When a Medical Malpractice Trial for Wrongful Death is Challenged by New Technology (And the Dog That Did Not Bark)

TASA ID: 2375

This is presented as an example of both the changing standards in contemporary medical practice and the introduction of new state-of-the-art advances in technology applying genetic testing of patients (pharmacogenetics) to determine drug toxicity specific to that patient.

I was chosen as the medical forensic expert witness not only on the basis of my many years of expertise related to drug safety and toxicity issues, but specifically because I had published on the topic of new testing for host susceptibility to particular drug toxicity based on phenotype and genotype.

The case was considered difficult to defend since the doctor charged with wrongful death had been recommended to trial after the required peer review board was presented information that usual blood testing for the toxic drugs in therapy and new genetic testing that could have prevented lethal use of one of those drugs were not accomplished by the treating specialist. Those who were involved in this case are not identified by name.

THE CASE

A rheumatologist begins aggressive immunosuppressive therapies to treat a Caucasian female with chronic rheumatoid arthritis. Usual initial laboratory tests were not obtained despite potent immunotherapy of rheumatoid arthritis.

Although the rheumatoid arthritis of the patient responds to these therapies, her general health acutely deteriorates, and upon returning from a controversial trip, she is rushed to the emergency room mortally ill. Despite aggressive measures, she quickly succumbs to catastrophic multiple organ system failures, including bone marrow failure.

A pre-mortal blood specimen determines that genetic testing could have predicted her vulnerability to catastrophic bone marrow depression from her most toxic drug, Imuran, an anticancer agent used in rheumatoid arthritis therapy.

The well-qualified rheumatology expert for the prosecution asserted improper medical management and monitoring.

A required peer review recommended the case go to a trial against the physician- defendant based on the wrongful death claim alleged by her family.

THE CIRCUMSTANCES 

It was a typical hot summer day in the small southwestern town when I was summoned to the courthouse as an expert witness. The defendant was charged with wrongful death by the family for his rheumatologic care of the 65-year-old Caucasian female that he treated for severe rheumatoid arthritis.

The patient had been referred to the rheumatologist by a local internist shortly after she had moved from California in the year prior with multiple health problems, including long-standing essential hypertension with morbid obesity, previous stroke and severe progressive rheumatoid arthritis.

The patient had not been compliant on previous symptomatic therapy for her rheumatoid arthritis. In addition to destructive changes of multiple peripheral joints, she had incapacitating weakness and loss of function and chronic intractable pain.

Upon referral, the rheumatologist had presented the patient and her family with literature on a new biological therapy for rheumatoid arthritis (Remicade). With informed consent, he initiated Remicade in combination with small sub-clinical doses of Imuran as an immunosuppressive combination agent.

Over the next weeks, the patient responded appropriately to this regimen although she experienced some flu-like symptoms common to this therapy. However, her medical status was fragile, and some months later she went back to her referring internist because of a fever, chills, her history, and what was diagnosed as a urinary tract infection.

At this point, however, she stubbornly informed her concerned internist that she must return to California for an important family event despite her failing health. The internist expressed his reservations about her trip in the face of her ongoing medical problems further complicated by immunosuppressive therapy in the face of infection. The internist then passed on his laboratory results to the defendant rheumatologist, who directly contacted the patient and insisted on examining her personally before she proceeded with any further plans.

The patient refused this request, left on the trip only to return days later severely ill, and was admitted directly by the internist to his local hospital.

It was determined by extensive admission testing that the patient had suffered a subarachnoid hemorrhage with congestive heart failure, liver dysfunction, and acute respiratory distress syndrome. Her blood studies indicated bone marrow failure with aplastic anemia.

Despite aggressive interventions, the patient deteriorated rapidly and within days died. At the time of her death, a pre-morbid blood sample revealed a genetic marker confirming a complete inability to metabolize her Imuran, producing a bone marrow toxic breakdown product.

THE CHARGES

The expert for the prosecution, as a respected academic rheumatologist, charged that the defendant rheumatologist was "inattentive" in his monitoring and testing of the patient under his management, leading to misdiagnosis and death.

He claimed that despite potent medication prescribed, the defendant had not obtained the routine blood counts required at the initial baseline visit of the patient. Nor had he repeated them after later abnormal blood test results demonstrated abnormal white and red blood cell counts and abnormal cell size and variation. He charged that not following up on these blood cell test abnormalities was "critical" and resulted in the fatal outcome. The rheumatology expert insisted that the genetic marker testing for Imuran toxicity (TMPT test) was positive, indicating that as many as one in 10 patients on Imuran with these markers could produce a toxic metabolite (TGN) which was bone marrow toxic.

He concluded that despite a long and respected career, the rheumatologist on trial had failed proper peer management responsibilities and that he was guilty of "inattentive" care. Thus, he alleged the lack of close monitoring and care by the defendant were not consistent with standards of his peer group, and the defendant was guilty of malpractice.

