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]{.underline}

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

[Also Attending]{.underline}

Dr. B. Tibor Roberts, NIDDK

Ms. Marcia Vital, NIDDK

The meeting began at 3:00 p.m.

1\. [Welcome]{.underline}

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)]{.underline}

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:

I.  Neuropathologically confirmed CJD

II. Clinically confirmed CJD

III. Clinically suspicious---insufficient information to confirm
     (Possible CJD)

IV. 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 27^th^ 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 ["]{.underline}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 27^th^ 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]{.underline}

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]{.underline}

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
(<http://www.endocrine.niddk.nih.gov/pubs/creutz/update.htm>), 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]{.underline}

Dr. Major referred the Committee to a recent [*NEJM*
review](http://content.nejm.org/cgi/content/full/357/11/1150) 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*](http://www.sciencemag.org/cgi/content/short/318/5852/930) 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](http://www.future-drugs.com/doi/full/10.1586/14787210.5.4.613?prevSearch=allfield%3A(prion))
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]{.underline}

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.