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2006D-0331: Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors; Exception from Informed Consent Requirements for Emergency Research (docket with meeting transcript and public comments). Accessed on 2006-12-16 at: http://www.fda.gov/ohrms/dockets/dockets/06d0331/06d0331.htm
The Polyheme® trial is one of a small number of emergency research studies conducted under exemption from informed consent. FDA requires sponsors of these studies to make certain information available to the public, some of which is posted in FDA docket 1995s-0158. The index of submissions to FDA docket 1995s-0158 is incomplete; many, but not all, submissions are available from http://www.fda.gov/ohrms/dockets/dockets/95s0158/95s0158.htm
Additional entries to FDA docket 1995s-0158 can be retrieved by entering
1995s-0158 in the FDA docket search at http://www.fda.gov/ohrms/dockets/default.htm
Links to submissions to FDA docket 1995s-0158 for the Polyheme® trial are available in The Polyheme Trial Pt. 2
Links to media articles and related publications about the Polyheme® trial are available in The Polyheme Trial Pt. 3
Links to articles on Polyheme® published in medical journals are available at The Polyheme® Trial Pt. 4
The formal name of the Polyheme® trial is: BB IND 10719 Poly-SFH-P Injection [Polymerized Human Hemoglobin (Pyridoxylated), PolyHeme®.] Protocol RTBSE-11-(N). A Phase III Randomized, Controlled, Open-Label, Multicenter Parallel Group Study Using Provisions for Exception from Informed Consent Requirements Designed to Evaluate the Safety of Poly-SFH-P Injection [Polymerized Human Hemoglobin (Pyridoxylated), PolyHeme®.] When Used to Treat Patients in Hemorrhagic Shock Following Traumatic Injuries in the Pre-Hospital Setting.
The PolyHeme® trial is sponsored by Northfield Laboratories Inc.
The registry at ClinicalTrials.gov provides a handy list of the 31 sites participating in the Polyheme® trial.
Poly-SFH-P Injection [Polymerized Human Hemoglobin (Pyridoxylated), PolyHeme®.] Protocol RTBSE-11-(N). Available from http://www.clinicaltrials.gov/ct/show/NCT00076648?order=1. Accessed 2006-02-17.
One way to understand the objections to the Polyheme® trial is to read the following:
Despite Heart Attack Deaths, PolyHeme Still Being Tested On Trauma Patients. Thomas M. Burton. The Wall Street Journal (republished by DeFrance Inc.). 2006-02-22.
FDA Needs to Consider Concerns of Human Research Protection Agency in Blood Substitute Study. Senator Charles Grassley. Press Release. 2006-03-13. Available from http://finance.senate.gov/press/Gpress/2005/prg031306.pdf. Attachments to Chairman Grassley's letter. 2006-02-23. Available from http://finance.senate.gov/press/Gpress/2005/prg031306attach%20.pdf
Artificial Blood (Polyheme) Trials: King and Kipnis. Women's Bioethics Project News Blog. Originally published on 2004-06-14. Republished with permission on 2006-03-06. Available from http://womensbioethics.blogspot.com/2006/03/artificial-blood-polyheme-trials-king.html
Kipnis K, King N MP, Nelson RM. An open letter to IRBs considering Northfield Laboratories' Polyheme trial. American Journal of Bioethics. 2006;15:34. Available from http://www.bioethics.net/journal/pdf/UAJB_A_166837.pdf. Accessibility verified 2006-03-10.
Kipnis K, King N MP, Nelson RM. Trials and errors: barriers to oversight of research conducted under the emergency research consent waiver. IRB: Ethics and Human Research. 2006;28(2):16-19. Available from http://www.thehastingscenter.org/publications/irb/irb.asp . (Free registration required.)
Readers shouldn't shy away from the two articles by Kipnis et al. simply because they're published in professional journals — both of them are straightforward, short, and to the point — but all the same, many of the key points were covered by Boston University's Leonard Glantz in an excellent radio interview last fall, the transcript of which is available on the web.
