withholding of the protocol and research methods from the community meeting because this is insufficient information for the public to be considered having given their informed consent. Apte also believes that Northfield Laboratories manipulated procedures to prevent the IRB at every institution involved in the study from communicating with each other when an issue was raised. Additionally, Apte believes that continuing the patient's on PolyHeme after they arrived at the hospital was a violation of one of the stipulations for emergency medicine research that a study involving an incapacitated patient can only be conducted without informed consent if the available treatments are "unproven or unsatisfactory." The blood transfusions available at a hospital are a clearly proven and satisfactory available treatment.

Bernard, A. C., Moore, E. E., Moore, F. A., Hides, G. A., Guthrie, B. J., Omert, L. A., ... & PolyHeme Study Group. (2011). Postinjury resuscitation with human polymerized hemoglobin prolongs early survival: a post hoc analysis. Journal of Trauma and Acute Care Surgery, 70(5), S34-S37.

This study suggests that its post hoc analysis shows that PolyHeme might still have promise to be used because patients fared worse, though not statistically significant, in their 30-day survival compared to the control group, but the patients given PolyHeme fared better in the first 8 hours of treatment than the control group. The authors suggest this could be especially helpful in a military situation in which a patient could be given PolyHeme in the field and in the helicopter on the way to a remote medical center.

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