U.S. Department of Health and Human Services

2008 Meeting Minutes

PUBLIC HEALTH SERVICE

 

Meeting of the

Interagency Coordinating Committee on

Human Growth Hormone and Creutzfeldt-Jakob Disease

December 18, 2008

National Institutes of Health

Bethesda, Maryland


Committee Members Attending

Dr. Judith Fradkin, NIDDK

Dr. Ellen Leschek, NIDDK

Dr. Eugene Major, NINDS

Dr. James Mills, NICHD (by speakerphone)

Dr. Griffin Rodgers, NIDDK, Chairman

Dr. Lawrence Schonberger, CDC (by speakerphone)

Dr. Diane Wysowski, FDA


Also Attending

Dr. B. Tibor Roberts, NIDDK

Ms. Joan Chamberlain, NIDDK

Ms. Kathy Kranzfelder, NIDDK

Dr. May Wong, NINDS


The meeting began at 2:00 p.m.

1. Welcome

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

2. Epidemiology Study Status Report and Status Report on the Westat Contract

Westat Contract:

Dr. Leschek reported that the contract with Westat—the company that offers support for the U.S. hGH/CJD epidemiological study, performs statistical analyses, surveys the Death Index and obtains death certificates as necessary—was renewed last June for 5 more years, beginning in 2008.

As described in last year’s minutes, Dr. Leschek reviewed both confirmed and possible U.S. cases of CJD in the following categories:

I. Neuropathologically confirmed CJD

II. Clinically confirmed CJD

III. Clinically suspicious—neurologic findings of uncertain etiology with insufficient information to confirm or exclude CJD

IV. Deaths under investigation

The Committee determined that in order to fall into category III, 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.)

Case Categories I and II:

As in 2007, 13 deaths are considered to have been neuropathologically confirmed as CJD (category I). Two more cases—which had previously been considered as “under investigation” (category IV)—are now listed as “clinically confirmed” (category II), bringing the total number of deaths in the cohort attributable to CJD to 28. All deaths confirmed as CJD received at least some of their hGH treatment prior to 1977, when Dr. Parlow’s laboratory began producing hGH for the National Hormone and Pituitary Program.

The two additions to the clinically confirmed category (II) were discussed last year. The first of these is a person who died in 2003 with a death certificate listing “CJD-End Stage” as the cause. Because the next-of-kin were unreachable and there were compelling public health reasons, Dr. Schonberger was able to obtain the medical records for this individual from the state. The Neurologic Review Group (NRG) examined the records and agreed that the clinical presentation of the case was fully consistent with CJD.

The other addition to the clinically confirmed category is an individual who died in 2007 after having reportedly been healthy until two years prior to death. Neither the death certificate nor the medical records had been obtained as of last year’s meeting, but the medical records were since made available to the NRG, which concurred that the course was highly probable for CJD. Dr. Leschek pointed out that the estimated incubation period; that is, the interval from the mid-point in time of hormone therapy to the onset of CJD symptoms was 29.5 years (354 months) for this case, at present the longest span of any of the confirmed cases. [Cases 17 and 19, at 27.3 years (328 months) each are the only other cases with an estimated incubation period exceeding 27 years (324 months).]

Case Category III:

Previously, just one individual had been placed in the “clinically suspicious—insufficient information to confirm” category. As a result of differences 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 in this category. For each, all of the criteria described above for category III apply. This brings to four the total number of clinically suspicious cases with insufficient information to confirm.

Case Category IV:

Cases remaining in this category from last year include a person whose father called to report that his son had been treated with hGH from 1976-1979, and had died in September 2005. The father reported neurologic symptoms consistent with CJD including loss of balance, impaired gait, shaking, depression, and diminished hearing and vision, but his son had not been under a doctor’s care for several years. No autopsy was performed. The father has not released the 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 that diagnosis. This death will remain under investigation. Dr. Leschek will try to provide Dr. Schonberger with more information about the case, so that he can attempt to obtain a release of medical records from the state.

