Anita Smith

1
Anita Smith

• Age 46
• Biogen-IDEC Clinical Trial
• C-1802/C-1808 142-101 (ALS)
• Enrolled in Tysabri Clinical Trial April 2002
• Died February 25, 2005 from PML

2
Anita Smith A Brief History

• 1985 Complaints
• Frequent (migraine) headaches
• Transitory left-sided head numbness
• September 1999 - December 2001 Complaints
• Right leg numbness, tingling, burning, mild
  spasticity and incoordination
• Right hand clumsiness
• Right eye blurry vision
• Leg cramping and generalized weakness
• Short term memory loss
• Mild urinary retention

3
Anita Smith Physical Examination

• Sept 1999 slight increased tone right arm and
  leg
• Oct 1999 NORMAL Physical Exam
• Feb 2000 NORMAL Physical Exam (Pt. started on
  AVONEX not clear why, Rx Zanaflex for leg
  cramps)
• May 2000 NORMAL Physical Exam (pt. started on
  Flomax for urinary retention 50 cc PVR)
• July 2000 NORMAL Physical Exam (complaints of
  urinary retention resolved)

4
Anita Smith Physical Exam

• August 2000 NORMAL Physical and ENT Exam
• Sept 2000 NORMAL Physical Exam
• March 2001 Physical Exam showed 4/5
  strength legs slightly spastic gait
  (Solumedrol 500 mg bid x 5 days)

5
Anita Smith Physical Exam

• Sept 2001 Physical Exam showed slightly
  spastic gait 4/5 strength all major muscle
  groups.
• Dec 2001 NORMAL Physical Exam 5 strength
  in all major muscle groups At Dec 2001
  visit Consider for ANTEGREN study

6
Anita Smith Family Interview

• Mr. Walter Smith, Mrs. Smiths husband and Ms.
  Beth Ann Smith, Mrs. Smiths daughter Personal
  Interview with Dr. Shoukimas on March 2, 2006.
• From the time of her first visit to enrollment
  in the study she thought of her problem as an
  annoyance. She worked, carried the laundry up
  and down stairs. She didnt get worse and she
  didnt get better. Her vision got better with
  glasses. (Mr. Walter Smith Interview March 2,
  2006)

7
Anita SmithClinical Tests

• September 1999
• MRI Non-specific white matter changes
• Some lesions may reflect infarction from
  previous migraine.
• Diagnosis Non-specific changes demyelination,
  vasculitis, small vessel ischemia, sequelae of
  migraine

8
Anita SmithClinical Tests

• September 2000
• MRI 2 new lesions. Would be unusual for
  demyelinating disease. Diagnostic possibilities
  unchanged MS, vasculitis, small vessel disease,
  migraine
• McDonald (Annals of Neurol. 2001 Vol 50)
  McDonald MRI criteria for evidence of
  demyelination IS NOT FULFILLED

9
Anita Smith Clinical Tests

• Nov 1999 Lumbar PunctureCerebral Spinal Fluid
  Analysis(80x conc.) NORMAL IgG, oligoclonal
  bands, 1 lymphocyte
• Electrophysiology (visual, auditory,
  somatosensory evoked potentials) NOT OBTAINED

10
The Diagnosis of Multiple Sclerosis

• CLINICAL 2 or more clinically symptomatic
  attacks 2 or more OBJECTIVE lesions
• This criteria is NOT MET in Anita Smiths case!
• Physical EXAMMINIMAL changes with subjective
  analysis (4/5 strength, minimally spastic gait)
• LABORATORY CSF Analysis NORMAL
• Evoked Potentials NOT DONE
• MRI x2 NON-specific changes (McDonald
  criteria NOT MET)

11
Did Anita Smith have Multiple Sclerosis?

• Diagnosis was NEVER clearly established.
• IF in fact it was present at all
• It was a MILD and STABLE form with MINIMAL
  Neurological manifestations.
• Objective tests were IGNORED.

12
Anita Smith Enrollment in Tysabri Clinical
TrialMRI on March 21, 2002

• Slide 2 and slide 3

13
MRI of Two Patients with Clinically Suspected
Multiple Sclerosis

• Patient 1 Patient 2

14
Anita Smiths Course after Enrollment

• Anita Smith was enrolled in April 2002 in a
  combined drug trial (Avonex and Tsyrabi) two
  potent immunosuppresant drugs. She was a
  minimally symptomatic patient whose diagnosis of
  multiple sclerosis is questionable.
• Anita Smith died on 02/25/05 of Progressive
  Multifocal Leukencephalopathy an often fatal
  infection seen in immunosuppresed patients.

15
WHY?

• The enrollment of Anita Smith into a clinical
  trial of two potent immunospressive drugs is
  almost incomprehensible and certainly raises
  grave ethical concerns about Biogen Idecs
  process of enrollment.
• The best explanation is that Biogen Idec acting
  through its physician representatives was the
  judge, jury and patient advocate when it had its
  own interests first (a successful study outcome).

16
The Implications of Anita Smiths Enrollment and
Death

• The FDA has already decided that new clinical
  trials can proceed with Tysabri. As we examine
  the enrollment process for Anita Smith, we must
  question and examine the SERIOUS concerns that
  Biogen Idec is incapable of proceeding in a safe
  manner with future clinical trials.
• Anita Smiths enrollment process may represent a
  systematic approach to enrollment of questionable
  patients. Therefore, if the enrollment process is
  put into question then the study findings that
  Biogen Idec has publicized widely in recent days
  MUST also be seriously put into question.

17
The Implications of Anita Smiths Enrollment and
Death

• Anita Smiths death has caused close examination
  of her medical record and clinical course by
  outside examiners. Her enrollment MRI film was
  unavailable to those who performed her autopsy
  and reported her case in the NEJM.NEJM
  2005Volume 353, Number 4 pp. 369-374.
• The enrollment MRI was obtained ONLY after a
  court order on Feb 24, 2006 and the film
  delivered finally on Feb 28, 2006 for outside
  review.
• This previously unavailable enrollment MRI is
  NOT DIAGNOSTIC of MS.

18
WHY Anita Smiths CASE is so IMPORTANT to the
Panel Today

• The entire enrollment process and appropriateness
  of Anita Smiths involvement in Biogen IDECs
  Tysabri-Avonex clinical trial MUST be
  questioned.
• We are not ALONE in this serious questioning.
  See recent discussions of Anita Smiths case
  in
• British Medical Journal - Dr. Abhijit
  ChaudhuriBMJ Volume 332 18 February 2006, p.
  416-417.Lessons for clinical trials from
  Natalizumab in multiple sclerosis
• Lancet- Annette Langer-Gould and Lawrence
  SteinmanLancet Volume 367 March 4, 2006
  pp.708-710.What went wrong in the natalizumab
  trials?

19
WHY Anita Smiths CASE is so IMPORTANT to the
Panel Today

• The Panel MUST QUESTION, as many other experts
  have, the serious implications of how Anita Smith
  was enrolled and possibly how other patients were
  enrolled as well, especially since new clinical
  trials by Biogen IDEC are anticipated and
  possible approval of Tysabri for clinical use.