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2007 Meeting Minutes

Public Health Service

Meeting of the Interagency Coordinating Committee on Human Growth Hormone and Creutzfeldt-Jakob Disease

November 29, 2007

National Institutes of Health - Bethesda, Maryland

Committee Members Attending Also Attending
Dr. Judith Fradkin, NIDDK
Dr. Ellen Leschek, NIDDK
Dr. Eugene Major, NINDS
Dr. James Mills, NICHD
Dr. Griffin Rodgers, NIDDK, Chairman (by speakerphone)
Dr. Lawrence Schonberger, CDC (by speakerphone)
Dr. Diane Wysowski, FDA		 Dr. B. Tibor Roberts, NIDDK
Ms. Marcia Vital, NIDDK

The meeting began at 3:00 p.m.

1. Welcome

Dr. Rodgers welcomed the group and asked Dr. Fradkin to lead the discussion.

2. Epidemiology Study Status Report (includes confirmed and suspected CJD due to U.S. hGH, follow-up of hGH recipient deaths, and the status of contract support for the Epidemiology Study)

Dr. Leschek reported that the current Westat contract ends in June 2008 and the NIDDK plans to renew the contract for an additional five years.

The Committee returned to its 2006 discussion of categorization of deaths in which CJD is confirmed or suspected. The current designations are:

  1. Neuropathologically confirmed CJD
  2. Clinically confirmed CJD
  3. Clinically suspicious - Insufficient information to confirm (Possible CJD)
  4. Deaths under investigation

The Committee determined that in order to fall into the third category, all of the following must apply:

  1. There is no autopsy data available for unambiguous diagnosis;
  2. The likelihood of CJD is deemed greater than 50% by at least one member of the Neurological Review Group (NRG) and less likely by at least one other NRG member;
  3. No additional medical information is likely to become available to the NRG for review;
  4. An alternative condition other than CJD exists which could account for neurologic symptoms. (The Committee noted that underlying antecedent neurological illness that caused GH deficiency often significantly complicates the establishment of a CJD diagnosis.)

Categories I and II:

As in 2006, 26 deaths are considered to be either neuropathologically or clinically confirmed as CJD (categories I and II), with 13 in each category. The Committee has also learned of a probable 27th CJD death, discussed in greater detail below, which is expected to be confirmed when medical records become available for review. All deaths confirmed as CJD received hGH prior to 1977, when Dr. Parlow’s laboratory began producing hGH for the National Hormone and Pituitary Program.

Category III:

Previously, just one individual (Westat ID No. 1270-115) had been placed in the “clinically suspicious—insufficient information to confirm” category. As a result of difference of opinion among NRG members about the likelihood of CJD and the fact that no further clinical information is likely to become available, the Committee decided to list three more deaths— Westat ID Nos. 1470-052 , 0240-051, and 006-0288—in this category. For each, all of the criteria described above for category III apply. This brings the total in category III to four.

As noted in the minutes of the 2006 meeting, one member of the NRG wished to speak to the treating physician for Westat ID 1290-071. As a result of that discussion, that NRG reviewer now concurs with the other reviewers who regard this case as unlikely. It will therefore no longer be listed as clinically suspicious/possible CJD.

Category IV:

Category IV (death under investigation), includes several hGH recipients for whom more information may be available to either confirm or rule out CJD.

The probable 27th CJD death mentioned above (Westat ID No. 0980-0160) occurred in May 2007 in an individual treated primarily with pre-1977 hGH, who was reportedly healthy until two years prior to death. The neurological manifestations and course were highly consistent with CJD, as was an MRI, but no cerebrospinal fluid was obtained and no autopsy was performed. Neither the death certificate nor the medical records have been obtained at this time, so it has not been possible for the NRG to formally review this death. Therefore, although it is anticipated that Westat ID No. 0980-0160 will ultimately be listed as clinically confirmed (Category II), it will officially remain under investigation until the documentary evidence has been assembled and considered by the NRG. Because the death certificate is not yet available from the state and is required for Westat to apply for medical records, Dr. Leschek, who has been in contact with the family, will make a direct request for the records. If the records cannot be obtained, Drs. Leschek and/or Schonberger will assemble a narrative of the information they have received on the case thus far, and present it to the NRG for review.