Similarly, Dr. Schonberger will seek records for a person whose case was discussed last year. The death certificate cites “aspiration pneumonia (2 days duration) due to dementia (1 year duration) due to radiation treatment for craniopharyngioma” as cause of death. Presence of dementia in a relatively young person is the basis for considering this as a possible CJD case, but, given the individual’s neurological history, other explanations are certainly possible. The death will remain officially under investigation, while the medical records are sought.

The Committee addressed the cases of two individuals not previously discussed for whom medical information was limited. One was listed as having died of glioblastoma at 42 years of age, while living in a group home. The person had signs of mental deterioration and progressive cerebellar issues in the weeks prior to death. NRG review notes seemed inconsistent, and Dr. Leschek will verify the reviewers’ conclusions and review this case for the next meeting.

The second individual was listed as having died of “cardiovascular collapse and CNS dysfunction of unknown nature” at age 39. The case is of significance in part because if it represents a case of CJD, it would be the first to have occurred in a patient treated with growth hormone produced entirely after the change in purification procedure that occurred in 1977. The treatments were indicated for multiple pituitary hormone deficiencies due to surgery, chemotherapy, and radiation for a pinealoma. The mother of this individual has expressed unwillingness to provide release of records. Dr. Mills pointed out that “cardiovascular collapse” in one so young suggests the possibility of adrenal insufficiency that might at least partially explain the neurological symptoms. Dr. Leschek said she would ascertain whether information is available on adrenal function in this individual.

Case Summary by Category:

Category # cases Net change since 2007
I 13 0
II 15 2
III 4 3
IV 4 -1

Updated Human Growth Hormone Lot Analysis:

After distribution of growth hormone for clinical use by the National Hormone and Pituitary Program was suspended in 1985, the Committee commissioned a study to see if material distributed by the program was capable of inducing CJD infection in primates. A sample of one growth hormone preparation designated lot 19-A was found to infect one of two animals which were inoculated with it. An analysis was performed to determine whether any of the patients who had developed CJD as of that time may have received material from lot 19-A. Because the NHPP did not have records of which specific lots of hormones were distributed to individual patients, the analysis assumed that all patients under treatment by a physician who received a particular lot might have been exposed to that lot if the patient received growth hormone from the physician in the year after the lot was distributed to the physician. At the time, it was found that none of the cases could be attributed to that lot, and this information was included in the Fact Sheet. The Committee had agreed that as new cases of CJD were identified, the lot analysis would be periodically updated. The results of such an update were presented at this meeting

Dr. Leschek presented lot re-analysis data compiled by Stephen Durako, of Westat. The analysis addressed all lots of growth hormone distributed for clinical use as well as specifically examining lot 19-A. For each lot, “cases at risk” refers to the number of people in the cohort under treatment with hGH at the time the lot was distributed. “Cases received” refers to people receiving growth hormone treatments at clinics to which the lot was distributed. The analysis found that no single lot was received by a majority of the 28 patients who subsequently developed CJD. It also found that lot 19-A was likely received by only two patients of the 28 patients who later went on to develop CJD. The analysis suggests that infectious PrP is likely to have been present in multiple preparations. Because patients were not necessarily administered growth hormone from every lot shipped to clinics where they were under treatment, and because the large number of comparisons increases the probability that some comparisons will appear statistically significant by random chance, it is not possible to determine whether any particular lot could be statistically associated with excess CJD risk. The re-analysis was consistent with the previous lot analysis in suggesting that multiple growth hormone preparations were likely to have transmitted CJD and in failing to find any preparation that could be definitively identified as conferring excess risk.