Transcript, The Kojo Nmamdi (radio) Show with guests Gerald Sandler M.D., Leonard Glantz Ph.D., and Christopher Michetti M.D. In: BB IND 10719 Poly-SFH-P Injection [Polymerized Human Hemoglobin (Pyridoxylated), PolyHeme®.] Protocol RTBSE-11-(N). 1995S-0158 Vol. 47 Sup. 43. Inova Fairfax Hospital (Fairfax, VA) community consultation and public disclosure. 2005-09-06. Available from http://www.fda.gov/ohrms/dockets/dockets/95s0158/95s-0158-sup0043-03-Tab-02-02-vol47.pdf. (The transcript begins on p.7)
Inaccurate and Misleading Information in Community Consultation and Public Disclosure: Misinformation
Several study sites provide information about adverse events in previous research with Polyheme® that appears to be inaccurate.
For example, the
Polyheme® Trauma Trial Information posted by Inova Fairfax Hospital provides the following Q and A:
Is PolyHeme® safe?
In clinical trials to date, PolyHeme® has demonstrated no clinically relevant adverse effects.
Has PolyHemeŽ been tested on humans before?
There have been 5 human clinical trials of PolyHeme®. (11)
A press release published on 2006-03-20 by Wishard Memorial Hospital states:
The IUPUI Institutional Review Board, which is responsible for research at both Methodist and Wishard hospitals, further states that recent national media accounts erroneously reported that the research community did not have knowledge of a PolyHeme® study in which 10 patients suffering from abdominal aortic aneurysm (ballooning in the wall of a major artery) died of heart attacks. The information from those studies was known and was determined not to be attributed to the use of PolyHeme®. (4)
national media to which this press release responds appears to be the recent Wall Street Journal story by Tom Burton. The WSJ story, however, did not report that
the research community did not have knowledge of a PolyHeme® study in which 10 patients suffering from abdominal aortic aneurysm (ballooning in the wall of a major artery) died of heart attacks. In fact Burton wrote that:
Northfield did tell trauma doctors about the heart attacks in the earlier study but did so confidentially and with an explanation that it didn't believe PolyHeme was responsible, according to company documents and interviews with doctors. (5)
What's problematic about the Wishard Memorial Hospital press release is that it appears to offer a straw man argument, e.g., it raises and defeats an unrelated proposition.
What's important is that Wishard Memorial Hospital's
Polyheme® Trial Documents, which were presumably used during the process of community consultation and public disclosure, stated that in
clinical trials to date, PolyHeme® has demonstrated no clinically relevant adverse effects. While it may be true that a causal relationship wasn't detected between Polyheme® and heart attack in subjects enrolled in the study on Acute Normovolemic Hemodilution (ANH) and surgical repair of abdominal aortic aneurysm, since the study hasn't been published we're forced to take Northfield's word for this. In fact, in at least one document Northfield states that it
cannot be determined whether or not heart attacks were caused by Polyheme®. (7)
It's not true, however, that were no adverse effects. Perhaps the worst is that little or none of this was raised and explained to people during community consultation.
It's also problematic that the following institutions also claim that Polyheme® demonstrated no clinically relevant adverse effects, or that Polyheme® has been well-tolerated in patients (properly called
There is reason to be skeptical about the basis for Wishard Memorial Hospital's conclusion that
information from those studies was known and was determined not to be attributed to the use of PolyHeme® in view of the recent withdrawal of a scheduled presentation of the results of the clinical trial testing Polyheme® in patients undergoing surgery for abdominal aortic aneurysm. On 2006-02-22 Northfield Laboratories Inc. published a press release denying allegations raised in Burton's WJS story, and ending with the following statement:
Lead ANH trial investigator Edward Norris, MD of Johns Hopkins University Hospital, will present the full study results at the Network for the Advancement of Transfusion Alternatives (NATA) meeting in April 2006. We believe his presentation will substantiate our conclusions as does our extensive experience with PolyHeme in trauma settings. (8)
Eight days later Northfield Laboratories Inc. did an about-face and issued a press release
correcting and replacing the previous announcement:
Contrary to a statement in the previous release, Dr. Edward Norris of Johns Hopkins University School of Medicine has withdrawn as a presenter of an abstract of the ANH study at the Network for the Advancement of Transfusion Alternatives (NATA) meeting in April 2006. Northfield was unable to provide him with access to the entire database from the study in sufficient time to permit his preparation for the presentation. Northfield's original press release dated February 22, 2006, did not mean to imply that Dr. Norris' presentation was designed to substantiate its conclusions about the data. (9)
As unusual as this was, there was an another wrinkle of which few people were aware: it appears Dr. Norris and Johns Hopkins demanded Northfield retract the press release and issue a corrected version.