Two deaths under investigation are similar in that Westat has been unable to contact next-of-kin to obtain medical records. Westat ID No. 0730-0239 died in 2003 with a death certificate listing “CJD-End Stage,” and Westat ID No. 1610-0752 died of “aspiration pneumonia (2 days duration) due to dementia (1 year duration) due to radiation treatment for craniopharyngioma.” Without medical records, NRG review has not been possible, and both deaths remain officially under investigation. Alternative approaches to obtain the records involving state health officials will be pursued.

The father of Westat ID No. 1180-032 called to report that his son had been treated with hGH from 1976-1979, and had died of CJD in September 2005. No autopsy was performed. The father has not released his medical records, and the death certificate lists cause of death as “unspecified natural disease process altered by decomposition.” Although the father believes his son died of CJD, the reported capacity of this patient to live alone up to death argues against CJD. This death will remain under investigation, and another effort will be made to obtain medical records.

“Craniopharyngioma” was listed as the cause of death on the death certificate of Westat patient ID No. 0400-058, as discussed in the minutes of the 2006 meeting. Neurologists on the NRG agreed there was no evidence of CJD, but both also noted that the records were missing information from the three years immediately prior to the patient’s death.  A request for those additional records remains unfulfilled. If no further information on this case is discovered in the coming year, it will no longer be considered under investigation.

3. Report on CJD in Foreign hGH Recipients

Dr. Schonberger reported that four additional cases of CJD linked to hGH treatment internationally have come to his attention, three in France and one in Brazil. This brings the total number of CJD cases outside the U.S. that are attributable to hGH to 172. The hGH used in New Zealand and Brazil was produced in the U.S. The table provides a country-by-country breakdown:

Country # of Patients
France 110
United Kingdom 51
New Zealand 6
Brazil 2
Australia 1
Holland 1
Qatar 1
Total 172

Table 1 presents the number of patients with CJD in specified countries.

4. Update on Public Inquiries

Ms. Vital has assumed responsibility for public inquiries previously handled by Dr. DeMouy prior to June 2007. She reported that from June through the date of this meeting, there had been seven telephone calls related to the cohort of U.S. NHPP hGH recipients, and three calls from individuals who found the website for other reasons. From September of 2006 to June of 2007 Dr. DeMouy responded to at least 10 contacts related to the cohort, and five unrelated to the cohort.

Ms. Vital also noted that often cohort-related calls are from individuals wondering why they have not received an NIH hGH-CJD Fact Sheet update in recent years. (After years of annual mailings, in 2003 a letter was sent to the cohort, indicating that the Fact Sheet would be available on the website (National Hormone and Pituitary Program (NHPP): Information for People Treated with Pituitary Human Growth Hormone), and could also be sent to anyone who requests it.) Cohort members who make such inquiries and who wish to receive the Fact Sheet when updates are made can be added to a list of members who prefer to receive mailings.

5. Brief highlights of progress in CJD research

Dr. Major referred the Committee to a recent NEJM review by Goldberg on evidence for the theory that the neurotoxicity observed in prion diseases may result from proteasome inhibition. Drs. Major and Schonbereger both noted a review in Science by Collinge and Clarke suggesting that the derivative of the PrP protein responsible for neurotoxicity forms as an intermediate or byproduct of prion propagation. The review ties this hypothesis into a larger theory concerning prion strains and the so-called “species barrier.”

Dr. Schonberger also highlighted a review on therapeutic approaches to prion disorders in Expert Review of Anti-infectious Therapy by Ludewigs et al. The review discusses some preliminary evidence that tetracycline or its derivatives might, by an unknown mechanism, reduce infectivity and/or increase lifespan in some people or animals infected with prion diseases. The Committee noted that as yet no peer-reviewed report of a randomized controlled clinical trial on such drugs has been published, but that such research is going forward in Europe. Similarly, research is going forward to develop pre-mortem diagnostic tests for CJD and other prion diseases.

6. Future meetings

It was suggested that future meetings be scheduled to allow the discussion to last up to two hours.

The meeting was adjourned at 4:50 p.m.

Griffin P. Rodgers, M.D.