3. Crescormon CJD Case in Austria

Dr. Schonberger discussed a CJD case reported in the February, 2008 issue of the Journal of Neurological and Neurosurgical Psychiatry (79:229-231). A 39 year old from Austria died of neuropathologically confirmed CJD, 22 years after receiving a 14 month course of commercially produced cadaveric hGH (Crescormon, from Kabi Pharma. While Kabi Pharma did not produce hormone for the NHPP, Crescormon was purified using size-exclusion chromatography, which was a key step added to the purification protocol used in the NHPP from 1977 through the end of the program in 1985. However apart from this detail, it is unclear from available information how similar the Kabi and post-1977 NHPP purification protocols were. Dr. Schonberger also noted that while Crescormon treatment is likely to have been responsible for the patient’s CJD, it is difficult to rule out other causes.

Dr. Fradkin asked the committee to consider whether the Crescormon case suggested a need to update the Fact Sheet. A sentence in the Fact Sheet (http://www.endocrine.niddk.nih.gov/pubs/creutz/update.htm) on cohort members who are definitively known to have contracted CJD reads “as of October 2005, none of these people began treatment with hGH after 1977, when Dr. Albert Parlow's laboratory began producing NHPP GH and a new purification step was added.” As of December 2008, this was still the case, and the Committee did not feel this portion of the Fact Sheet requires updating at this time.

4. Report on CJD in Foreign hGH Recipients

Dr. Schonberger reported that five additional cases of CJD linked to hGH treatment have been reported in the United Kingdom, along with the one described above in Austria. Dr. Schonberger also corrected the reported number of cases for Holland, which should be two. This brings the total number of CJD cases outside the U.S. that are attributable to hGH to 179. The hGH used in New Zealand and Brazil was produced in the U.S. The table below provides a country-by-country breakdown as of December, 2008:


CJD Cases Associated with hGH Treatment Internationally:

France
110
United Kingdom
56
New Zealand
6
Brazil
2
Holland
2
Australia
1
Austria
1
Qatar
1
Non-U.S. Total
179


5. Update on Public Inquiries

Ms. Chamberlain, who assumed responsibility for public inquiries previously handled by Ms. Vital and Dr. DeMouy, reported that in 2008 as of the date of the meeting she had handled 32 public inquires pertaining to the NHPP. Most of these were fairly routine, such as inquiries about Fact Sheet updates, and new addresses for cohort members. Drs. Fradkin and Leschek noted that records of calls from cohort members should be kept by Westat.

6. Fact Sheet Update

Ms. Kranzfelder noted that the Fact Sheet had not been substantially revised when it became a web document, and retained textual references to its having been a letter, as well as other anachronisms. She remarked that there was also some confusion regarding growth hormone nomenclature. Therefore she endeavored to update and clean up the document for 2008.

Dr. Leschek noted that Dr. Wysowski had provided some comments on the new draft, and that when those had been incorporated, she would review the document and provide further edits as necessary. Dr. Wysowski suggested that a request for identification of new colon cancer cases in the Fact Sheet would be problematic because of the absence of common risk factors. The Committee agreed and suggested that the request be dropped. Dr. Schonberger noted that the number of U.S. variant CJD cases (unrelated to hGH) reported in the Fact Sheet was out of date.

Dr. Fradkin suggested that after Dr. Leschek provides her edits, a new draft Fact Sheet should be sent to the Committee, which should be given two weeks to suggest additional edits.

7. Brief highlights of progress in CJD research

Dr. Major drew attention to two primary research papers (Castilla et al., EMBO J. 2008; 27:2557-2566; and Castilla, J. et alCell 2008; 134, 757–768) on in vitro prion propagation using a technology called protein misfolding cyclic amplification (PMCA). He noted that these papers and related topics are also described in a review by Adriano Aguzzi (Nature Neuroscience 2008; 11, 1239-1240).

Dr. Schonberger highlighted a paper by Gambetti et al. (Ann Neurol. 2008;63:697-708) on a novel human disease associated with a protease-sensitive form of PrP; and another byMahillo-Fernandez et al. (Neuroepidemiology 2008;31:229–240) showing that a considerable number of apparently sporadic CJD cases may originate from surgery-related accidental transmission.

The meeting was adjourned at 4:10 p.m.

Griffin P. Rodgers, M.D.

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