Statement regarding PolyHeme
Contrary to a statement made as part of a press release by Northfield Laboratories of Evanston, Ill, on Feb. 22, 2006, a Johns Hopkins Medicine faculty member, Edward Norris, M.D., is not presenting information about a clinical trial of the company's blood substitute PolyHeme at the annual meeting of the Network for the Advancement of Transfusion Alternatives (NATA) in April 2006; was not given access to full study results from Northfield; and does not and cannot substantiate Northfield's claim that PolyHeme was unlikely to have been the cause of 10 heart attacks and 2 deaths in patients receiving the blood substitute as part of a clinical trial that ended in 2000.
Johns Hopkins Medicine has asked Northfield to retract its February 22 release and to reissue a corrected version.
The company's release challenged a Wall Street Journal article that questions the Acute Normovolemic Hemodilution (ANH) multi-center clinical trial, begun in the late 1990s.
Dr. Norris was among those who participated in the clinical trial. (12)
A detailed story was published the next day by Julie Bell, the very smart reporter at the Baltimore Sun.
Blood substitute raises questions. Julie Bell. The Baltimore Sun. 2006-03-24. Available from http://www.baltimoresun.com/news/health/bal-hs.blood24mar24,0,2392664.story?track=rss
According to Bell, Johns Hopkins administrators took the unusual step of announcing that Dr. Norris would not present results from the contentious Acute Normovolemic Hemodilution (ANH) multi-center clinical trial as planned in April because he
did not receive all the data he needed from the manufacturer to make a presentation on the blood substitute PolyHeme.
If Northfield previously disclosed all results from the Acute Normovolemic Hemodilution (ANH) trial, as is implied by Wishard Memorial Hospital, it's difficult to understand why this information couldn't have been provided to Dr. Norris. If Northfield didn't disclose all the results of this trial it's difficult to understand how Wishard Memorial could draw conclusions based on incomplete information.
Irritatingly enough the Wishard Memorial press release goes on to assert that
All 32 sites conducting the study have reviewed and decided to continue enrolling participants. This is contradicted by the press release published by Northfield Laboratories Inc. on 2006-03-14, which states that a
few sites recently suspended patient enrollment temporarily while reviewing their activities. Three are once again enrolling. As of 2006-03-26, the trial registration at Clinicaltrials.gov lists three study sites where enrollment is suspended. (6)
If nothing else this supports the proposition that every trial should be registered before enrollment begins and registration should include provisions for disclosure of results.
There's another issue nobody's said much about: Polyheme® and similar products can interfere with crucial clinical laboratory tests. This is mentioned in passing in the FDA Draft Guidance for Industry: Criteria for Safety and Efficacy Evaluation of Oxygen Therapeutics as Red Blood Cell Substitutes:
We recommend that you evaluate and resolve interference of hemoglobin solutions with measurements of clinical laboratory parameters for all relevant clinical laboratory instrumentation. Colorimetric interference with a number of clinical laboratory assessments that are important for individual patient management may occur with hemoglobin-based oxygen therapeutics. Manufacturers of oxygen therapeutics should anticipate ongoing support of clinical laboratories and evaluation of the effects of either hemoglobin-based oxygen carriers or perfluorochemical emulsions on new instruments or methods of analyte determination. (19)
Some of Northfield Laboratories' previous research has been criticized on a number of grounds. For example:
UNIDENTIFIED PARTICIPANT: My question is to Dr. Gould. I would like to congratulate Northfield for their ongoing efforts in trauma. Certainly you are in the forefront of investigating the role of anti-oxygen carrying fluid in patients with post-traumatic hypertension. It seems to me that what you have for now is a result of one — I would say the first — prospective studies that directly compared any blood substitute with the standard of care in which you were able to show that your product, Polyheme, can sustain life. It can do that with minimal side effects and can also reduce the need for allogeneic blood transfusion. However, the study was severely criticized, primarily because of the small number of patients — I believe 44 total. And also for the fact that it did not include any efficacy criteria such as morbidity and mortality.
