# Presentation: 082977

## 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
- 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

## 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)

## 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 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

-  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

- 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 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 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

- CLINICAL  2 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)
- LABORATORY CSF Analysis		NORMAL
- 	Evoked Potentials:  	NOT DONE
- 	MRI x2: 			NON-specific changes 				(McDonald criteria _NOT MET)_

## 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: Enrollment in Tysabri Clinical TrialMRI on March 21, 2002

- Slide #2 and slide #3

## MRI of Two Patients with Clinically Suspected Multiple Sclerosis

-    Patient #1		   Patient #2

##  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.

## 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 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 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 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

- 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 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.