THE RESPONSE

At the time of my testimony, I had been made aware by preparation with the defense counsel of these foregoing events and that the defendant had been highly defensive in his cross examination, just as he had in his peer-review pre-trial. He did not explain earlier supposedly abnormal laboratory testing results and lapses in follow-up monitoring. I, thus, faced a jury that had endured days of highly technical discussion of diseases, drug use, FDA guidelines for monitoring, and complex issues of blood tests and interpretations. Finally, the highly complex and technical issue of genetic testing results had been only superficially invoked to this jury that was presumably overwhelmed at this point.

So, I began at the beginning. I explained that rheumatoid arthritis itself in its active and severe stages was a deadly disease with greater than three times the mortality expectation for a person of the deceased's age. I pointed out that the severe pain, disability and suffering had to be weighed against the risks and benefits of the new, more potent, but potentially toxic drugs used for its management. Informed consent was critical to this and had indeed properly occurred in this case.

I then pointed out that in the defendant's office, all patients were seen by a registered nurse after each visit, to review instructions and give patients a blue slip to obtain requests for laboratory testing. But, unfortunately, this patient had a poor record of compliance. And when it was found that she had skipped testing, a blood count was promptly obtained. The complete blood count, though abnormal, was consistent with usual findings in more active rheumatoid arthritis care. Anemia and abnormal white counts and variation in cell size are actually common in more active chronic rheumatoid disease.

In addition, later, when appropriate follow-up testing was obtained, lab results on the patient had not changed significantly. Thus, when the expert for the prosecution claimed continuing therapy a "critical" oversight, the follow-up blood testing revealed blood count results not consistent with drug toxicity but  actually usual for more advanced rheumatoid disease, as the patient had been seen and examined regularly by the rheumatologist and staff.

Furthermore, our patient was not in the 10% moderate risk group with a dominant and recessive abnormal allele gene for her TMPT test. Rather, she was in the rare one out of 1413 homozygous recessive group that cannot metabolize nor tolerate Imuran without fatal consequences! Further proof of this was the toxic level of the TGN metabolite from Imuran, also found in the pre-mortal blood at the time the fateful TMPT test.

So why had she survived without fatal bone marrow failure after so many months on Imuran?  This is reminiscent of the 'dog that didn't bark' clue in the Sherlock Homes mystery, "Silver Blaze."  

For this alerted us to obtain pharmacy records that confirmed that the patient herself was not taking her Imuran for months at a time! This explained why her blood count results were not evidence of Imuran toxicity in the earlier months of therapy, as bone marrow failure had not occurred much earlier in her clinical course since she had not taken the Imuran as prescribed.

As to the genetic testing, I had published in my article "Anticipating Rather Than Confirming Drug Toxicity Through Selective Laboratory Testing" (Journal of Clinical Rheumatology, Vol 9, No 6, 386-387, December 2003) that absent FDA official approval, unreimbursed expenses would pose a practical barrier to such testing. Yet in the case of the cost/benefit analysis of monitoring potent, expensive alkylating agents for serious chronic diseases as rheumatoid arthritis... "With the recent advent of genetic testing... for safer use of more toxic drugs, what price can we put on death as the final outcome of rationing testing?" Thus, the TMPT was recognized initially as valid for risk testing by the FDA. But since the FDA delayed giving it official sanction for years, third party payers would not reimburse the over-$400 cost to the patient, and doctors would not usually encourage it under those screening circumstances.

CONCLUDING REMARKS

By obtaining the patient's prescription records, we were able to show that she rarely took her azathioprine: none during the period her laboratory testing was questioned, and only at the end, from just before her fatal trip and hospitalization when aplastic anemia was found in association with other overwhelming system failures.

Coupled with the multiple disease outcomes, the TPMT implications should not be considered in isolation of the altered state of cognition and poor compliance of this sick, elderly patient neglecting her rheumatologist's oral and written laboratory requests. Most importantly, the expensive, unreimbursed TMPT testing would not have been ordered then. Thus, it was not the standard of care.

Consequently, only since this case has the FDA given official sanction to such testing requiring third party coverage of costs. Sadly, I must repeat from my warning in my article on this issue that this was "at the price of yet another death" before the long-awaited official sanction required for reimbursement of TMPT testing.

So an obese, elderly, hypertensive female with prior stroke and long-standing severe rheumatoid disease was treated effectively for a disease that has three times the mortality risk compared to a normal person of same demographics.

Thus, weighing all relevant, significant, clinical circumstances coupled with the fatal complex co-morbidities, the case demanded a complete consideration of the panoply of problems that more fully explain the circumstances of this death.

THE VERDICT

Accordingly, the jury concluded that the defendant had met the standard of care in attempting to control this dastardly problem and was innocent of charges.

Contemporary changes in healthcare delivery were reflected in this case. State-of-the-art technological advances were considered in light of practical cost limitations that alter choice. These continuing changes in our healthcare delivery system continue to affect tomorrow's standards. Yet, host issues and compliance continue to be central to outcome.

This article discusses issues of general interest and does not give any specific legal, medical, or business advice pertaining to any specific circumstances.  Before acting upon any of its information, you should obtain appropriate advice from a lawyer or other qualified professional.

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