On the other hand, you have some favorable results also from Phase II clinical trials, in which you have demonstrated some beneficial effect on mortality. However, in this study you don't have any control groups. And the question that I have for you is what is your game plan or what is your strategy based on the information that you have in hand, especially because it seems that you advocate the use of mortality as an endpoint, which as you know takes a lot of time and a significant number of patients to show differences?
DR. GOULD: That is a good question. And at this point in time, I can only say we are impressed with these results or gratified with these results and we are reviewing them in detail to decide just how to proceed. I can't give you a specific answer at this moment. (10)
Extensive background with summaries of the issues in regulation, law, and ethics: 21 CFR Parts 50, 56, 312, 314, 601, 812, and 814. Protection of Human Subjects; Informed Consent; Proposed Rule. Department of Health and Human Services, Food and Drug Administration. 60 FR 183 (1995-09-21) pp. 49085-49103. [Docket No. 95N-0158] RIN 0910-AA60. Available from http://www.fda.gov/OHRMS/DOCKETS/98fr/092195.txt
Also excellent: Preamble to 21 CFR Parts 50, 56, 312, 314, 601, 812, and 814. Protection of Human Subjects; Informed Consent II. Department of Health and Human Services, Food and Drug Administration. 61 FR 191 (1996-10-02). Available from http://www.fda.gov/oc/gcp/preambles/61fr/61fr.html
21 CFR 50 et. al. 45 CFR 46. Protection of Human Subjects; Informed Consent and Waiver of Informed Consent Requirements in Certain Emergency Research; Requirements. Final Rules. Department of Health and Human Services, Food and Drug Administration. 61 FR 191 (1996-10-02) pp. 51498-51531. Available from http://www.fda.gov/ohrms/dockets/dockets/95s0158/95s-0158-nfr00001-vol1.pdf
FDA Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research. Draft Guidance. 2000-03-30. Available from http://www.fda.gov/ora/compliance_ref/bimo/emrfinal.pdf
For background on the type of circumstances in which the exemption from informed consent at 21 CFR 50.24 came about, readers may be interested in: Wall Street Journal; Winslow, A.
FDA Halts Test on Device That Shows Promise for the Victims of Cardiac Arrest. 19940511/P. Bates: 2046936882. Available from http://tobaccodocuments.org/pm/2046936882.html
Additional information relevant to the Polyheme® trial:
FDA Draft Guidance for Industry: Criteria for Safety and Efficacy Evaluation of Oxygen Therapeutics as Red Blood Cell Substitutes. 2004-10-28. Available from http://www.fda.gov/cber/gdlns/oxytherbld.htm
Essig E. Northfield Laboratories Inc. Public comment on FDA Draft Guidance for Industry: Criteria for Safety and Efficacy Evaluation of Oxygen Therapeutics as Red Blood Cell Substitutes. 2005-01-25. Available from http://www.fda.gov/ohrms/dockets/dockets/04d0462/04d-0462-c000005-01-vol1.pdf
FDA Guidance for Industry: Special Protocol Assessment. 2002-05. Available from http://www.fda.gov/cber/gdlns/protocol.htm
1. Crawford L. Letter to Bernard A. Schwetz D.V.M., Ph.D., Director, Office for Human Research Protections. 2005-03-01. Available from http://finance.senate.gov/press/Gpress/2005/prg031306attach%20.pdf
2. Leading Trauma Surgeon Declares 'The Future Is Now' for Blood Substitutes. Northfield Laboratories Inc. Press Release. 2002-10-08. Available from http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/10-08-2002/0001814900&EDATE=
3. Gould SA, Moore EE, Hoyt DB, Ness PM, Norris EJ, Carson JL, Hides GA, Freeman IH, DeWoskin R, Moss GS. The life-sustaining capacity of human polymerized hemoglobin when red cells might be unavailable. J Am Coll Surg. 2002 Oct;195(4):445-52. Abstract available from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12375748
