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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. Anita Smith: A Brief History. 1985 Complaints: Frequent (migraine) headaches Transitory left-sided head numbness

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anita smith

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

anita smith a brief history
Anita Smith: A Brief History
  • 1985 Complaints:
  • Frequent (migraine) headaches
  • Transitory left-sided head numbness
  • September 1999 - December 2001Complaints:
  • 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
anita smith physical examination
Anita Smith: Physical Examination
  • Sept 1999 “slight increased tone right arm and leg”
  • Oct 1999 NORMALPhysical Exam
  • Feb 2000 NORMALPhysical 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 NORMALPhysical Exam (complaints of urinary retention resolved)
anita smith physical exam
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)
anita smith physical exam5
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”
anita smith family interview
Anita Smith: Family Interview
  • Mr. Walter Smith, Mrs. Smith’s husband and Ms. Beth Ann Smith, Mrs. Smith’s 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 didn’t get worse and she didn’t get better. Her vision got better with glasses.” (Mr. Walter Smith Interview March 2, 2006)
anita smith clinical tests
Anita Smith:Clinical 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”

anita smith clinical tests8
Anita Smith:Clinical 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
anita smith clinical tests9
Anita Smith: Clinical Tests
  • Nov 1999 Lumbar Puncture:Cerebral Spinal Fluid Analysis(80x conc.): NORMAL IgG, oligoclonal bands, 1 lymphocyte
  • Electrophysiology (visual, auditory, somatosensory evoked potentials): NOT OBTAINED
the diagnosis of multiple sclerosis
The Diagnosis of Multiple Sclerosis
  • CLINICAL2 or more clinically symptomatic attacks 2 or more OBJECTIVE lesions
  • This criteria is NOT MET in Anita Smith’s case!
  • Physical EXAMMINIMAL changes with subjective analysis (4+/5 strength, minimally spastic gait)

Evoked Potentials: NOT DONE

MRI x2: NON-specific changes (McDonald criteria NOT MET)

did anita smith have multiple sclerosis
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.
anita smith s course after enrollment
Anita Smith’s 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.
  • 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 Idec’s 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).
the implications of anita smith s enrollment and death
The Implications of Anita Smith’s 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 Smith’s 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.
the implications of anita smith s enrollment and death17
The Implications of Anita Smith’s Enrollment and Death
  • Anita Smith’s 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 2005;Volume 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.
why anita smith s case is so important to the panel today
WHY Anita Smith’s CASE is so IMPORTANT to the Panel Today
  • The entire enrollment process and appropriateness of Anita Smith’s involvement in Biogen IDEC’s Tysabri-Avonex clinical trial MUST be questioned.
  • We are not ALONE in this serious questioning. See recent discussions of Anita Smith’s 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?
why anita smith s case is so important to the panel today19
WHY Anita Smith’s 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.