4. PolyHeme® Trial Update. Wishard Memorial Hospital Press Release. 2006-03-20. Available from http://www.wishard.edu/news/release.php?id=38
5. Despite Heart Attack Deaths, PolyHeme Still Being Tested On Trauma Patients. Thomas M. Burton. The Wall Street Journal (republished by DeFrance Inc.). 2006-02-22. Available from http://www.defrance.org/artman/publish/printer_1531.shtml
6. Northfield Laboratories Statement Regarding Its Pivotal Phase III Trial. Northfield Laboratories Inc. Press Release. 2006-03-14. Available from http://phx.corporate-ir.net/phoenix.zhtml?c=91374&p=irol-newsArticle&ID=831844&highlight=. Poly-SFH-P Injection [Polymerized Human Hemoglobin (Pyridoxylated), PolyHeme®.] Protocol RTBSE-11-(N). Available from http://www.clinicaltrials.gov/ct/show/NCT00076648?order=1
7. Polyheme® Trial Documents. Wishard Memorial Hospital. 2004-05-19. Available from http://www.wishard.edu/news/pdf/PolyHeme%20Trial%20Documents.pdf. Questions and Answers The Polyheme® Trauma Trial. Northfield Laboratories. Undated. Available from http://www.northfieldlabs.com/downloads/PolyHeme%20TraumaTrialFAQ.pdf
8. Northfield Laboratories Strongly Disputes Wall Street Journal Story Conclusions. Northfield Laboratories Inc. Press Release. 2006-02-22. Available from http://phx.corporate-ir.net/phoenix.zhtml?c=91374&p=irol-newsArticle&ID=820512&highlight=
9. CORRECTING and REPLACING Northfield Laboratories Strongly Disputes Wall Street Journal Story Conclusions. Northfield Laboratories Inc. Press Release. 2006-03-20. Available from http://phx.corporate-ir.net/phoenix.zhtml?c=91374&p=irol-newsArticle&ID=833811&highlight=
10. FDA CBER Workshop on Criteria for Safety and Efficacy Evaluation of Oxygen Therapeutics as Red Cell Substitutes. Meeting Minutes. 1999-09-27. Available from http://www.fda.gov/cber/minutes/oxygen092799.htm
11. Polyheme® Trauma Trial Information. Inova Fairfax Hospital. Available from http://www.inova.org/inovapublic.srt/news/faq.jsp. Accessed 2006-03-18.
12. Statement regarding PolyHeme. Johns Hopkins Medicine. Press Release. 2006-03-23. Available from http://www.hopkinsmedicine.org/Press_releases/2006/03_23a_06.html
13. E.E. Moore. Blood substitutes: the future is now. J Am Coll Surg. 2003;196(1):1-17. Available from http://dx.doi.org/10.1016/S1072-7515(02)01704-0. (Select the link for
Article via Science Direct.)
14. Questions and Answers The Polyheme® Trauma Trial. Northfield Laboratories. Undated. Available from http://www.northfieldlabs.com/downloads/PolyHeme%20TraumaTrialFAQ.pdf
15. Miami Valley Hospital (Dayton, OH) community consultation and public disclosure. Variously dated including material from 2005-08-08. Available from http://www.fda.gov/ohrms/dockets/dockets/95s0158/95s-0158-sup0049-02-Comm-Consultation-Doc-vol52.pdf
16. The orginal document appears to have been removed within the last several days. Questions and Answers The Polyheme® Trauma Trial. Albany Medical Center. Accessed on 2006-03-21 from http://www.amc.edu/polyheme/polyhemeinfo.htm
17. Efficacy Considerations, Trauma. FDA Draft Guidance for Industry: Criteria for Safety and Efficacy Evaluation of Oxygen Therapeutics as Red Blood Cell Substitutes. 2004-10-28. Available from http://www.fda.gov/cber/gdlns/oxytherbld.htm
18. Clinical Evaluation, Trauma. FDA Draft Guidance for Industry: Criteria for Safety and Efficacy Evaluation of Oxygen Therapeutics as Red Blood Cell Substitutes. 2004-10-28. Available from http://www.fda.gov/cber/gdlns/oxytherbld.htm
19. FDA Draft Guidance for Industry: Criteria for Safety and Efficacy Evaluation of Oxygen Therapeutics as Red Blood Cell Substitutes. 2004-10-28. Available from http://www.fda.gov/cber/gdlns/oxytherbld.htm
Last Updated: 2008-04-04
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